Difference between revisions of "Multiple myeloma"

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!colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26"|'''Section editor'''
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<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
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[[#top|Back to Top]]
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|style="background-color:#F0F0F0"|[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]
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</div>
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|<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>Seattle, WA</big><br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]
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{{#lst:Editorial board transclusions|pcd}}
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''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Multiple_myeloma_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Multiple myeloma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br>
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<br><big>'''Note: due to its size/complexity, the multiple myeloma page has been split into sub-pages:'''
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''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Multiple_myeloma_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''.
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*[[Multiple_myeloma,_induction|Induction (transplant eligible and ineligible)]]
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{| class="wikitable" style="float:right; margin-right: 5px;"
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*[[Multiple_myeloma,_consolidation_and_maintenance|First-line consolidation and maintenance]]
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*[[Multiple_myeloma,_relapsed-refractory|Relapsed/refractory, including subsequent consolidation and maintenance]]
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|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
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*[[Smoldering multiple myeloma]]
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
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'''This page will remain as a consolidated location for guidelines and prognostic information.
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</big>
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*''We have moved [[How I Treat]] articles to a dedicated page.''
 
{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
 
<section begin=guidelines />
 
<section begin=guidelines />
 
=Guidelines=
 
=Guidelines=
 +
'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
  
−
==[https://www.asco.org ASCO]==
+
==[https://www.asco.org ASCO]/CCO==
−
*'''2018:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.76.6402 Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/29341831 PubMed]
+
*'''2019:''' Mikhael et al. [https://doi.org/10.1200/jco.18.02096 Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline] [https://pubmed.ncbi.nlm.nih.gov/30932732/ PubMed]
 +
*'''2018:''' Anderson et al. [https://doi.org/10.1200/JCO.2017.76.6402 Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology Clinical Practice Guideline update] [https://pubmed.ncbi.nlm.nih.gov/29341831/ PubMed]
 +
**'''2007:''' Kyle et al. [https://doi.org/10.1200/jco.2007.12.1269 American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma] [https://pubmed.ncbi.nlm.nih.gov/17515569/ PubMed]
 +
**'''2002:''' Berenson et al. [https://doi.org/10.1200/jco.2002.06.037 American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma] [https://pubmed.ncbi.nlm.nih.gov/12202673/ PubMed]
  
 
==[http://www.b-s-h.org.uk/ BSH]/[http://www.ukmf.org.uk/ UKMF]==
 
==[http://www.b-s-h.org.uk/ BSH]/[http://www.ukmf.org.uk/ UKMF]==
−
*'''2017:''' [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14827/full Guidelines for the use of imaging in the management of patients with myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/28677897 PubMed]
+
*'''2017:''' [https://doi.org/10.1111/bjh.14827 Guidelines for the use of imaging in the management of patients with myeloma] [https://pubmed.ncbi.nlm.nih.gov/28677897/ PubMed]
−
*'''2017:''' [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14514/abstract Guidelines for screening and management of late and long-term consequences of myeloma and its treatment] [https://www.ncbi.nlm.nih.gov/pubmed/28107574 PubMed]
+
*'''2017:''' [https://doi.org/10.1111/bjh.14514 Guidelines for screening and management of late and long-term consequences of myeloma and its treatment] [https://pubmed.ncbi.nlm.nih.gov/28107574/ PubMed]
−
*'''2014:''' [http://www.ukmf.org.uk/wp-content/uploads/2014/10/Updates-to-the-guidelines-Oct-2014.pdf Updates to the guidelines for the diagnosis and management of multiple myeloma] [https://www.ncbi.nlm.nih.gov/pubmed/24801672 PubMed]
+
*'''2014:''' [http://www.ukmf.org.uk/wp-content/uploads/2014/10/Updates-to-the-guidelines-Oct-2014.pdf Updates to the guidelines for the diagnosis and management of multiple myeloma] [https://pubmed.ncbi.nlm.nih.gov/24801672/ PubMed]
 +
**'''2011:''' [https://doi.org/10.1111/bjh.12926 Guidelines for the diagnosis and management of multiple myeloma 2011] [https://pubmed.ncbi.nlm.nih.gov/24801672/ PubMed]
  
 
==[http://myeloma-europe.org.linux9.curanetserver.dk/index.php European Myeloma Network (EMN)]==
 
==[http://myeloma-europe.org.linux9.curanetserver.dk/index.php European Myeloma Network (EMN)]==
−
*'''2018:''' [http://www.haematologica.org/content/103/2/197 From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives]
+
*'''2020:''' Ludwig et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7787974/ Recommendations for vaccination in multiple myeloma: a consensus of the European Myeloma Network] [https://pubmed.ncbi.nlm.nih.gov/32814840/ PubMed]
 +
*'''2018:''' Caers et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6278986/ European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when] [https://pubmed.ncbi.nlm.nih.gov/30171031/ PubMed]
 +
*'''2018:''' Gay et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5792264/ From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives] [https://pubmed.ncbi.nlm.nih.gov/29217780/ PubMed]
  
−
==[http://www.esmo.org/ ESMO]==
+
==EHA/[https://www.esmo.org/ ESMO]==
−
*'''2017:''' [https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdx096 Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+
*'''2021:''' Dimopoulos et al. [https://doi.org/10.1016/j.annonc.2020.11.014 Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/33549387/ PubMed]
 +
**'''2017:''' Moreau et al. [https://doi.org/10.1093/annonc/mdx096 Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/23956208/ PubMed]
 +
**'''2013:''' Moreau et al. [https://doi.org/10.1093/annonc/mdt297 Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/23956208/ PubMed]
 +
**'''2010:''' Harousseau & Dreyling. [https://doi.org/10.1093/annonc/mdq178 Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555068/ PubMed]
 +
**'''2009:''' Harousseau & Dreyling. [https://doi.org/10.1093/annonc/mdp140 Multiple myeloma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454476/ PubMed]
 +
**'''2008:''' Harousseau & Dreyling. [https://doi.org/10.1093/annonc/mdn088 Multiple myeloma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456769/ PubMed]
 +
**'''2007:''' Harousseau. [https://doi.org/10.1093/annonc/mdm032 Multiple myeloma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491042/ PubMed]
 +
**'''2005:''' Harousseau et al. [https://doi.org/10.1093/annonc/mdi818 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of multiple myeloma] [https://pubmed.ncbi.nlm.nih.gov/15888750/ PubMed]
  
 
==[http://imwg.myeloma.org/ IMWG]==
 
==[http://imwg.myeloma.org/ IMWG]==
−
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920674/ Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group]
+
*'''2021:''' Moreau et al. [https://doi.org/10.1016/S1470-2045(20)30756-7 Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group] [https://www.ncbi.nlm.nih.gov/pubmed/33662288 PubMed]
−
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2015.65.0044 International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment] [https://www.ncbi.nlm.nih.gov/pubmed/26976420 PubMed]
+
*'''2021:''' Terpos et al. [https://doi.org/10.1016/S1470-2045(20)30559-3 Treatment of multiple myeloma-related bone disease: recommendations from the Bone Working Group of the International Myeloma Working Group] [https://pubmed.ncbi.nlm.nih.gov/33545067/ PubMed]
−
*'''2014:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918540/ International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation]
 
−
*'''2013:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878084/ International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease]
 
  
−
==[https://www.nccn.org/ NCCN]==
+
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920674/ Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group] [https://www.ncbi.nlm.nih.gov/pubmed/27002115 PubMed]
−
*[https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf NCCN Guidelines - Multiple Myeloma]
+
*'''2016:''' [https://doi.org/10.1200/JCO.2015.65.0044 International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment] [https://pubmed.ncbi.nlm.nih.gov/26976420/ PubMed]
−
<section end=guidelines />
+
*'''2014:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918540/ International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation] [https://pubmed.ncbi.nlm.nih.gov/24419113/ PubMed]
−
<section begin=1st-line />
+
*'''2013:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878084/ International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease] [https://pubmed.ncbi.nlm.nih.gov/23690408/ PubMed]
−
=First-line therapy (including transplant ineligible), randomized data=
 
−
''Note: most but not all multiple myeloma first-line regimens specify whether patients are transplant eligible, or not. The top-line inclusion criteria from each prospectively enrolling regimen are reported.''
 
  
−
==Bortezomib & Dexamethasone {{#subobject:b2104f|Regimen=1}}==
+
==NCCN==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445 NCCN Guidelines - Multiple Myeloma]
−
|-
+
*'''2020:''' Kumar et al. [https://doi.org/10.6004/Jnccn.2020.0057 Multiple Myeloma, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/33285522/ PubMed]
−
|[[#top|back to top]]
+
*'''2017:''' Kumar et al. [https://doi.org/10.6004/jnccn.2017.0023 Multiple Myeloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology] [https://pubmed.ncbi.nlm.nih.gov/28188192/ PubMed]
−
|}
+
*'''2016:''' Anderson et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6016087/ NCCN Guidelines Insights: Multiple Myeloma, Version 3.2016] [https://pubmed.ncbi.nlm.nih.gov/27059188/ PubMed]
−
BD: '''<u>B</u>'''ortezomib, '''<u>D</u>'''examethasone
+
*'''2015:''' Anderson et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4891187/ Multiple Myeloma, Version 2.2016: Clinical Practice Guidelines in Oncology] [https://pubmed.ncbi.nlm.nih.gov/26553768/ PubMed]
−
<br>Bd: '''<u>B</u>'''ortezomib, low-dose '''<u>d</u>'''examethasone
+
*'''2011:''' Anderson et al. [https://doi.org/10.6004/Jnccn.2011.0095 Multiple myeloma.] [https://pubmed.ncbi.nlm.nih.gov/21975914/ PubMed]
−
<br>Bort-Dex: '''<u>Bort</u>'''ezomib, '''<u>Dex</u>'''amethasone
+
*'''2009:''' Anderson et al. [https://doi.org/10.6004/Jnccn.2009.0061 NCCN clinical practice guidelines in oncology: multiple myeloma.] [https://pubmed.ncbi.nlm.nih.gov/19878637/ PubMed]
−
<br>Vd: '''<u>V</u>'''elcade (Bortezomib), low-dose '''<u>d</u>'''examethasone
+
*'''2007:''' Anderson et al. [https://doi.org/10.6004/Jnccn.2007.0014 Multiple myeloma. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/17335683/ PubMed]
−
<br>VD: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone
+
*'''2004:''' Anderson et al. [https://doi.org/10.6004/Jnccn.2004.0029 Multiple myeloma clinical practice guidelines in oncoloqy.] [https://pubmed.ncbi.nlm.nih.gov/19795598/ PubMed]
  
−
===Variant #1 {{#subobject:59cfe6|Variant=1}}===
+
==SITC==
−
{| class="wikitable" style="width: 100%; text-align:center;"
+
*'''2020:''' Shah et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7359060/ The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma] [https://pubmed.ncbi.nlm.nih.gov/32661116/ PubMed]
−
!style="width: 25%"|Study
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<section end=guidelines />
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://jco.ascopubs.org/content/33/33/3921.long Niesvizky et al. 2015 (UPFRONT)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase IIIb (E)
 
−
|[[#VMP|VMP]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[[#VTD|VTD]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
 
 
−
''This regimen was meant for transplant ineligible patients.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
**Cycles 5 to 8: 20 mg PO once per day on days 1, 2, 4, 5
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Bortezomib_monotherapy|Bortezomib consolidation]]
 
−
 
 
−
===Variant #2 {{#subobject:6a8cb5|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/118/22/5752.full Moreau et al. 2011 (IFM 2007-02)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#VTD|vtD]]
 
−
|style="background-color:#d73027"|Inferior VGPR rate
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours).''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 & 2: 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
 
−
**Cycles 3 & 4: 40 mg (route not specified) once per day on days 1 to 4
 
−
 
 
−
'''21-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then autologous hematopoietic cell transplant]]
 
−
 
 
−
===Variant #3 {{#subobject:9d60fb|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/30/4621.long Harousseau et al. 2010 (IFM 2005-01)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#VAD|VAD]]
 
−
|style="background-color:#d9ef8b"|Might have superior PFS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients age less than or equal to 65 years with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 h).''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12
 
−
**Cycles 3 & 4: 40 mg PO once per day on days 1 to 4
 
−
 
 
−
====Supportive medications====
 
−
*One of the following bisphosphonates recommended:
 
−
**[[Pamidronate (Aredia)]] 90 mg IV once every 4 weeks until first transplant
 
−
**[[Zoledronic acid (Zometa)]] 4 mg IV once every 4 weeks until first transplant
 
−
*"Antibiotics, antifungal agents, and antiviral prophylaxis in accordance with local practice."
 
−
 
 
−
'''21-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#DCEP|DCEP consolidation]] versus [[#Melphalan.2C_then_auto_HSCT|high-dose melphalan with autologous hematopoietic cell transplant]]
 
−
 
 
−
===Variant #4, weekly bortezomib {{#subobject:5f56bd|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13243/full Girnius et al. 2014]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> IV once per week on days 1, 8, 15, 22
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
 
−
 
 
−
'''35-day cycle for up to 6 cycles based on response and tolerance of side effects'''
 
−
 
 
−
===References===
 
−
<!-- Presented at the 48th Annual Meeting of the American Society of Hematology (ASH), December 9-12, 2006, Orlando, FL; the 49th Annual Meeting of the ASH, December 8-11, 2007, Atlanta, GA; the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 30-June 3, 2008, Chicago, IL; and the 2008 Annual Meeting of the American Society of Hematology ASH/ASCO Joint Symposium, December 7, 2008, San Francisco, CA. -->
 
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# '''IFM 2005-01:''' Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010 Oct 20;28(30):4621-9. Epub 2010 Sep 7. [http://jco.ascopubs.org/content/28/30/4621.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823406 PubMed]
 
−
## '''Subgroup analysis:''' Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D, Marit G, Benboubker L, Voillat L, Mathiot C, Kolb B, Macro M, Campion L, Wetterwald M, Stoppa AM, Hulin C, Facon T, Attal M, Minvielle S, Harousseau JL. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010 Oct 20;28(30):4630-4. Epub 2010 Jul 19. [http://jco.ascopubs.org/content/28/30/4630.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20644101 PubMed]
 
−
# Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. [http://www.bloodjournal.org/content/118/22/5752.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21849487 PubMed]
 
−
# Girnius SK, Lee S, Kambhampati S, Rose MG, Mohiuddin A, Houranieh A, Zimelman A, Grady T, Mehta P, Behler C, Hayes TG, Efebera YA, Prabhala RH, Han A, Yellapragada SV, Klein CE, Roodman GD, Lichtenstein A, Munshi NC. A Phase II trial of weekly bortezomib and dexamethasone in veterans with newly diagnosed multiple myeloma not eligible for or who deferred autologous stem cell transplantation. Br J Haematol. 2015 Apr;169(1):36-43. Epub 2015 Jan 8. Epub 2014 Sep 18. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13243/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25572917 PubMed]
 
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<!-- Presented at the 53rd American Society of Hematology (ASH) Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011; and the 55th ASH Annual Meeting and Exposition, New Orleans, LA, December 7-10, 2013. -->
 
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# '''UPFRONT:''' Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. [http://jco.ascopubs.org/content/33/33/3921.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26056177 PubMed]
 
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==CPR {{#subobject:6ec39f|Regimen=1}}==
 
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{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|[[#top|back to top]]
 
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|}
 
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CPR: '''<u>C</u>'''yclophosphamide, '''<u>P</u>'''rednisone, '''<u>R</u>'''evlimid (Lenalidomide)
 
−
 
 
−
===Regimen {{#subobject:7999a2|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
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!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (E)
 
−
|[[#MPR|MPR]]
 
−
|style="background-color:#fee08b"|Might have inferior PFS
 
−
|-
 
−
|[[#Rd|Rd]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This is the dosing used after a mid-protocol amendment.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day on days 1 to 21
 
−
*[[Prednisone (Sterapred)]] 25 mg PO once every other day
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] or [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] at physician's discretion (mandatory)
 
−
 
 
−
'''28-day cycle for 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_monotherapy|Lenalidomide]] versus [[#Lenalidomide_.26_Prednisone_3|RP]] maintenance
 
−
 
 
−
===References===
 
−
# Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. [http://www.bloodjournal.org/content/127/9/1102.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26729895 PubMed]
 
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==CTD {{#subobject:658a40|Regimen=1}}==
 
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{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|[[#top|back to top]]
 
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|}
 
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CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
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<br>CTDa: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone, '''<u>a</u>'''ttenuated
 
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===Variant #1, CTD {{#subobject:e5fcc6|Variant=1}}===
 
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{| class="wikitable" style="width: 100%; text-align:center;"
 
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!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
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!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/119/1/7.long Morgan et al. 2011 (MRC Myeloma IX)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#CVAD|CVAD]]
 
−
|style="background-color:#d3d3d3"|Not reported
 
−
|-
 
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|}
 
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''This is an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per week
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, increasing to 200 mg PO once per day "if tolerated"
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 12 to 15
 
−
 
 
−
====Supportive medications====
 
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*Venous thromboembolism (VTE) prophylaxis was given at physician discretion, but it was suggested that low-risk patients receive [[Aspirin]] and high-risk patients receive [[Warfarin (Coumadin)]] or [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] according to risk categories as described by ''Palumbo A et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414–23. [https://www.nature.com/leu/journal/v22/n2/full/2405062a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18094721 PubMed]''
 
−
*Patients in the study were randomized to one of the following until progression:
 
−
**[[Clodronate (Bonefos)|Sodium clodronate (Bonefos)]] 1600 mg PO once per day
 
−
**[[Zoledronic acid (Zometa)]] 4 mg IV once every 21 to 28 days
 
−
 
 
−
'''21-day cycle for 4 to 6 cycles until maximum response'''
 
−
====Subsequent treatment====
 
−
*Responding patients: [[#Melphalan.2C_then_auto_HSCT|High-dose melphalan and autologous hematopoietic cell transplant]]
 
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===Variant #2, CTDa {{#subobject:db34fc|Variant=1}}===
 
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{| class="wikitable" style="width: 100%; text-align:center;"
 
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!style="width: 25%"|Study
 
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!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
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!style="width: 25%"|Comparator
 
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!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
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|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152492/ Morgan et al. 2011 (MRC Myeloma IX)]
 
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|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#MP|MP]]
 
−
|style="background-color:#d3d3d3"|Not reported
 
−
|-
 
−
|}
 
−
 
 
−
''This is a nonintensive treatment pathway, as determined by performance status, informed discussion, and patient preference.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per week
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day on days 1 to 28; dose is increased every 4 weeks in 50 mg increments, up to a maximum dose of 200 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18
 
−
 
 
−
====Supportive medications====
 
−
*For the first 12 weeks of treatment, thromboprophylaxis--for example, with [[Warfarin (Coumadin)]] or [[:Category:Low molecular weight heparins|low molecular weight heparin]]--was recommended
 
−
*Patients in the study were randomized to a bisphosphonate and received one of the following until progression:
 
−
**[[Clodronate (Bonefos)|Sodium clodronate (Bonefos)]] 1600 mg PO once per day
 
−
**[[Zoledronic acid (Zometa)]] 4 mg IV once every 21 to 28 days
 
−
 
 
−
'''28-day cycle for 6 to 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Thalidomide_monotherapy|Thalidomide maintenance]] versus [[Multiple_myeloma_-_historical#Observation|no further treatment]]
 
−
 
 
−
===References===
 
−
# '''MRC Myeloma IX:''' Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. [http://www.bloodjournal.org/content/119/1/7.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22021371 PubMed]
 
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## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291601/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22058209 PubMed]
 
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## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. [http://clincancerres.aacrjournals.org/content/19/21/6030.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23995858 PubMed]
 
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==CVAD {{#subobject:c3a1db|Regimen=1}}==
 
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{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|-
 
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|[[#top|back to top]]
 
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|}
 
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CVAD: '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:51a834|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/119/1/7.long Morgan et al. 2011 (MRC Myeloma IX)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#CTD|CTD]]
 
−
|style="background-color:#d3d3d3"|Not reported
 
−
|-
 
−
|}
 
−
''This is an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15
 
−
*[[Vincristine (Oncovin)]] 0.4 mg/day IV continuous infusion on days 1 to 4 (total dose per cycle: 1.6 mg)
 
−
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 4 (total dose per cycle: 36 mg/m<sup>2</sup>)
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 12 to 15
 
−
 
 
−
====Supportive medications====
 
−
*Patients in the study were randomized to a bisphosphonate and received one of the following until progression:
 
−
**[[Clodronate (Bonefos)|Sodium clodronate (Bonefos)]] 1600 mg PO once per day
 
−
**[[Zoledronic acid (Zometa)]] 4 mg IV once every 21 to 28 days
 
−
 
 
−
'''21-day cycle for 4 to 6 cycles until maximum response'''
 
−
====Subsequent treatment====
 
−
*Responding patients: [[#Melphalan.2C_then_auto_HSCT|High-dose melphalan and autologous hematopoietic cell transplant]]
 
−
 
 
−
===References===
 
−
# '''MRC Myeloma IX:''' Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. [http://www.bloodjournal.org/content/119/1/7.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22021371 PubMed]
 
−
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291601/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22058209 PubMed]
 
−
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. [http://clincancerres.aacrjournals.org/content/19/21/6030.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23995858 PubMed]
 
−
 
 
−
==D-VMP {{#subobject:5cbbd5|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|-
 
−
|[[#top|back to top]]
 
−
|}
 
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D-VMP: '''<u>D</u>'''aratumumab, '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone
 
−
===Regimen {{#subobject:e15b5d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1714678 Mateos et al. 2017 (ALCYONE)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VMP|VMP]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with newly diagnosed, documented multiple myeloma who were not eligible for high-dose chemotherapy with stem-cell transplantation owing to coexisting conditions or an age of 65 years or older. Note that dexamethasone is substitute for prednisone on day 1.''
 
−
====Chemotherapy====
 
−
*[[Daratumumab (Darzalex)]] as follows:
 
−
**Cycle 1: 16 mg/kg IV once per day on days 1, 8, 15, 22, 29, 36
 
−
**Cycles 2 to 9: 16 mg/kg IV once per day on days 1 & 22
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Cycle 1: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
 
−
**Cycles 2 to 9: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 22, 29
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 2 to 4
 
−
 
 
−
====Supportive medications====
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO/IV once prior to each dose of [[Daratumumab (Darzalex)]]
 
−
 
 
−
'''42-day cycle for 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Daratumumab_monotherapy|Daratumumab maintenance]]
 
−
===References===
 
−
# '''ALCYONE:''' Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. [http://www.nejm.org/doi/full/10.1056/NEJMoa1714678 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231133 PubMed]
 
−
 
 
−
==MPR {{#subobject:327863|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
MPR: '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>R</u>'''evlimid (Lenalidomide)
 
−
<br>MPL: '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>L</u>'''enalidomide
 
−
===Variant #1, 0.13/1.5/10 {{#subobject:926cbb|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (E)
 
−
|[[#CPR|CPR]]
 
−
|style="background-color:#d9ef8b"|Might have superior PFS
 
−
|-
 
−
|[[#Rd|Rd]]
 
−
|style="background-color:#d9ef8b"|Might have superior PFS
 
−
|-
 
−
|}
 
−
''This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant was intended for patients older than 75.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 0.13 mg/kg PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 1.5 mg/kg PO once per day on days 1 to 4
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] or [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] at physician's discretion (mandatory)
 
−
 
 
−
'''28-day cycle for 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_monotherapy|Lenalidomide]] versus [[#Lenalidomide_.26_Prednisone_3|Lenalidomide & Prednisone maintenance]]
 
−
 
 
−
===Variant #2, 0.18/1.5/10 {{#subobject:a0c09c|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (E)
 
−
|[[#CPR|CPR]]
 
−
|style="background-color:#d9ef8b"|Might have superior PFS
 
−
|-
 
−
|[[#Rd|Rd]]
 
−
|style="background-color:#d9ef8b"|Might have superior PFS
 
−
|-
 
−
|}
 
−
''This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant was intended for patients aged 65 to 75.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 1.5 mg/kg PO once per day on days 1 to 4
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] or [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] at physician's discretion (mandatory)
 
−
 
 
−
'''28-day cycle for 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_monotherapy|Lenalidomide]] versus [[#Lenalidomide_.26_Prednisone_3|Lenalidomide & Prednisone maintenance]]
 
−
 
 
−
===Variant #3, 0.18/2/10 {{#subobject:a4f37a|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/25/28/4459.long Palumbo et al. 2007]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJMoa1112704 Palumbo et al. 2012 (MM-015)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#MP|MP]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|MPR
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/9/1109.long Zweegman et al. 2016 (HOVON87/NMSG18)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#MPT|MPT-T]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''In '''Palumbo et al. 2007''' this regimen was intended for newly diagnosed multiple myeloma patients greater than or equal to 65 years, or younger if ineligible for high-dose therapy. In '''MM-015''' this regimen was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were not candidates for transplantation (greater than or equal to 65 years of age). In '''HOVON87/NMSG18''' this regimen was intended for patients greater than 65 years of age or patients less than or equal to 65 of age and not eligible for high-dose chemotherapy and peripheral stem cell transplantation with newly diagnosed symptomatic MM.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21
 
−
 
 
−
====Supportive medications====
 
−
*'''HOVON87/NMSG18:'''
 
−
**[[Aspirin]] 75 or 80 mg PO once per day or [[Carbasalate calcium (Ascal)]] 100 mg PO once per day
 
−
***Patients with a history of VTE received [[:Category:Low molecular weight heparins|LMWH]] instead
 
−
**[[:Category:Bisphosphonates|Bisphosphonates]] at physician discretion
 
−
**Prophylactic antibiotics at physician discretion
 
−
*'''MM-015:''' [[Aspirin]] 75 to 100 mg PO once per day as thromboprophylaxis
 
−
*'''Palumbo et al. 2007:''' [[Ciprofloxacin (Cipro)]] 500 mg PO BID and [[Aspirin]] 100 mg PO once per day
 
−
 
 
−
'''28-day cycle for 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]
 
−
 
 
−
===Variant #4, 5/100/10 {{#subobject:eb79d9|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ Stewart et al. 2015 (ECOG E1A06)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#MPT|MPT-T]]
 
−
|style="background-color:#eeee01"|Seems to have non-inferior PFS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients who were greater than or equal to 65 years or were less than 65 years and were not candidates for autologous hematopoietic cell transplantation or had declined transplant.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 4
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] was required (dose not specified)
 
−
**Full anticoagulation was used for patients at "higher risk" for DVT
 
−
*[[Pamidronate (Aredia)]] 90 mg IV once per month recommended for patients with "active bone disease"
 
−
 
 
−
'''28-day cycle for 12 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]
 
−
 
 
−
===References===
 
−
# Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, Crippa C, Ciccone G, Omedè P, Ambrosini MT, Gay F, Bringhen S, Musto P, Foà R, Knight R, Zeldis JB, Boccadoro M, Petrucci MT; GIMEMA--Italian Multiple Myeloma Network. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian Multiple Myeloma Network. J Clin Oncol. 2007 Oct 1;25(28):4459-65. Epub 2007 Sep 4. [http://jco.ascopubs.org/content/25/28/4459.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17785703 PubMed]
 
−
# '''MM-015:''' Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. [http://www.nejm.org/doi/full/10.1056/NEJMoa1112704 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22571200 PubMed]
 
−
# '''ECOG E1A06:''' Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. [http://www.bloodjournal.org/content/126/11/1294.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26157076 PubMed]
 
−
# '''EMN01:''' Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. [http://www.bloodjournal.org/content/127/9/1102.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26729895 PubMed]
 
−
# '''HOVON87/NMSG18:''' Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. [http://www.bloodjournal.org/content/127/9/1109.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26802176 PubMed]
 
−
 
 
−
==MPT {{#subobject:210ba4|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
MPT: '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>T</u>'''halidomide
 
−
 
 
−
===Variant #1, "MPT-T" {{#subobject:d23667|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/9/1109.long Zweegman et al. 2016 (HOVON87/NMSG18)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#MPR|MPR-R]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients greater than 65 years of age or patients less than or equal to 65 of age and not eligible for high-dose chemotherapy and peripheral stem cell transplantation with newly diagnosed symptomatic MM.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 75 or 80 mg PO once per day or [[carbasalate calcium]] 100 mg PO once per day
 
−
**Patients with a history of VTE received [[:Category:Low molecular weight heparins|LMWH]] instead
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] at physician discretion
 
−
*Prophylactic antibiotics at physician discretion
 
−
 
 
−
'''28-day cycle for 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Thalidomide_monotherapy|Thalidomide maintenance]]
 
−
 
 
−
===Variant #2, "MPT-T" {{#subobject:009af3|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ Stewart et al. 2015 (ECOG E1A06)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#MPR|mPR-R]]
 
−
|style="background-color:#eeee01"|Seems to have non-inferior PFS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients who were greater than or equal to 65 years or were less than 65 years and were not candidates for autologous hematopoietic cell transplantation or had declined transplant.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] was required (dose not specified)
 
−
**Full anticoagulation was used for patients at "higher risk" for DVT
 
−
*[[Pamidronate (Aredia)]] 90 mg IV once per month recommended for patients with "active bone disease"
 
−
 
 
−
'''28-day cycle for 12 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Thalidomide_monotherapy|Thalidomide maintenance]]
 
−
 
 
−
===Variant #3 {{#subobject:5b7e29|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJMoa1402551 Benboubker et al. 2014 (FIRST)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Rd|Rd]]
 
−
|style="background-color:#d73027"|Inferior OS (*)
 
−
|-
 
−
|[[#Rd|Rd18]]
 
−
|style="background-color:#fee08b"|Might have inferior OS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. Efficacy compared to Rd continuous is based on the 2017 update.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] starting dose as follows:
 
−
**Age up to 75 years AND ANC at least 1500/uL AND platelets at least 100 x 10<sup>9</sup>/L: 0.25 mg/kg PO once per day on days 1 to 4
 
−
**Older than 75 years AND ANC at least 1500/uL AND platelets at least 100 x 10<sup>9</sup>/L: 0.2 mg/kg PO once per day on days 1 to 4
 
−
**Age up to 75 years AND ANC less than 1500/uL but greater than or equal to 1000/uL OR platelets less than 100 x 10<sup>9</sup>/L but greater than or equal to 50 x 10<sup>9</sup>/L: 0.125 mg/kg PO once per day on days 1 to 4
 
−
**Older than 75 years AND ANC less than 1500/uL but greater than or equal to 1000/uL OR platelets less than 100 x 10<sup>9</sup>/L but greater than or equal to 50 x 10<sup>9</sup>/L: 0.1 mg/kg PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] starting dose as follows:
 
−
**Age up to 75 years: 200 mg PO once per day
 
−
**Older than 75 years: 100 mg PO once per day
 
−
 
 
−
'''42-day cycle for 12 cycles'''
 
−
 
 
−
===Variant #4 {{#subobject:2b9587|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2010.01524.x/abstract Beksac et al. 2010 (TMSG-2005-001)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#MP|MP]]
 
−
|style="background-color:#91cf60"|Seems to have superior ORR
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting conditions.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
 
 
−
'''42-day cycle for 9 cycles'''
 
−
 
 
−
===Variant #5 {{#subobject:6dc18c|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/116/9/1405.long Waage et al. 2010 (NMSG12)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#MP|MP]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with previously untreated symptomatic MM, who were not eligible for high-dose treatment with autologous stem cell support.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] as follows:
 
−
**Cycle 1: 200 mg PO once per day for one week, then increased to 400 mg PO once per day
 
−
**Cycle 2 onwards: 400 mg PO once per day
 
−
 
 
−
'''42-day cycles until plateau phase'''
 
−
====Subsequent treatment====
 
−
*[[#Thalidomide_monotherapy|Thalidomide maintenance]]
 
−
 
 
−
===Variant #6, "MP-T" {{#subobject:e2f96|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/19/3160.long Wijermans et al. 2010 (HOVON 49)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#MP|MP]]
 
−
|style="background-color:#d9ef8b"|Might have superior OS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with previously untreated MM older than age 65 years.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 5
 
−
*[[Prednisone (Sterapred)]] 1 mg/kg PO once per day on days 1 to 5
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Bisphosphonates|Bisphosphonate]] use recommended with [[Pamidronate (Aredia)]] or [[Clodronate (Bonefos)]]; "a maximum treatment period of 2 years was recommended in patients without active disease."
 
−
*During induction therapy, [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] use recommended with [[Nadroparin (Fraxiparine)]] 2,850 units anti-Xa (for patients greater than 90 kg, dose of 5,700 units anti-Xa)
 
−
 
 
−
'''28-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*Thalidomide continues at 200 mg PO once per day for 28 days, then [[#Thalidomide_monotherapy|maintenance thalidomide]]
 
−
 
 
−
===Variant #7 {{#subobject:1474b2|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/27/22/3664.long Hulin et al. 2009 (IFM 01/01)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#MP|MP]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients who had stage II or III newly diagnosed multiple myeloma according to the [[#Durie-Salmon_Staging_System_-_1975|Durie-Salmon criteria]] and were at least 75 years of age. Certain stage I patients were allowed; see text for details.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 0.2 mg/kg PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
 
 
−
'''42-day cycle for 12 cycles'''
 
−
 
 
−
===Variant #8 {{#subobject:6de9f0|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan="2"|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2807%2961537-2/fulltext Facon et al. 2007 (IFM 99-06)]
 
−
|rowspan="2" style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#MP|MP]]
 
−
|style="background-color:#1a9850"|Superior OS
 
−
|-
 
−
|MEL100
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with newly diagnosed multiple myeloma aged 65 to 75 years.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day, increased as tolerated after 4 weeks on therapy to maximum dose of 400 mg once per day
 
−
 
 
−
'''42-day cycle for 12 cycles'''
 
−
 
 
−
===Variant #9 {{#subobject:8813e2|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2806%2968338-4/fulltext Palumbo et al. 2006]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#MP|MP]]
 
−
|style="background-color:#91cf60"|Seems to have superior PFS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with newly diagnosed multiple myeloma aged 60 to 85 years.''
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 4 mg/m<sup>2</sup> PO once per day on days 1 to 7
 
−
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 7
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 28
 
−
 
 
−
====Supportive medications====
 
−
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day on days 1 to 28 of cycles 1 to 4
 
−
 
 
−
'''28-day cycle for 6 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Thalidomide_monotherapy|Thalidomide maintenance]]
 
−
 
 
−
===References===
 
−
# Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network (GIMEMA). Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006 Mar 11;367(9513):825-31. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2806%2968338-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16530576 PubMed]
 
−
## '''Update:''' Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14. Epub 2008 May 27. [http://www.bloodjournal.org/content/112/8/3107.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18505783 PubMed]
 
−
# '''IFM 99-06:''' Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, Renaud M, Harousseau JL, Guillerm G, Chaleteix C, Dib M, Voillat L, Maisonneuve H, Troncy J, Dorvaux V, Monconduit M, Martin C, Casassus P, Jaubert J, Jardel H, Doyen C, Kolb B, Anglaret B, Grosbois B, Yakoub-Agha I, Mathiot C, Avet-Loiseau H; Intergroupe Francophone du Myélome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007 Oct 6;370(9594):1209-18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2807%2961537-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17920916 PubMed] content property of [http://hemonc.org HemOnc.org]
 
−
<!-- Presented in part in abstract format at the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007; XIth International Myeloma Workshop, Kos Island, Greece, June 25-30, 2007; and the American Society of Hematology, Atlanta, GA, December 8-11, 2007. -->
 
−
# '''IFM 01/01:''' Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C, Dib M, Guillerm G, Salles B, Eschard JP, Lenain P, Casassus P, Azaïs I, Decaux O, Garderet L, Mathiot C, Fontan J, Lafon I, Virion JM, Moreau P. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009 Aug 1;27(22):3664-70. Epub 2009 May 18. [http://jco.ascopubs.org/content/27/22/3664.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19451428 PubMed]
 
−
# '''NMSG12:''' Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, Carlson K, Dahl IM, Forsberg K, Gulbrandsen N, Haukås E, Hjertner O, Hjorth M, Karlsson T, Knudsen LM, Nielsen JL, Linder O, Mellqvist UH, Nesthus I, Rolke J, Strandberg M, Sørbø JH, Wisløff F, Juliusson G, Turesson I; Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010 Sep 2;116(9):1405-12. Epub 2010 May 6. [http://www.bloodjournal.org/content/116/9/1405.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20448107 PubMed]
 
−
# '''HOVON 49:''' Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P; Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010 Jul 1;28(19):3160-6. Epub 2010 Jun 1. [http://jco.ascopubs.org/content/28/19/3160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20516439 PubMed]
 
−
# '''TMSG-2005-001:''' Beksac M, Haznedar R, Firatli-Tuglular T, Ozdogu H, Aydogdu I, Konuk N, Sucak G, Kaygusuz I, Karakus S, Kaya E, Ali R, Gulbas Z, Ozet G, Goker H, Undar L. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011 Jan;86(1):16-22. Epub 2010 Nov 22. [https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2010.01524.x/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20942865 PubMed]
 
−
# '''Meta-analysis:''' Fayers PM, Palumbo A, Hulin C, Waage A, Wijermans P, Beksaç M, Bringhen S, Mary JY, Gimsing P, Termorshuizen F, Haznedar R, Caravita T, Moreau P, Turesson I, Musto P, Benboubker L, Schaafsma M, Sonneveld P, Facon T; Nordic Myeloma Study Group; Italian Multiple Myeloma Network; Turkish Myeloma Study Group; Hemato-Oncologie voor Volwassenen Nederland; Intergroupe Francophone du Myélome; European Myeloma Network. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood. 2011 Aug 4;118(5):1239-47. Epub 2011 Jun 13. [http://www.bloodjournal.org/content/118/5/1239.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21670471 PubMed]
 
−
# '''FIRST:''' Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. [http://www.nejm.org/doi/full/10.1056/NEJMoa1402551 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1402551/suppl_file/nejmoa1402551_appendix.pdf link to supplemental appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25184863 PubMed]
 
−
## '''Update:''' Hulin C, Belch A, Shustik C, Petrucci MT, Dührsen U, Lu J, Song K, Rodon P, Pégourié B, Garderet L, Hunter H, Azais I, Eek R, Gisslinger H, Macro M, Dakhil S, Goncalves C, LeBlanc R, Romeril K, Royer B, Doyen C, Leleu X, Offner F, Leupin N, Houck V, Chen G, Ervin-Haynes A, Dimopoulos MA, Facon T. Updated outcomes and impact of age with lenalidomide and low-dose dexamethasone or melphalan, prednisone, and thalidomide in the randomized, phase III FIRST trial. J Clin Oncol. 2016 Oct;34(30):3609-17. Epub 2016 Jun 20. [http://jco.ascopubs.org/content/34/30/3609.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27325857 PubMed]
 
−
## '''Update:''' Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis NJ, Banos A, Tiab M, Delforge M, Cavenagh JD, Geraldes C, Lee JJ, Chen C, Oriol A, De La Rubia J, White D, Binder D, Lu J, Anderson KC, Moreau P, Attal M, Perrot A, Arnulf B, Qiu L, Roussel M, Boyle E, Manier S, Mohty M, Avet-Loiseau H, Leleu X, Ervin-Haynes A, Chen G, Houck V, Benboubker L, Hulin C. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018 Jan 18;131(3):301-310. Epub 2017 Nov 17. [http://www.bloodjournal.org/content/131/3/301.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29150421 PubMed]
 
−
# '''ECOG E1A06:''' Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. [http://www.bloodjournal.org/content/126/11/1294.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26157076 PubMed]
 
−
# Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. [http://www.bloodjournal.org/content/127/9/1109.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26802176 PubMed]
 
−
 
 
−
==PAD {{#subobject:955a56|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
PAD: '''<u>P</u>'''S-341 (Bortezomib), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
 
−
<br>PAd: '''<u>P</u>'''S-341 (Bortezomib), '''<u>A</u>'''driamycin (Doxorubicin), low-dose '''<u>d</u>'''examethasone
 
−
<br>''Note that this regimen is sometimes called VAD but this can create a lot of confusion with the [[Multiple_myeloma_-_historical#VAD|"original" VAD which uses '''<u>V</u>'''incristine]].''
 
−
<br>VAD: '''<u>V</u>'''elcade (Bortezomib), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
 
−
<br>BDD: '''<u>B</u>'''ortezomib, '''<u>D</u>'''oxorubicin, '''<u>D</u>'''examethasone
 
−
===Variant #1, SC bortezomib, low-dose dex ("PAd") {{#subobject:60f72e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.nature.com/leu/journal/v29/n8/full/leu201580a.html Mai et al. 2015 (GMMG-MM5)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VDC|VCD]]
 
−
|style="background-color:#eeee01"|Non-inferior VGPR or better rate
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients 18 to 70 years of age with newly diagnosed MM who required systemic chemotherapy based on the CRAB criteria. Note that the bortezomib route was changed from IV to SC with a mid-protocol amendment.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 4
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
 
 
−
====Supportive medications====
 
−
*[[Trimethoprim/Sulfamethoxazole_(Bactrim_DS)|Cotrimoxazole]] (dose not specified)
 
−
*[[Acyclovir (Zovirax)]] (dose not specified)
 
−
*[[:Category:Bisphosphonates|Bisphosphonate]] IV every 4 weeks
 
−
 
 
−
'''28-day cycle for 3 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic cell transplant]]
 
−
 
 
−
===Variant #2, IV bortezomib, limited duration (3 cycles) {{#subobject:3fc8cd|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (HOVON-65/GMMG-HD4)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#VAD|VAD]]
 
−
|style="background-color:#1a9850"|Superior PFS (*)
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients 18 to 65 years of age with newly diagnosed MM, [[#Durie-Salmon_Staging_System_-_1975|Durie-Salmon stage]] II to III, [[#ECOG_performance_status_.28WHO.2FZubrod_score.29|WHO performance status]] 0 to 2, or WHO 3 when caused by MM. Note that in the initial publication, this arm seemed to have an overall survival advantage; this was no longer present in the updated report of 2017; PFS was the primary endpoint. Stem cells collected 4 to 6 weeks after induction therapy''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 4
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
 
 
−
====Supportive medications====
 
−
(described in the appendix of Sonneveld et al. 2012):
 
−
*One of the following bisphosphonates recommended:
 
−
**[[Pamidronate (Aredia)]] 90 mg IV once every 4 to 6 weeks x at least 2 years
 
−
**[[Zoledronic acid (Zometa)]] 4 mg IV once every 4 to 6 weeks x at least 2 years
 
−
**[[Ibandronate (Boniva)]] 6 mg IV once every 4 to 6 weeks x at least 2 years
 
−
*"Prophylactic antibiotics" (no further specifics) during induction therapy
 
−
*Erythropoietin and pain medications at physician discretion
 
−
*One of the following for Herpes zoster prophylaxis throughout bortezomib induction:
 
−
**[[Acyclovir (Zovirax)]] 800 mg PO per day (did not specify whether taken once per day or as a divided twice per day dose)
 
−
**[[Valacyclovir (Valtrex)]] 1000 mg PO per day (did not specify whether taken once per day or as a divided twice per day dose)
 
−
 
 
−
'''28-day cycle for 3 cycles'''
 
−
====Subsequent treatment====
 
−
*HOVON-65: [[#Melphalan.2C_then_auto_HSCT|Single high-dose melphalan & autologous hematopoietic cell transplant]]
 
−
*GMMG-HD4: [[#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan & autologous hematopoietic cell transplant]]
 
−
 
 
−
===Variant #3, IV bortezomib, limited duration (4 cycles) {{#subobject:36a261|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2005.05519.x/full Oakervee et al. 2005]
 
−
|style="background-color:#ffffbe"|Phase II, <20 pts (*)
 
−
|-
 
−
|}
 
−
''Note that while this is reported as a phase II, it was also a dose-finding study; only 14 patients were treated at the dose here.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11
 
−
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 4
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
 
−
**Cycles 2 to 4: 40 mg PO once per day on days 1 to 4
 
−
 
 
−
'''21-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Stem_cell_mobilization#Cyclophosphamide_.26_G-CSF|Cyclophosphamide stem cell mobilization]], then [[#Melphalan.2C_then_auto_HSCT|high-dose melphalan & autologous hematopoietic cell transplant]]
 
−
 
 
−
===Variant #4, low-dose bortezomib {{#subobject:30a4d0|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/30/4635.long Ludwig et al. 2010]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''This is not specifically a first-line regimen but most patients enrolled on the phase II trial were untreated (50 out of 68)''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11
 
−
**Patients without grade 3 or 4 toxicity during the first two cycles could have bortezomib dose increased to 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11
 
−
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 & 4
 
−
**Patients without grade 3 or 4 toxicity during the first two cycles could have number of doxorubicin doses increased to 9 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 40 mg (route not specified) once per day on days 1, 4, 8, 11
 
−
 
 
−
'''21-day cycle for up to 8 cycles'''
 
−
===References===
 
−
# Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, Agrawal S, Stec J, Schenkein D, Esseltine DL, Cavenagh JD. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005 Jun;129(6):755-62. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2005.05519.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15953001 PubMed]
 
−
<!-- Presented in part at the 13th Congress of the European Haematology Association, June 12-15, 2008, Copenhagen, Denmark; the 50th Annual Meeting of the American Society of Hematology, December 6-9, 2008, San Francisco, CA; and the 51st Annual Meeting of the American Society of Hematology, December 5-8, 2009, New Orleans, LA. -->
 
−
# Ludwig H, Adam Z, Hajek R, Greil R, Tóthová E, Keil F, Autzinger EM, Thaler J, Gisslinger H, Lang A, Egyed M, Womastek I, Zojer N. Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study. J Clin Oncol. 2010 Oct 20;28(30):4635-41. Epub 2010 Sep 7. [http://jco.ascopubs.org/content/28/30/4635.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823423 PubMed]
 
−
# '''HOVON-65/GMMG-HD4:''' Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. [http://jco.ascopubs.org/content/30/24/2946.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22802322 PubMed]
 
−
## '''Subgroup analysis:''' Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. [http://www.bloodjournal.org/content/119/4/940.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22160383 PubMed]
 
−
## '''Update:''' Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. [https://www.nature.com/articles/leu2017211 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28761118 PubMed]
 
−
# '''GMMG-MM5:''' Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. [https://www.nature.com/leu/journal/v29/n8/full/leu201580a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25787915 PubMed]
 
−
 
 
−
==Rd {{#subobject:cf79ea|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone
 
−
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone
 
−
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone
 
−
<br>Len-Dex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone
 
−
===Variant #1, limited duration (4 cycles) {{#subobject:75359c|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70284-0/abstract Rajkumar et al. 2009 (ECOG E4A03)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#RD|RD]]
 
−
|style="background-color:#1a9850"|Superior OS
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956597/ Gay et al. 2010]
 
−
|style="background-color:#ffffbe"|Retrospective
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1402888 Palumbo et al. 2014 (GIMEMA RV-MM-PI-209)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract Gay et al. 2015 (EMN-441)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|}
 
−
''In '''ECOG E4A03''' this is the low-dose dexamethasone arm, and was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h. '''GIMEMA RV-209''' was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were 65 years of age or younger. '''EMN-441''' was intended for transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
(as described in Rajkumar et al. 2009):
 
−
*One of the following bisphosphonates:
 
−
**[[Pamidronate (Aredia)]] 90 mg IV over 2 to 4 hours once every 4 weeks
 
−
**[[Zoledronic acid (Zometa)]] 4 mg IV over 15 minutes once every 4 weeks
 
−
*Thromboprophylaxis mandatory (added mid-protocol after excess rates of DVT)
 
−
 
 
−
'''28-day cycle for 4 cycles (see below)'''
 
−
====Subsequent treatment====
 
−
*ECOG E4A03: Responding patients could choose after 4 cycles to proceed to [[#Melphalan.2C_then_auto_HSCT|high-dose melphalan with autologous hematopoietic cell transplant]] or to continue Rd indefinitely
 
−
*ECOG E4A03, nonresponders: [[#Thal-Dex_3|Thal-Dex]] (details not described)
 
−
*GIMEMA RV-MM-PI-209: [[#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan with autologous hematopoietic cell transplant]] versus [[#MPR_2|MPR consolidation]]
 
−
*EMN-441: [[#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan with autologous hematopoietic cell transplant]] versus CRD consolidation
 
−
 
 
−
===Variant #2, limited duration (6 cycles) {{#subobject:6b80b3|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext Durie et al. 2016 (SWOG S0777)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#RVD|VRd]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior OS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle for 6 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Rd_2|Rd maintenance]]
 
−
 
 
−
===Variant #3, limited duration (9 cycles) {{#subobject:37a149|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (E)
 
−
|[[#CPR|CPR]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[[#MPR|MPR]]
 
−
|style="background-color:#fee08b"|Might have inferior PFS
 
−
|-
 
−
|}
 
−
''This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Age 65 to 75 years: 40 mg PO once per day on days 1, 8, 15, 22
 
−
**Age greater than 75 years: 20 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] or [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] at physician's discretion (mandatory)
 
−
 
 
−
'''28-day cycle for 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_monotherapy|Lenalidomide]] versus [[#Lenalidomide_.26_Prednisone_3|RP]] maintenance
 
−
 
 
−
===Variant #4, limited duration (18 cycles, "Rd18") {{#subobject:cad6e3|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJMoa1402551 Benboubker et al. 2014 (FIRST)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (E)
 
−
|Rd continuous
 
−
|style="background-color:#ffffbf"|Seems not superior (*)
 
−
|-
 
−
|[[#MPT|MPT]]
 
−
|style="background-color:#1a9850"|Superior OS (*)
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. Efficacy based on the 2017 update.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] starting dose as follows:
 
−
**Normal renal function: 25 mg PO once per day on days 1 to 21
 
−
**Moderate renal impairment (CrCl 30 to 50 mL/min/1.73m<sup>2</sup>): 10 mg PO once per day on days 1 to 21
 
−
**Severe renal impairment (CrCl less than 30 mL/min/1.73m<sup>2</sup>): 15 mg PO once every other day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] starting dose as follows:
 
−
**Age less than or equal to 75: 40 mg PO once per day on days 1, 8, 15, 22
 
−
**Age greater than 75: 20 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle for 18 cycles'''
 
−
 
 
−
===Variant #5, indefinite 28-day cycles {{#subobject:919b70|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJMoa1402551 Benboubker et al. 2014 (FIRST)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (E)
 
−
|Rd18
 
−
|style="background-color:#ffffbf"|Seems not superior (*)
 
−
|-
 
−
|[[#MPT|MPT]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. Efficacy compared to Rd18 based on the 2017 update.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] starting dose as follows:
 
−
**Normal renal function: 25 mg PO once per day on days 1 to 21
 
−
**Moderate renal impairment (CrCl 30 to 50 mL/min/1.73m<sup>2</sup>): 10 mg PO once per day on days 1 to 21
 
−
**Severe renal impairment (CrCl less than 30 mL/min/1.73m<sup>2</sup>): 15 mg PO once every other day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] starting dose as follows:
 
−
**Age up to 75 years: 40 mg PO once per day on days 1, 8, 15, 22
 
−
**Older than 75 years: 20 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle given until disease progression'''
 
−
 
 
−
===Variant #6, indefinite with 35-day induction cycles {{#subobject:616f4b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031379/ Zonder et al. 2010 (SWOG S0232)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy|Dexamethasone]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|}
 
−
''This regimen was intended for transplantation-ineligible or -denying patients who had to have symptomatic disease with a measurable M-protein, be at least 18 years old, and have a performance status less than 3 (unless resulting from myeloma). Note that the first 3 cycles, termed "induction" in the protocol, were 35-day cycles.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] as follows:
 
−
**Cycles 1 to 3: 25 mg PO once per day on days 1 to 28 of a 35-day cycle
 
−
**Cycle 4 onwards: 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 of a 35-day cycle
 
−
**Cycle 4 onwards: 40 mg PO once per day on days 1 to 4
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 325 mg PO once per day unless already on anticoagulation therapy
 
−
 
 
−
'''28-day cycles (*)'''
 
−
 
 
−
===Variant #7, indefinite 28-day cycles, first 4 with high-dose dex {{#subobject:cb906d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895238/ Rajkumar et al. 2005]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
**Cycle 5 onwards: 40 mg PO once per day on days 1 to 4
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 80 mg or 325 mg (depending on physician choice) PO once per day for thromboprophylaxis
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005 Dec 15;106(13):4050-3. Epub 2005 Aug 23. [http://www.bloodjournal.org/content/106/13/4050.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895238/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/16118317 PubMed]
 
−
# Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010 Jan;11(1):29-37. Epub 2009 Oct 21. Erratum in: Lancet Oncol. 2010 Jan;11(1):14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70284-0/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042271/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19853510 PubMed]
 
−
# '''Retrospective:''' Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am J Hematol. 2010 Sep;85(9):664-9. [http://dx.doi.org/10.1002/ajh.21777 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956597/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20645430 PubMed]
 
−
# Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BG, Barlogie B. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood. 2010 Dec 23;116(26):5838-41. Epub 2010 Sep 27. [http://www.bloodjournal.org/content/116/26/5838.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031379/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20876454 PubMed]
 
−
# Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. [http://www.nejm.org/doi/full/10.1056/NEJMoa1402888 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25184862 PubMed]
 
−
# Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. [http://www.nejm.org/doi/full/10.1056/NEJMoa1402551 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1402551/suppl_file/nejmoa1402551_appendix.pdf link to supplemental appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25184863 PubMed]
 
−
## '''Update:''' Hulin C, Belch A, Shustik C, Petrucci MT, Dührsen U, Lu J, Song K, Rodon P, Pégourié B, Garderet L, Hunter H, Azais I, Eek R, Gisslinger H, Macro M, Dakhil S, Goncalves C, LeBlanc R, Romeril K, Royer B, Doyen C, Leleu X, Offner F, Leupin N, Houck V, Chen G, Ervin-Haynes A, Dimopoulos MA, Facon T. Updated outcomes and impact of age with lenalidomide and low-dose dexamethasone or melphalan, prednisone, and thalidomide in the randomized, phase III FIRST trial. J Clin Oncol. 2016 Oct;34(30):3609-17. Epub 2016 Jun 20. [http://jco.ascopubs.org/content/34/30/3609.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27325857 PubMed]
 
−
## '''Update:''' Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis NJ, Banos A, Tiab M, Delforge M, Cavenagh JD, Geraldes C, Lee JJ, Chen C, Oriol A, De La Rubia J, White D, Binder D, Lu J, Anderson KC, Moreau P, Attal M, Perrot A, Arnulf B, Qiu L, Roussel M, Boyle E, Manier S, Mohty M, Avet-Loiseau H, Leleu X, Ervin-Haynes A, Chen G, Houck V, Benboubker L, Hulin C. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018 Jan 18;131(3):301-310. Epub 2017 Nov 17. [http://www.bloodjournal.org/content/131/3/301.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29150421 PubMed]
 
−
# Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26596670 PubMed]
 
−
# Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. [http://www.bloodjournal.org/content/127/9/1102.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26729895 PubMed]
 
−
# '''SWOG S0777:''' Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527. Epub 2016 Dec 22. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28017406 PubMed]
 
−
 
 
−
==RVD {{#subobject:97fba9|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
RVD: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone
 
−
<br>VDR: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>R</u>'''evlimid (Lenalidomide)
 
−
<br>VRD: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone
 
−
<br>VRd: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
 
 
−
===Variant #1 {{#subobject:81b266|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext Durie et al. 2016 (SWOG S0777)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Rd|Rd]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|}
 
−
''This regimen is intended for patients with previously untreated multiple myeloma who were not planned for immediate autologous stem-cell transplant.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Rd_2|Rd maintenance]]
 
−
===Variant #2 {{#subobject:d90d76|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=3|[http://www.bloodjournal.org/content/119/19/4375.long Kumar et al. 2012 (EVOLUTION)]
 
−
|rowspan=3 style="background-color:#1a9851"|Randomized Phase II (C)
 
−
|[[#VDC|VDC]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[[#VDC|VDC-mod]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[[#RVDC|VDCR]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a [[#Karnofsky_performance_scale|Karnofsky Performance Status]] greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Bortezomib_monotherapy|Bortezomib consolidation]]
 
−
 
 
−
===Variant #3 {{#subobject:45268d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1611750 Attal et al. 2017 (IFM 2009)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
''This regimen is intended for patients 65 years of age or younger with symptomatic, measurable, newly diagnosed multiple myeloma.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
'''21-day cycle for 3 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]] versus [[#RVD_2|RVD consolidation]]
 
−
 
 
−
===Variant #4 {{#subobject:fdbb24|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/32/25/2712.full Roussel et al. 2014]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Low_molecular_weight_heparins |Low–molecular weight heparin (LMWH)]]
 
−
*[[:Category:Antivirals |Antiviral therapy]] with example [[Valacyclovir (Valtrex) | valacyclovir]] given, for herpes zoster prevention
 
−
*[[:Category:Antibacterials |Antibiotic prophylaxis]] with example [[Amoxicillin |amoxicillin]] given, for bacterial infections
 
−
 
 
−
'''21-day cycle for 3 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan and autologous hematopoietic cell transplant]]
 
−
 
 
−
===Variant #5 {{#subobject:94d215|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324254/ Richardson et al. 2010]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
''This is the MTD level "4M" described in the manuscript.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
**Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 81 mg or 325 mg PO once per day
 
−
*[[:Category:Antivirals |Antiviral therapy]], such as [[Acyclovir (Zovirax)]] 400 mg PO once per day
 
−
*[[:Category:Bisphosphonates|Bisphosphonate]]
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*Patients who responded and tolerated therapy could optionally proceed to [[#RVD_2|RVD maintenance]]
 
−
 
 
−
===References===
 
−
# Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, Delaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine DL, Anderson KC. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010 Aug 5;116(5):679-86. Epub 2010 Apr 12. [http://www.bloodjournal.org/content/116/5/679.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324254/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20385792 PubMed]
 
−
<!-- Presented in abstract form at the 51st American Society of Hematology (ASH) annual meeting, New Orleans, LA, December 7, 2009; the 52nd ASH annual meeting, Orlando, FL, December 6, 2010; and the 13th International Myeloma Workshop, Paris, France, May 5, 2011.-->
 
−
# Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22422823 PubMed]
 
−
# Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. [http://jco.ascopubs.org/content/32/25/2712.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25024076 PubMed]
 
−
# '''SWOG S0777:''' Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527. Epub 2016 Dec 22. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28017406 PubMed]
 
−
# Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. [http://www.nejm.org/doi/full/10.1056/NEJMoa1611750 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28379796 PubMed]
 
−
 
 
−
==RVDC {{#subobject:336f84|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
RVDC: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide
 
−
<br>VDCR: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide)
 
−
 
 
−
===Regimen {{#subobject:78af20|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=3|[http://www.bloodjournal.org/content/119/19/4375.long Kumar et al. 2012 (EVOLUTION)]
 
−
|rowspan=3 style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|[[#VDC|VDC]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[[#VDC|VDC-mod]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[[#RVD|VDR]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a [[#Karnofsky_performance_scale|Karnofsky Performance Status]] greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15
 
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 325 mg PO once per day
 
−
**[[Warfarin (Coumadin)]] or [[Enoxaparin (Lovenox)]] could be used based on physician discretion
 
−
*[[:Category:PCP_prophylaxis|PCP prophylaxis]] recommended
 
−
*[[Acyclovir (Zovirax)]] prophylaxis for Herpes zoster recommended
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] could be used "as necessary"
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Bortezomib_monotherapy|Bortezomib consolidation]]
 
−
 
 
−
===References===
 
−
<!-- Presented in abstract form at the 51st American Society of Hematology (ASH) annual meeting, New Orleans, LA, December 7, 2009; the 52nd ASH annual meeting, Orlando, FL, December 6, 2010; and the 13th International Myeloma Workshop, Paris, France, May 5, 2011.-->
 
−
# Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22422823 PubMed]
 
−
 
 
−
==TAD {{#subobject:b583de|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
TAD: '''<u>T</u>'''halidomide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
 
−
===Regimen {{#subobject:42403f|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/115/6/1113 Lokhorst et al. 2009 (HOVON 50/GMMG-HD3)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#VAD|VAD]]
 
−
|style="background-color:#1a9850"|Superior EFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 200 to 400 mg PO once per day
 
−
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 4
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
 
 
−
'''28-day cycle for 3 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Stem_cell_mobilization#CAD_.26_G-CSF|CAD & G-CSF stem-cell mobilization]]
 
−
 
 
−
===References===
 
−
<!-- Presented in part at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 7, 2008. -->
 
−
# '''HOVON 50/GMMG-HD3:''' Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. [http://www.bloodjournal.org/content/115/6/1113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19880501 PubMed]
 
−
 
 
−
==Thal-Dex {{#subobject:13b509|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
TD: '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
−
<br>Thal-Dex: '''<u>Thal</u>'''idomide, '''<u>Dex</u>'''amethasone
 
−
===Variant #1 {{#subobject:f79d0|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://www.bloodjournal.org/content/120/8/1589.long Rosiñol et al. 2012 (PETHEMA GEM05MENOS65)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (C)
 
−
|[[#VTD|VTD]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior PFS
 
−
|-
 
−
|VBMCP/VBAD/B
 
−
|style="background-color:#d3d3d3"|Not reported
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with newly diagnosed and untreated symptomatic MM who were less than or equal to 65 years of age with measurable serum and/or urine M protein.''
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] as follows:
 
−
**Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
 
−
**Cycle 2 onwards: [[Thalidomide (Thalomid)]] 200 mg PO once per day on days 1 to 28
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Low_molecular_weight_heparins|Low-molecular weight heparin]] or [[Aspirin]] recommended
 
−
 
 
−
'''28-day cycle for 6 cycles'''
 
−
 
 
−
===Variant #2 {{#subobject:437335|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61424-9/fulltext Cavo et al. 2010 (GIMEMA MM-BO2005)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#VTD|VTD]]
 
−
|style="background-color:#d73027"|Inferior CR/nCR rate
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma.''
 
−
====Chemotherapy, induction====
 
−
*[[Thalidomide (Thalomid)]] as follows:
 
−
**Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to 21
 
−
**Cycles 2 & 3: 200 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12
 
−
 
 
−
'''21-day cycle for 3 cycles, then proceed to first stem cell transplant'''
 
−
 
 
−
====Chemotherapy, first stem cell transplant====
 
−
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> (route not specified) once on day -2
 
−
*Autologous hematopoietic cell rescue
 
−
 
 
−
'''Wait until count recovery, then proceed to thalidomide & dexamethasone therapy'''
 
−
 
 
−
====Chemotherapy, thalidomide & dexamethasone therapy====
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
 
−
 
 
−
'''28-day cycles for 3 to 6 months, then proceed to second stem cell transplant'''
 
−
 
 
−
====Chemotherapy, second stem cell transplant====
 
−
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> (route not specified) once on day -2
 
−
*Autologous hematopoietic cell rescue
 
−
 
 
−
'''Wait until 3 months after second transplant, then proceed to thalidomide & dexamethasone therapy'''
 
−
 
 
−
====Chemotherapy, thalidomide & dexamethasone consolidation====
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 20 to 23
 
−
 
 
−
====Supportive medications====
 
−
*[[Acyclovir (Zovirax)]] prophylaxis recommended
 
−
 
 
−
'''35-day cycle for 2 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_2|Dexamethasone maintenance]]
 
−
 
 
−
===Variant #3 {{#subobject:d90960|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904367/ Rajkumar et al. 2008]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy|Dexamethasone]]
 
−
|style="background-color:#1a9850"|Superior TTP
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h.''
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] as follows:
 
−
**Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
 
−
**Cycle 2 onwards: 200 mg PO once per day on days 1 to 28
 
−
*[[Dexamethasone (Decadron)]] as folows:
 
−
**Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
**Cycle 5 onwards: 40 mg PO once per day on days 1 to 4
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #4 {{#subobject:b1c11d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
!style="width: 20%"|[[Levels_of_Evidence#Toxicity|Toxicity]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/20/21/4319.long Rajkumar et al. 2002]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://jco.ascopubs.org/content/24/3/431.long Rajkumar et al. 2006]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy|Dexamethasone]]
 
−
|style="background-color:#91cf60"|Seems to have superior RR
 
−
|style="background-color:#d73027"|Inferior toxicity
 
−
|-
 
−
|}
 
−
''In '''Rajkumar et al. 2006''' his regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h.''
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day on days 1 to 28
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Odd-numbered cycles: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
**Even-numbered cycles: 40 mg PO once per day on days 1 to 4
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #5 {{#subobject:bc8d0f|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.haematologica.org/content/89/7/826.long Cavo et al. 2004 (Bologna 2002)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] as follows:
 
−
**Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to end of month
 
−
**Cycles 2 to 4: 200 mg PO once per day on days 1 to end of month
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
**Cycles 2 & 4: 40 mg PO once per day on days 1 to 4
 
−
 
 
−
'''Monthly cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*Responders: [[#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan, then autologous hematopoietic cell transplant]].''
 
−
 
 
−
===References===
 
−
# Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, Geyer S, Iturria N, Fonseca R, Lust JA, Kyle RA, Witzig TE. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol. 2002 Nov 1;20(21):4319-23. [http://jco.ascopubs.org/content/20/21/4319.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12409330 PubMed]
 
−
# '''Dose escalation study:''' Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]
 
−
# '''Bologna 2002:''' Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, Testoni N, Tonelli M, de Vivo A, Palareti G, Tura S, Baccarani M. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica. 2004 Jul;89(7):826-31. [http://www.haematologica.org/content/89/7/826.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15257934 PubMed]
 
−
## '''Sub-analysis:''' Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D, de Vivo A, Testoni N, Nicci C, Terragna C, Grafone T, Perrone G, Ceccolini M, Tura S, Baccarani M; Bologna 2002 study. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood. 2005 Jul 1;106(1):35-9. Epub 2005 Mar 10. [http://www.bloodjournal.org/content/106/1/35 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15761019 PubMed]
 
−
# Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern Cooperative Oncology Group. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006 Jan 20;24(3):431-6. Epub 2005 Dec 19. [http://jco.ascopubs.org/content/24/3/431.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16365178 PubMed]
 
−
# Rajkumar SV, Rosiñol L, Hussein M, Catalano J, Jedrzejczak W, Lucy L, Olesnyckyj M, Yu Z, Knight R, Zeldis JB, Bladé J. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol. 2008 May 1;26(13):2171-7. Epub 2008 Mar 24. [http://jco.ascopubs.org/content/26/13/2171.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904367/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18362366 PubMed]
 
−
# '''GIMEMA MM-BO2005:''' Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. Erratum in: Lancet. 2011 Nov 26;378(9806):1846. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61424-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21146205 PubMed]
 
−
## '''Update:''' Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. [http://www.bloodjournal.org/content/120/1/9.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22498745 PubMed]
 
−
# '''PETHEMA GEM05MENOS65:''' Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. [http://www.bloodjournal.org/content/120/8/1589.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22791289 PubMed]
 
−
 
 
−
==VAD doxil {{#subobject:6dfa10|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
DVD: '''<u>D</u>'''oxil (Liposomal Doxorubicin), '''<u>V</u>'''incristine, '''<u>D</u>'''examethasone
 
−
<br>DVd: '''<u>D</u>'''oxil (Liposomal Doxorubicin), '''<u>V</u>'''incristine, low-dose '''<u>d</u>'''examethasone
 
−
<br>VAD doxil: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin liposomal (Doxil), '''<u>D</u>'''examethasone
 
−
 
 
−
===Variant #1, indefinite ("DVd") {{#subobject:72393d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.21662/full Rifkin et al. 2006]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#VAD|VAd]]
 
−
|style="background-color:#eeee01"|Non-inferior ORR
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients greater than or equal to 18 years and fulfilling a diagnosis of stage II or III MM according to the [[#Durie-Salmon_Staging_System_-_1975|Durie and Salmon criteria]].''
 
−
====Chemotherapy====
 
−
*[[Pegylated liposomal doxorubicin (Doxil)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose per cycle capped at 2 mg) IV over 5 minutes once on day 1
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
 
−
 
 
−
'''28-day cycles, given until maximal response, progression of disease, or unacceptable toxicity'''
 
−
 
 
−
===Variant #2, limited duration (4 cycles) {{#subobject:f03965|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://annonc.oxfordjournals.org/content/14/7/1039.long Dimopoulos et al. 2003]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#VAD|VAD]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[http://annonc.oxfordjournals.org/content/18/8/1369.long Zervas et al. 2007]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|TVAD-Doxil
 
−
|style="background-color:#fc8d59"|Seems to have inferior OS
 
−
|-
 
−
|}
 
−
'''''Dimopoulos et al. 2003''' was open to all patients with previously untreated multiple myeloma who were considered candidates for systemic treatment. '''Zervas et al. 2007''' was open to patients aged 18 to 75 years old with previously untreated symptomatic MM and a life expectancy of greater than 6 months.''
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
 
−
*[[Pegylated liposomal doxorubicin (Doxil)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
**Cycles 2 & 4: 40 mg PO once per day on days 1 to 4
 
−
 
 
−
====Supportive medications====
 
−
*In the cited Segeren et al. 1999 VAD protocol reference:
 
−
*[[Fluconazole (Diflucan)]] 200 mg PO once per day
 
−
*[[Trimethoprim/Sulfamethoxazole (Bactrim DS)|Trimethoprim/Sulfamethoxazole]] 960 mg (paper did not specify which component was 960 mg) PO BID for "prophylaxis"
 
−
 
 
−
'''28-day cycle for 4 cycles'''
 
−
 
 
−
===Variant #3, limited duration (6 to 8 cycles) {{#subobject:121c56|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.10946/full Hussein et al. 2002]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Pegylated liposomal doxorubicin (Doxil)]] 40 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO/IV once per day on days 1 to 4
 
−
 
 
−
====Supportive medications====
 
−
*Vitamin B6 200 mg PO once per day to help reduce risk of palmar-plantar erythrodysesthesia (PPE)
 
−
 
 
−
'''28-day cycle for 6 to 8 cycles'''
 
−
 
 
−
===References===
 
−
# Hussein MA, Wood L, Hsi E, Srkalovic G, Karam M, Elson P, Bukowski RM. A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients. Cancer. 2002 Nov 15;95(10):2160-8. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.10946/full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12412170 PubMed]
 
−
# Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A, Katodritou I, Kokkini G, Terpos E, Vyniou N, Tzilianos M, Chatzivassili A, Kyrtsonis MC, Panayiotidis P, Maniatis A; Greek Myeloma Study Group. Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol. 2003 Jul;14(7):1039-44. [http://annonc.oxfordjournals.org/content/14/7/1039.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12853344 PubMed]
 
−
# Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA. Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III multicenter randomized trial. Cancer. 2006 Feb 15;106(4):848-58. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.21662/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16404741 PubMed]
 
−
# Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E, Zikos P, Maniatis A, Dimopoulos MA; Greek Myeloma Study Group. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Ann Oncol. 2007 Aug;18(8):1369-75. [http://annonc.oxfordjournals.org/content/18/8/1369.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17693650 PubMed]
 
−
 
 
−
==VAD-P {{#subobject:9671a6|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VAD-P: '''<u>Vi</u>'''ncristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone, '''<u>P</u>'''rednisone
 
−
 
 
−
===Regimen {{#subobject:1e6b59|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/99/9/3163.long Berenson et al. 2002 (SWOG 9210)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#VAD-P.2FQ|VAD-P/Q]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 0.4 mg/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1.6 mg)
 
−
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 36 mg/m<sup>2</sup>)
 
−
**Poor-risk patients received 6.75 mg/m<sup>2</sup>/day in cycle 1 (total dose 27 mg/m<sup>2</sup>), with increase to full dose starting cycle 2 if no undue toxicity
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 50 mg PO once per day on days 9, 11, 13, 15, 17, 19
 
−
 
 
−
'''21-day cycles for at least 6 months or until at least 25% regression of disease'''
 
−
 
 
−
''Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy were randomized to low-dose prednisone versus [[Multiple_myeloma_-_historical#Prednisone_monotherapy||high-dose prednisone]] maintenance.''
 
−
 
 
−
===References===
 
−
# Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, Barlogie B, Salmon SE. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood. 2002 May 1;99(9):3163-8. [http://www.bloodjournal.org/content/99/9/3163.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11964279 PubMed]
 
−
 
 
−
==VAD-P/Q {{#subobject:5a391a|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VAD-P/Q: '''<u>Vi</u>'''ncristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone, '''<u>P</u>'''rednisone, '''<u>Q</u>'''uinine
 
−
 
 
−
===Regimen {{#subobject:9bebf1|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/99/9/3163.long Berenson et al. 2002 (SWOG 9210)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VAD-P|VAD-P]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 0.4 mg/day IV continuous infusion over 4 days on days 2 to 5 (total dose per cycle: 1.6 mg)
 
−
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 2 to 5 (total dose per cycle: 36 mg/m<sup>2</sup>)
 
−
**Poor-risk patients received 6.75 mg/m<sup>2</sup>/day in cycle 1 (total dose 27 mg/m<sup>2</sup>), with increase to full dose starting cycle 2 if no undue toxicity
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 2 to 5
 
−
*[[Prednisone (Sterapred)]] 50 mg PO once per day on days 10, 12, 14, 16, 18, 20
 
−
*[[Quinine (Qualaquin)]] 400 mg PO TID on days 1 to 6
 
−
 
 
−
'''21-day cycle for at least 6 months or until at least 25% regression of disease'''
 
−
====Subsequent treatment====
 
−
*Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy: low-dose prednisone versus [[Multiple_myeloma_-_historical#Prednisone_monotherapy|high-dose prednisone]] maintenance
 
−
 
 
−
===References===
 
−
# Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, Barlogie B, Salmon SE. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood. 2002 May 1;99(9):3163-8. [http://www.bloodjournal.org/content/99/9/3163.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11964279 PubMed]
 
−
 
 
−
==VDC {{#subobject:f725ee|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide
 
−
<br>VDC-mod: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide ('''<u>mod</u>'''ified dose)
 
−
<br>VCD: '''<u>V</u>'''elcade (Bortezomib), '''<u>C</u>'''yclophosphamide, '''<u>D</u>'''examethasone
 
−
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone
 
−
 
 
−
===Variant #1 {{#subobject:eed411|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/21/2569.long Moreau et al. 2016 (IFM 2013-04)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VTD|VTD]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior ORR rate
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours).''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> PO once per day on days 1, 8, 15
 
−
*[[Dexamethasone (Decadron)]] 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
 
−
 
 
−
'''21-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*Autologous hematopoietic cell transplant, with choice of conditioning regimen, whether to perform tandem transplant, and whether to give maintenance at the discretion of the treating center
 
−
 
 
−
===Variant #2, "VCD" {{#subobject:5f53d0|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.nature.com/leu/journal/v29/n8/full/leu201580a.html Mai et al. 2015 (GMMG-MM5)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#PAD|PAd]]
 
−
|style="background-color:#eeee01"|Non-inferior VGPR or better rate
 
−
|-
 
−
|}
 
−
 
 
−
''This regimen was intended for patients 18 to 70 years of age with newly diagnosed MM who required systemic chemotherapy based on the CRAB criteria. Note that the bortezomib route was changed from IV to SC with a mid-protocol amendment.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Cyclophosphamide (Cytoxan)]] 900 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
====Supportive medications====
 
−
*[[Trimethoprim/Sulfamethoxazole_(Bactrim_DS)|Cotrimoxazole]] (dose not specified)
 
−
*[[Acyclovir (Zovirax)]] (dose not specified)
 
−
*[[:Category:Bisphosphonates|Bisphosphonate]] IV every 4 weeks
 
−
 
 
−
'''21-day cycle for 3 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic cell transplant]]
 
−
 
 
−
===Variant #3, "VDC" {{#subobject:c78302|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://www.bloodjournal.org/content/119/19/4375.long Kumar et al. 2012 (EVOLUTION)]
 
−
|rowspan=2 style="background-color:#1a9851"|Randomized Phase II (C)
 
−
|[[#RVD|VDR]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[[#RVDC|VDCR]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
 
 
−
''This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a [[#Karnofsky_performance_scale|Karnofsky Performance Status]] greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation. The only difference between this regimen and VDC-mod is the number of cyclophosphamide doses.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15
 
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 325 mg PO once per day
 
−
**[[Warfarin (Coumadin)]] or [[Enoxaparin (Lovenox)]] could be used based on physician discretion
 
−
*[[:Category:PCP_prophylaxis|PCP prophylaxis]] recommended
 
−
*[[Acyclovir (Zovirax)]] prophylaxis for Herpes zoster recommended
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] could be used "as necessary"
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Bortezomib_monotherapy|Bortezomib consolidation]]
 
−
 
 
−
===Variant #4, "VDC-mod" {{#subobject:a29211|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=3|[http://www.bloodjournal.org/content/119/19/4375.long Kumar et al. 2012 (EVOLUTION)]
 
−
|rowspan=3 style="background-color:#91cf61"|Randomized Phase II, less than 20 in this arm (C)
 
−
|[[#RVD|VDR]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[[#RVDC|VDCR]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a [[#Karnofsky_performance_scale|Karnofsky Performance Status]] greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation. This arm only had 17 patients enrolled; other arms of the EVOLUTION trial all had greater than 20 patients enrolled. The only difference between this and regimen #1 is the number of cyclophosphamide doses.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15
 
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 325 mg PO once per day
 
−
**[[Warfarin (Coumadin)]] or [[Enoxaparin (Lovenox)]] could be used instead, based on physician discretion
 
−
*[[:Category:PCP_prophylaxis|PCP prophylaxis]] recommended
 
−
*[[Acyclovir (Zovirax)]] prophylaxis for Herpes zoster recommended
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] could be used "as necessary"
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Bortezomib_monotherapy|Bortezomib consolidation]]
 
−
 
 
−
===Variant #5, "CyBorD", once per week bortezomib {{#subobject:d82b2d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/115/16/3416.long Reeder et al. 2010]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''This regimen was described in a letter to the editor of Blood.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22
 
−
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
**Cycles 3 & 4: 40 mg PO once per week
 
−
 
 
−
'''28-day cycle for 4 cycles'''
 
−
 
 
−
===Variant #6, "CyBorD" {{#subobject:3f805b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711213/ Reeder et al. 2009]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Proton pump inhibitors|Proton pump inhibitor (PPI)]]
 
−
*[[Acyclovir (Zovirax)]]
 
−
*[[:Category:Fluoroquinolone|Quinolone antibiotic]]
 
−
*Antifungal mouthwash recommended
 
−
 
 
−
'''28-day cycle for 4 to 12 cycles'''
 
−
 
 
−
===References===
 
−
# Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, Noble B, Pirooz NA, Spong JE, Piza JG, Zepeda VH, Mikhael JR, Leis JF, Bergsagel PL, Fonseca R, Stewart AK. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009 Jul;23(7):1337-41. Epub 2009 Feb 19. [https://www.nature.com/leu/journal/v23/n7/full/leu200926a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711213/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19225538 PubMed]
 
−
# Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Laumann K, Hentz J, Pirooz NA, Piza JG, Tiedemann R, Mikhael JR, Bergsagel PL, Leis JF, Fonseca R, Stewart AK. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010 Apr 22;115(16):3416-7. [http://www.bloodjournal.org/content/115/16/3416.long link to original letter] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20413666 PubMed]
 
−
<!-- Presented in abstract form at the 51st American Society of Hematology (ASH) annual meeting, New Orleans, LA, December 7, 2009; the 52nd ASH annual meeting, Orlando, FL, December 6, 2010; and the 13th International Myeloma Workshop, Paris, France, May 5, 2011.-->
 
−
# Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22422823 PubMed]
 
−
# '''Meta-Analysis:''' Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24861981 PubMed]
 
−
# '''GMMG-MM5:''' Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. [https://www.nature.com/leu/journal/v29/n8/full/leu201580a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25787915 PubMed]
 
−
# Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. Epub 2016 Mar 21. [http://www.bloodjournal.org/content/127/21/2569.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27002117 PubMed]
 
−
 
 
−
==VMP {{#subobject:c029ec|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VMP: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone
 
−
<br>MPV: '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>V</u>'''elcade (Bortezomib)
 
−
===Variant #1, 4 cycles {{#subobject:916d56|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/108/7/2165.long Mateos et al. 2006]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
''Note: this was the phase II portion of this phase I/II study.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
'''42-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#VMP_2|VMP consolidation]]
 
−
 
 
−
===Variant #2, 6 cycles, bi-weekly bortezomib {{#subobject:64da89|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bbmt.org/article/S1083-8791(09)00398-X/abstract Gasparetto et al. 2009]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Melphalan (Alkeran)]] 6 mg/m<sup>2</sup> PO once per day on days 1 to 7, '''given at least 1 hour prior to bortezomib'''
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 7
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] recommended
 
−
*[[Acyclovir (Zovirax)]] (dose not specified) recommended
 
−
 
 
−
'''28-day cycle for up to 6 cycles'''; treatment could be given beyond 6 cycles at investigator discretion
 
−
 
 
−
===Variant #3, 6 cycles, bi-weekly bortezomib x 1, then weekly bortezomib x 5 {{#subobject:48440e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext Mateos et al. 2010 (GEM2005)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#VTP|VTP]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS (*)
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with untreated multiple myeloma, 65 years and older. Efficacy is based on the 2014 update.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Cycle 1: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
 
−
**Cycles 2 to 5: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
====Supportive medications====
 
−
*Patients with bone disease received [[:Category:Bisphosphonates|bisphosphonates]]
 
−
*Prophylactic [[Acyclovir (Zovirax)|aciclovir]] was recommended.
 
−
 
 
−
'''42-day cycle for 1 cycle, then 35-day cycle for 5 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#VP_2|VP]] versus [[#VT|VT]] maintenance
 
−
 
 
−
===Variant #4, 8 cycles {{#subobject:b06c6b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://jco.ascopubs.org/content/33/33/3921.long Niesvizky et al. 2015 (UPFRONT)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Bortezomib_.26_Dexamethasone|VD]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[[#VTD|VTD]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''This regimen was meant for transplant ineligible patients.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4 '''every other cycle'''
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4 '''every other cycle'''
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Bortezomib_monotherapy|Bortezomib consolidation]]
 
−
 
 
−
===Variant #5, 9 cycles, bi-weekly bortezomib x 1, then weekly bortezomib x 8 {{#subobject:9994d0|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1714678 Mateos et al. 2017 (ALCYONE)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#D-VMP|D-VMP]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with newly diagnosed, documented multiple myeloma who were not eligible for high-dose chemotherapy with stem-cell transplantation owing to coexisting conditions or an age of 65 years or older.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Cycle 1: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
 
−
**Cycles 2 to 9: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 22, 29
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
'''42-day cycle for 9 cycles'''
 
−
 
 
−
===Variant #6, 9 cycles, bi-weekly bortezomib x 4, then weekly bortezomib x 5 {{#subobject:5c31d4|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa0801479 San Miguel et al. 2008 (VISTA)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#MP|MP]]
 
−
|style="background-color:#1a9850"|Superior OS
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/34/5101.long Palumbo et al. 2010]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#VMPT|VMPT-VT]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior OS
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123433/ San-Miguel et al. 2014]
 
−
|style="background-color:#1a9851"|Randomized Phase II (C)
 
−
|VMP & Siltuximab
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''In '''Palumbo et al. 2010''' and '''VISTA''' this regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting conditions.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Cycles 1 to 4: 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32
 
−
**Cycles 5 to 9: 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 22, 29
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] given to patients with myeloma-associated bone disease unless contraindicated (only mentioned in San Miguel et al. 2008)
 
−
 
 
−
'''42-day cycle for 9 cycles'''
 
−
 
 
−
===Variant #7, 9 cycles, weekly bortezomib {{#subobject:2eb356|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/34/5101.long Palumbo et al. 2010]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#VMPT|VMPT-VT]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior OS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting conditions. This dosing is the result of a mid-protocol amendment.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
'''35-day cycle for 9 cycles'''
 
−
 
 
−
===References===
 
−
# Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Díaz-Mediavilla J, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, de Arriba F, Alegre A, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006 Oct 1;108(7):2165-72. Epub 2006 Jun 13. [http://www.bloodjournal.org/content/108/7/2165.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16772605 PubMed]
 
−
## '''Update:''' Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Garcia-Sanchez P, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, Alegre A, de Arriba F, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica. 2008 Apr;93(4):560-5. Epub 2008 Mar 5. [http://www.haematologica.org/content/93/4/560.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18322252 PubMed]
 
−
# San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG; VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-17. [http://www.nejm.org/doi/full/10.1056/NEJMoa0801479 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18753647 PubMed]
 
−
## '''Update:''' Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Esseltine DL, Liu K, Cakana A, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010 May 1;28(13):2259-66. Epub 2010 Apr 5. [http://jco.ascopubs.org/content/28/13/2259.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20368561 PubMed]
 
−
## '''Update:''' San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Delforge M, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Deraedt W, Cakana A, van de Velde H, Richardson PG. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013 Feb 1;31(4):448-55. Epub 2012 Dec 10. [http://jco.ascopubs.org/content/31/4/448.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23233713 PubMed]
 
−
# Gasparetto C, Gockerman JP, Diehl LF, de Castro CM, Moore JO, Long GD, Horwitz ME, Keogh G, Chute JP, Sullivan KM, Neuwirth R, Davis PH, Sutton LM, Anderson RD, Chao NJ, Rizzieri D. "Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma. Biol Blood Marrow Transplant. 2010 Jan;16(1):70-7. Epub 2009 Sep 3. [http://www.bbmt.org/article/S1083-8791(09)00398-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19733251 PubMed]
 
−
# Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739218 PubMed]
 
−
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. [http://www.bloodjournal.org/content/120/13/2581 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22889759 PubMed]
 
−
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. [http://www.bloodjournal.org/content/124/12/1887 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25102853 PubMed]
 
−
# Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. [http://jco.ascopubs.org/content/28/34/5101.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20940200 PubMed]
 
−
## '''Post-hoc analysis:''' Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. [http://www.bloodjournal.org/content/116/23/4745.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20807892 PubMed]
 
−
## '''Subset analysis:''' Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. [http://www.bloodjournal.org/content/118/22/5759.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21951682 PubMed]
 
−
## '''Update:''' Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: Updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. [http://jco.ascopubs.org/content/32/7/634.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24449241 PubMed]
 
−
# San-Miguel J, Bladé J, Shpilberg O, Grosicki S, Maloisel F, Min CK, Polo Zarzuela M, Robak T, Prasad SV, Tee Goh Y, Laubach J, Spencer A, Mateos MV, Palumbo A, Puchalski T, Reddy M, Uhlar C, Qin X, van de Velde H, Xie H, Orlowski RZ. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood. 2014 Jun 26;123(26):4136-42. Epub 2014 May 15. Erratum in: Blood. 2014 Aug 14;124(7):1201. [http://www.bloodjournal.org/content/123/26/4136.long link to original article] '''refers to protocol in [http://www.nejm.org/doi/full/10.1056/NEJMoa0801479 San Miguel et al. 2008]''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123433/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24833354 PubMed]
 
−
<!-- Presented at the 53rd American Society of Hematology (ASH) Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011; and the 55th ASH Annual Meeting and Exposition, New Orleans, LA, December 7-10, 2013. -->
 
−
# '''UPFRONT:''' Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. [http://jco.ascopubs.org/content/33/33/3921.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26056177 PubMed]
 
−
# '''ALCYONE:''' Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. [http://www.nejm.org/doi/full/10.1056/NEJMoa1714678 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231133 PubMed]
 
−
 
 
−
==VMP, then Rd {{#subobject:adb844|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VMP, then Rd: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, followed by '''<u>R</u>'''evlimid (Lenalidomide), low dose '''<u>d</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:9bda27|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/4/420.long Mateos et al. 2015 (PETHEMA GEM05)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VMP.2FRd|VMP/Rd]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients aged greater than or equal to 65 years with newly diagnosed, untreated, symptomatic, measurable MM.''
 
−
 
 
−
====Chemotherapy, VMP portion, first cycle====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
'''42-day cycle for 1 cycle, then:'''
 
−
 
 
−
====Chemotherapy, VMP portion, remainder====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per week on days 1, 8, 15, 22
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
'''28-day cycle for 8 cycles, followed by:'''
 
−
 
 
−
====Chemotherapy, Rd portion====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle for 9 cycles'''
 
−
 
 
−
====Supportive medications====
 
−
*During [[Bortezomib (Velcade)|bortezomib]] therapy:
 
−
**[[:Category:Bisphosphonates|Bisphosphonates]]
 
−
**[[:Category:Antivirals |Prophylactic antiviral therapy]]
 
−
*During [[Lenalidomide (Revlimid)|lenalidomide]] therapy:
 
−
**Mandatory thromboprophylaxis with either [[Aspirin]] or [[:Category:Low_molecular_weight_heparins |low–molecular weight heparin]]
 
−
 
 
−
===References===
 
−
# '''PETHEMA GEM05:''' Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016 Jan 28;127(4):420-5. Epub 2015 Oct 23. [http://www.bloodjournal.org/content/127/4/420.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26500339 PubMed]
 
−
 
 
−
==VMP/Rd {{#subobject:765398|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VMP/Rd: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone alternating with '''<u>R</u>'''evlimid (Lenalidomide), low dose '''<u>d</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:fd772b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/4/420.long Mateos et al. 2015 (PETHEMA GEM05)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VMP.2C_then_Rd|VMP, then Rd]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients aged greater than or equal to 65 years with newly diagnosed, untreated, symptomatic, measurable MM.''
 
−
 
 
−
====Chemotherapy, VMP portion, first cycle====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
'''42-day cycle for 1 cycle, then Rd cycle #1:'''
 
−
 
 
−
====Chemotherapy, VMP portion, remaining cycles====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per week on days 1, 8, 15, 22
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
'''28-day cycle for 8 cycles, alternating with Rd:'''
 
−
 
 
−
====Chemotherapy, Rd portion====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle alternating with VMP x 9 cycles'''
 
−
 
 
−
====Supportive medications====
 
−
*During [[Bortezomib (Velcade)|bortezomib]] therapy:
 
−
**[[:Category:Bisphosphonates|Bisphosphonates]]
 
−
**[[:Category:Antivirals |Prophylactic antiviral therapy]]
 
−
*During [[Lenalidomide (Revlimid)|lenalidomide]] therapy:
 
−
**Mandatory thromboprophylaxis with either [[Aspirin]] or [[:Category:Low_molecular_weight_heparins |low–molecular weight heparin]]
 
−
 
 
−
===References===
 
−
# Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016 Jan 28;127(4):420-5. Epub 2015 Oct 23. [http://www.bloodjournal.org/content/127/4/420.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26500339 PubMed]
 
−
 
 
−
==VMPT {{#subobject:6b6370|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VMPT: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>T</u>'''halidomide
 
−
 
 
−
===Variant #1 {{#subobject:cb90b1|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/34/5101.long Palumbo et al. 2010]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VMP|VMP]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with newly diagnosed myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Cycles 1 to 4: 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32
 
−
**Cycles 5 to 9: 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 22, 29
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day on days 1 to 42
 
−
 
 
−
'''42-day cycle for 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#VT|VT maintenance]]
 
−
 
 
−
===Variant #2 {{#subobject:5cdd9|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/34/5101.long Palumbo et al. 2010]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VMP|VMP]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|}
 
−
 
 
−
''This regimen was intended for patients with newly diagnosed myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant represents a mid-protocol change (in 2007) where cycle length was decreased from 6 to 5 weeks and bortezomib was changed to weekly dosing.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day on days 1 to 42
 
−
 
 
−
'''35-day cycle for 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#VT|VT maintenance]]
 
−
 
 
−
===References===
 
−
# Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. [http://jco.ascopubs.org/content/28/34/5101.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20940200 PubMed]
 
−
## '''Post-hoc analysis:''' Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. [http://www.bloodjournal.org/content/116/23/4745.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20807892 PubMed]
 
−
## '''Subset analysis:''' Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. [http://www.bloodjournal.org/content/118/22/5759.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21951682 PubMed]
 
−
## '''Update:''' Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. [http://jco.ascopubs.org/content/32/7/634.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24449241 PubMed]
 
−
 
 
−
==VTD {{#subobject:dbab97|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VTD: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
−
<br>vTD: low-dose '''<u>v</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
−
 
 
−
===Variant #1 {{#subobject:eed411|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/21/2569.long Moreau et al. 2016 (IFM 2013-04)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VDC|VCD]]
 
−
|style="background-color:#91cf60"|Seems to have superior ORR rate
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours).''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
 
−
 
 
−
'''21-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*Autologous hematopoietic cell transplant, with choice of conditioning regimen, whether to perform tandem transplant, and whether to give maintenance at the discretion of the treating center
 
−
 
 
−
===Variant #2 {{#subobject:b082c7|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://jco.ascopubs.org/content/33/33/3921.long Niesvizky et al. 2015 (UPFRONT)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Bortezomib_.26_Dexamethasone|VD]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[[#VMP|VMP]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
 
 
−
''This regimen was intended for patients with newly diagnosed, symptomatic, measurable MM requiring systemic therapy, and who were ineligible for stem-cell transplantation because of age (greater than or equal to 65 years), comorbidities, or personal preference.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
**Cycles 5 to 8: 20 mg PO once per day on days 1, 2, 4, 5
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Bortezomib_monotherapy|Bortezomib consolidation]]
 
−
 
 
−
===Variant #3 {{#subobject:6f69a9|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/31/2/247.long Ludwig et al. 2013]
 
−
|style="background-color:#1a9851"|Randomized Phase II (C)
 
−
|VTDC
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients aged 18 to 70 years with previously untreated, measurable MM requiring systemic therapy, who were candidates for high-dose chemotherapy and autologous hematopoietic cell transplant.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12
 
−
 
 
−
'''21-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*Patients who remained eligible for transplant: [[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic cell transplant]]
 
−
*Transplant ineligible patients or patients achieving CR could undergo 4 additional cycles of VTD
 
−
 
 
−
===Variant #4 {{#subobject:18f973|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[http://www.bloodjournal.org/content/120/8/1589.long Rosiñol et al. 2012 (PETHEMA GEM05MENOS65)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Thal-Dex|TD]]
 
−
|style="background-color:#91cf60"|Seems to have superior PFS
 
−
|-
 
−
|VBMCP/VBAD/B
 
−
|style="background-color:#91cf60"|Seems to have superior PFS
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with newly diagnosed and untreated symptomatic MM who were 65 years of age or younger with measurable serum and/or urine M protein.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] as follows:
 
−
**Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
 
−
**Cycles 2 to 6: 200 mg PO once per day on days 1 to 28
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Low_molecular_weight_heparins|Low molecular weight heparin (LMWH)]] or [[Aspirin]] recommended
 
−
 
 
−
'''28-day cycle for 6 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan autologous hematopoietic cell transplant]]
 
−
 
 
−
===Variant #5, "vTD" {{#subobject:788138|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/118/22/5752.full Moreau et al. 2011 (IFM 2007-02)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Bortezomib_.26_Dexamethasone|VD]]
 
−
|style="background-color:#1a9850"|Superior VGPR rate
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ Lok et al. 2014]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|}
 
−
'''''IFM 2007-02''' was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours). '''Lok et al. 2014''' uses the same dosing except that bortezomib is given SC.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV/SC once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 & 2: 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
 
−
**Cycles 3 & 4: 40 mg (route not specified) once per day on days 1 to 4
 
−
 
 
−
'''21-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic cell transplant]]
 
−
 
 
−
===Variant #6 {{#subobject:ac1b9a|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961424-9/fulltext Cavo et al. 2010 (GIMEMA MM-BO2005)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Thal-Dex|TD]]
 
−
|style="background-color:#1a9850"|Superior CR/nCR rate
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma.''
 
−
 
 
−
====Chemotherapy, induction therapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] as follows:
 
−
**Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to 21
 
−
**Cycles 2 & 3: 200 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
'''21-day cycle for 3 cycles, then proceed to first stem cell transplant'''
 
−
 
 
−
====Chemotherapy, first stem cell transplant====
 
−
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> once on day -2
 
−
*autologous hematopoietic cell rescue
 
−
 
 
−
'''Wait until count recovery, then proceed to thalidomide & dexamethasone therapy'''
 
−
 
 
−
====Chemotherapy, thalidomide & dexamethasone therapy====
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
 
−
 
 
−
'''28-day cycle for 3 to 6 months, then proceed to second stem cell transplant'''
 
−
 
 
−
====Chemotherapy, second stem cell transplant====
 
−
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> once on day -2
 
−
*autologous hematopoietic cell rescue
 
−
 
 
−
'''Wait until 3 months after second transplant, then proceed to bortezomib, thalidomide, dexamethasone therapy'''
 
−
 
 
−
====Chemotherapy, VTD therapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
 
−
 
 
−
'''35-day cycle for 2 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_2|Dexamethasone maintenance]]
 
−
 
 
−
====Supportive medications====
 
−
*[[Acyclovir (Zovirax)]] prophylaxis recommended
 
−
 
 
−
===Variant #7 {{#subobject:4901ec|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.25143/full Kaufman et al. 2010]
 
−
|style="background-color:#ffffbe"|Retrospective
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] prophylaxis to decrease risk of DVTs
 
−
*Prophylactic "treatment with antiviral and antibiotic medications"
 
−
 
 
−
'''21-day cycle for 3 to 4 cycles'''
 
−
 
 
−
===References===
 
−
# '''Retrospective:''' Kaufman JL, Nooka A, Vrana M, Gleason C, Heffner LT, Lonial S. Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma: a retrospective study. Cancer. 2010 Jul 1;116(13):3143-51. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25143/full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20564642 PubMed]
 
−
# Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961424-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21146205 PubMed]
 
−
## '''Update:''' Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. [http://www.bloodjournal.org/content/120/1/9.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22498745 PubMed]
 
−
# Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. [http://www.bloodjournal.org/content/118/22/5752.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21849487 PubMed]
 
−
# Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. [http://www.bloodjournal.org/content/120/8/1589.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22791289 PubMed]
 
−
<!-- Presented in part at the 51st Annual Meeting of the American Society of Hematology, New Orleans, LA, December 5-8, 2009, and the 50th Annual Meeting of the European Hematology Association, Barcelona, Spain, June 10-13, 2010. -->
 
−
# Ludwig H, Viterbo L, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Ricci D, Cakana A, Enny C, Feng H, van de Velde H, Harousseau JL. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol. 2013 Jan 10;31(2):247-55. Epub 2012 Oct 22. [http://jco.ascopubs.org/content/31/2/247.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23091109 PubMed]
 
−
## '''Update:''' Ludwig H, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Chaturvedi S, Ataman O, Enny C, Feng H, van de Velde H, Viterbo L. Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up. Br J Haematol. 2015 Nov;171(3):344-54. Epub 2015 Jul 7. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13582/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758383/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26153365 PubMed]
 
−
# Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous Bortezomib incorporated into the Bortezomib-Thalidomide-Dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. [http://www.haematologica.org/content/99/3/e33.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24532044 PubMed]
 
−
# '''Meta-Analysis:''' Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24861981 PubMed]
 
−
<!-- Presented at the 53rd American Society of Hematology (ASH) Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011; and the 55th ASH Annual Meeting and Exposition, New Orleans, LA, December 7-10, 2013. -->
 
−
# '''UPFRONT:''' Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. [http://jco.ascopubs.org/content/33/33/3921.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26056177 PubMed]
 
−
# '''IFM2013-04:''' Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. Epub 2016 Mar 21. [http://www.bloodjournal.org/content/127/21/2569.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27002117 PubMed]
 
−
 
 
−
==VTP {{#subobject:56d6fe|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VTP: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>P</u>'''rednisone
 
−
 
 
−
===Regimen {{#subobject:f707bc|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext Mateos et al. 2010 (GEM2005)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VMP|VMP]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior OS (*)
 
−
|-
 
−
|}
 
−
''This regimen was intended for patients with untreated multiple myeloma, 65 years and older. Efficacy is based on the 2014 update.''
 
−
====First cycle====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day on days 1 to 15, then 100 mg PO once per day on days 16 to 42
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
====Supportive medications====
 
−
*Patients with bone disease received [[:Category:Bisphosphonates|bisphosphonates]]
 
−
*Prophylactic [[Acyclovir (Zovirax)|aciclovir]] was recommended.
 
−
*Thromboprophylaxis with either [[Aspirin]] or [[:Category:Low_molecular_weight_heparins|low-molecular-weight heparin]]
 
−
 
 
−
'''42-day cycle for 1 cycle, then'''
 
−
 
 
−
====Remainder of induction====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
====Supportive medications====
 
−
*Patients with bone disease received [[:Category:Bisphosphonates|bisphosphonates]]
 
−
*Prophylactic [[Acyclovir (Zovirax)|aciclovir]] was recommended.
 
−
*Thromboprophylaxis with either [[Aspirin]] or [[:Category:Low_molecular_weight_heparins|low-molecular-weight heparin]]
 
−
 
 
−
'''35-day cycle for 5 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#VP_2|VP]] versus [[#VT|VT]] maintenance
 
−
 
 
−
===References===
 
−
# Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739218 PubMed]
 
−
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. [http://www.bloodjournal.org/content/120/13/2581 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22889759 PubMed]
 
−
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. [http://www.bloodjournal.org/content/124/12/1887 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25102853 PubMed]
 
−
 
 
−
==Zoledronic acid therapy {{#subobject:78cd0d|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:39fa9f|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ Morgan et al. 2010 (MRC Myeloma IX)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|Clodronic acid
 
−
| style="background-color:#91cf60" |Seems to have superior OS
 
−
|-
 
−
|}
 
−
''Note: this agent was not given as monotherapy, but is included separately from the regimens that it was given with, based on the RCT design.''
 
−
====Supportive medications====
 
−
*[[Zoledronic acid (Zometa)]] as follows:
 
−
**During induction: 4 mg IV over 15 minutes once every 3 to 4 weeks
 
−
**Consolidation onwards: 4 mg IV over 15 minutes once every 4 weeks
 
−
 
 
−
'''Continued indefinitely'''
 
−
===References===
 
−
# '''MRC Myeloma IX:''' Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62051-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21131037 PubMed]
 
−
 
 
−
=First-line therapy (including transplant ineligible), non-randomized or retrospective data=
 
−
''Note: most but not all multiple myeloma first-line regimens specify whether patients are transplant eligible, or not. We will begin to break this section in those respective subsections.''
 
−
 
 
−
==BBD {{#subobject:c09648|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
BBD: '''<u>B</u>'''endamustine, '''<u>B</u>'''ortezomib, '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:c9fe76|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.14536/abstract Berdeja et al. 2017]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bendamustine]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15
 
−
*[[Dexamethasone (Decadron)]] 20 mg (route not specified) once per day on days 1, 2, 8, 9, 15, 16
 
−
 
 
−
'''28-day cycle for up to 8 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Bortezomib_monotherapy_2|Bortezomib maintenance]]
 
−
 
 
−
===References===
 
−
# Berdeja JG, Bauer T, Arrowsmith E, Essell J, Murphy P, Reeves JA Jr, Boccia RV, Donnellan W, Flinn I. Phase II study of bendamustine, bortezomib and dexamethasone (BBD) in the first-line treatment of patients with multiple myeloma who are not candidates for high dose chemotherapy. Br J Haematol. 2017 Apr;177(2):254-262. Epub 2017 Feb 7. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14536/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28169430 PubMed]
 
−
 
 
−
==BiRD {{#subobject:4ea159|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
BiRD: '''<u>Bi</u>'''axin, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone
 
−
===Regimen {{#subobject:d718cd|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/111/3/1101.long Niesvizky et al. 2007]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Clarithromycin (Biaxin)]] as follows:
 
−
**Cycle 1: 500 mg PO BID on days 2 to 28
 
−
**Cycle 2 onwards: 500 mg PO BID on days 1 to 28
 
−
*[[Lenalidomide (Revlimid)]] as follows:
 
−
**Cycle 1: 25 mg PO once per day on days 3 to 21
 
−
**Cycle 2 onwards: 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycle 1: 40 mg PO once per day on days 1, 2, 3, 8, 15, 22
 
−
**Cycle 2 onwards: 40 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 81 mg PO once per day
 
−
*[[Omeprazole (Prilosec)]] 20 mg PO once per day
 
−
*[[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] PO BID, 3 times a week
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Niesvizky R, Jayabalan DS, Christos PJ, Furst JR, Naib T, Ely S, Jalbrzikowski J, Pearse RN, Zafar F, Pekle K, Larow A, Lent R, Mark T, Cho HJ, Shore T, Tepler J, Harpel J, Schuster MW, Mathew S, Leonard JP, Mazumdar M, Chen-Kiang S, Coleman M. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008 Feb 1;111(3):1101-9. Epub 2007 Nov 7. [http://www.bloodjournal.org/content/111/3/1101.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17989313 PubMed]
 
−
## '''Update:''' Rossi A, Mark T, Jayabalan D, Christos P, Zafar F, Pekle K, Pearse R, Chen-Kiang S, Coleman M, Niesvizky R. BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma. Blood. 2013 Mar 14;121(11):1982-1985. Epub 2013 Jan 8. [http://www.bloodjournal.org/content/121/11/1982.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596960/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23299315 PubMed]
 
−
# '''Retrospective:''' Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am J Hematol. 2010 Sep;85(9):664-9. [http://dx.doi.org/10.1002/ajh.21777 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956597/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20645430 PubMed]
 
−
 
 
−
==CCyd {{#subobject:a634d0|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CCyd: '''<u>C</u>'''arfilzomib, '''<u>Cy</u>'''clophosphamide, '''<u>d</u>'''examethasone
 
−
<br>KCyd: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>Cy</u>'''clophosphamide, '''<u>d</u>'''examethasone
 
−
===Variant #1, bi-weekly carfilzomib {{#subobject:c2c7b4|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/124/1/63 Bringhen et al. 2014 (IST-CAR-506)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1 & 2 then 36 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16
 
−
**Cycles 2 to 9: 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle for 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Carfilzomib_monotherapy|Carfilzomib maintenance]]
 
−
 
 
−
===Variant #2, weekly carfilzomib ("wKCyd") {{#subobject:148a16|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.nature.com/articles/leu2017327 Bringhen et al. 2017 (IST-CAR-561)]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
''Note: this is the MTD established for the phase II portion of the trial.''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] 70 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle for 9 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Carfilzomib_monotherapy|Carfilzomib maintenance]]
 
−
 
 
−
===References===
 
−
<!-- # '''Abstract:''' Palumbo, Antonio; Bringhen, Sara; Villani, Oreste; Siniscalchi, Agostina; Russo, Eleonora; Uccello, Giuseppina; Cerrato, Chiara; Gilestro, Milena; Rossi, Davide; Boccadoro, Mario. Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients. ASH Annual Meeting Abstracts 2012 120: 730 [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/730 link to abstract] -->
 
−
# '''IST-CAR-506:''' Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omedé P, Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3;124(1):63-9. Epub 2014 May 22. [http://www.bloodjournal.org/content/124/1/63 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24855212 PubMed]
 
−
# '''IST-CAR-561:''' Bringhen S, D'Agostino M, De Paoli L, Montefusco V, Liberati AM, Galieni P, Grammatico S, Muccio VE, Esma F, De Angelis C, Musto P, Ballanti S, Offidani M, Petrucci MT, Gaidano G, Corradini P, Palumbo A, Sonneveld P, Boccadoro M. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia. 2018 Apr;32(4):979-985. Epub 2017 Nov 16. [https://www.nature.com/articles/leu2017327 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29263440 PubMed]
 
−
 
 
−
==CMP {{#subobject:95301c|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CMP: '''<u>C</u>'''arfilzomib, '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone
 
−
 
 
−
===Regimen {{#subobject:f7a7ed|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/125/20/3100.long Moreau et al. 2015]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
''This trial was open to patients older than 65 years of age. Although not explicitly stated, this is considered to be a transplant ineligible population in France. The carfilzomib dose of 36 mg/m<sup>2</sup> was considered to be the MTD in this trial.''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1 & 2, then 36 mg/m<sup>2</sup> IV once per day on days 8, 9, 22, 23, 29, 30
 
−
**Cycles 2 to 9: 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 22, 23, 29, 30
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup>/day PO on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 4
 
−
 
 
−
'''42-day cycle for 9 cycles'''
 
−
 
 
−
===References===
 
−
<!-- Philippe Moreau, MD, PhD1*, Brigitte Kolb2*, Cyrille Hulin, MD3*, Denis Caillot, MD4*, Lotfi Benboubker, MD5*, Mourad Tiab, MD6*, Cyrille Touzeau, MD7*, Xavier Leleu, MD8, Murielle Roussel, MD9*, Carine Chaleteix, MD10*, Michel Attal9 and Thierry Facon, MD. Carfilzomib PLUS Melphalan and Prednisone (CMP) Is A Promising Combination Therapy For The Treatment Of Elderly Patients With NEWLY Diagnosed Multiple Myeloma: Results Of A PHASE I/II Trial In 68 CASES. ASH 2013 Abstract 1933. -->
 
−
# Moreau P, Kolb B, Attal M, Caillot D, Benboubker L, Tiab M, Touzeau C, Leleu X, Roussel M, Chaleteix C, Planche L, Chiffoleau A, Fortin J, Avet-Loiseau H, Mary JY, Hulin C, Facon T. Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma. Blood. 2015 May 14;125(20):3100-4. Epub 2015 Mar 17. [http://www.bloodjournal.org/content/125/20/3100.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25784682 PubMed]
 
−
 
 
−
==CRd (Carfilzomib) {{#subobject:d9be10|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CRd: '''<u>C</u>'''arfilzomib, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
<br>KRd: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
 
 
−
===Variant #1 {{#subobject:a2dc49|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://oncology.jamanetwork.com/article.aspx?articleid=2363017 Korde et al. 2016]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''The minimal difference between this and variant #2 below is the steroid dosing.''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1, 2, then 36 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16
 
−
**Cycles 2 to 8: 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycle 1: 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
 
−
**Cycles 2 to 4: 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
 
−
**Cycles 5 to 8: 10 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
 
−
 
 
−
'''28-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*Transplant eligible patients underwent stem cell collection after the 4th cycle but were not obligated to proceed to transplant.
 
−
*If transplant was not undertaken, patients proceeded to [[#Lenalidomide_monotherapy|lenalidomide extension]] after the 8th cycle
 
−
 
 
−
===Variant #2 {{#subobject:7401c8|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ Jakubowiak et al. 2012]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
 
 
−
''This is the MTD dosing in this phase I/II trial.''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1, 2, then 36 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16
 
−
**Cycles 2 to 8: 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 4: 40 mg (route not specified) once per week on days 1, 8, 15, 22
 
−
**Cycles 1 & 2 at clinician's discretion: 4 mg IV/PO once per day on days 2, 9, 16 (in addition to above)
 
−
**Cycles 5 to 8: 20 mg (route not specified) once per week on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*Transplant eligible patients underwent stem cell collection after the 4th cycle but were not obligated to proceed to transplant
 
−
*If transplant was not undertaken, patients proceeded to [[#CRd_.28Carfilzomib.29_2|CRd maintenance]] after the 8th cycle
 
−
 
 
−
===References===
 
−
# Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. [http://www.bloodjournal.org/content/120/9/1801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22665938 PubMed]
 
−
<!--
 
−
# '''Abstract:''' Korde, Neha; Zingone, Adriana; Kwok, Mary; Manasanch, Elisabet E.; Costello, Rene; Zuchlinski, Diamond; Mulquin, Marcia; Maric, Irina; Calvo, Katherine R; Braylan, Raul C.; Yuan, Constance; Tembhare, Prashant Ramesh; Stetler-Stevenson, Maryalice; Arthur, Diane C; Raffeld, Mark; Xi, Liqiang; Choyke, Peter; Kurdziel, Karen; Lindenberg, Liza; Steinberg, Seth M.; Roschewski, Mark; Landgren, Ola. Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone (CRd) in Newly Diagnosed Multiple Myeloma (MM) Patients ASH Annual Meeting Abstracts 2012 120: 732 [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/732 link to abstract] -->
 
−
# Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol. 2015 Sep;1(6):746-54. [http://oncology.jamanetwork.com/article.aspx?articleid=2363017 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26181891 PubMed]
 
−
 
 
−
==CRd (Cyclophosphamide) {{#subobject:fdc431|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|[[#top|back to top]]
 
−
|}
 
−
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:ccb917|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901994/ Kumar et al. 2011]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 325 mg PO once per day
 
−
*[[:Category:Low_molecular_weight_heparins|LMWH]] or [[Warfarin (Coumadin)]] for patients with history of thrombotic events or at "higher" risk
 
−
 
−
'''28-day cycle for 4 to 12 cycles'''
 
−
====Subsequent treatment====
 
−
*At physician discretion, patient could proceed to [[#Lenalidomide_monotherapy|lenalidomide maintenance]] +/- dexamethasone, after the 12th cycle, until progression
 
−
 
 
−
===References===
 
−
# Kumar SK, Lacy MQ, Hayman SR, Stewart K, Buadi FK, Allred J, Laumann K, Greipp PR, Lust JA, Gertz MA, Zeldenrust SR, Bergsagel PL, Reeder CB, Witzig TE, Fonseca R, Russell SJ, Mikhael JR, Dingli D, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol. 2011 Aug;86(8):640-5. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901994/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21630308 PubMed]
 
−
 
 
−
==CYKLONE {{#subobject:0c91d6|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|}
 
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CYKLONE: '''<u>C</u>'''yclophosphamide, '''<u>K</u>'''yprolis (Carfilzomib), Tha'''<u>L</u>'''lidomide, Dexamethas'''<u>ONE</u>'''
 
−
 
 
−
===Regimen {{#subobject:cf729e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521972/ Mikhael et al. 2015]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
 
 
−
''The carfilzomib dose here is the MTD dose, tested in N=29 patients. The authors state that patients could proceed to autologous hematopoietic cell transplant after four cycles but do not provide criteria to undergo transplant as opposed to continuing CYKLONE.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO on days 1, 8, 15
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
**Cycle 2 onwards: 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 28
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] or [[:Category:Low_molecular_weight_heparins|LMWH]] for patients intolerant of aspirin
 
−
*[[Acyclovir (Zovirax)]] 400 mg PO BID
 
−
*[[:Category:Antibacterials|Antibacterials]] (not further specified)
 
−
*250 to 500 ml of IVF prior to cycle 1 doses of [[Carfilzomib (Kyprolis)]] and then only for patients "at risk for tumor lysis syndrome" in subsequent cycles
 
−
 
 
−
'''28-day cycle for 4 to 12 cycles (see note)'''
 
−
===References===
 
−
# Mikhael JR, Reeder CB, Libby EN, Costa LJ, Bergsagel PL, Buadi F, Mayo A, Nagi Reddy SK, Gano K, Dueck AC, Stewart AK. Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol. 2015 Apr;169(2):219-27. Epub 2015 Feb 13. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13296/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521972/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25683772 PubMed]
 
−
 
 
−
==IRd {{#subobject:74c2a1|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|-
 
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|[[#top|back to top]]
 
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|}
 
−
IRd: '''<u>I</u>'''xazomib, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
===Regimen {{#subobject:6b49cb|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71125-8/abstract Kumar et al. 2014]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
 
 
−
''This is the MTD dose of this phase I/II trial.''
 
−
====Chemotherapy====
 
−
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle for up to 12 cycles'''
 
−
====Subsequent treatment====
 
−
*Transplant-eligible patients could proceed to [[#Melphalan.2C_then_auto_HSCT|autologous hematopoietic cell transplant]] after 6 cycles
 
−
*Patients who did not undergo transplant proceeded to [[#Ixazomib_monotherapy|ixazomib maintenance]] after the 12th cycle
 
−
 
 
−
===References===
 
−
<!-- Presented at ASH 2012 and ASH 2014, Abstract 82: Long-Term Ixazomib Maintenance Is Tolerable and Improves Depth of Response Following Ixazomib-Lenalidomide-Dexamethasone Induction in Patients (Pts) with Previously Untreated Multiple Myeloma (MM): Phase 2 Study Results -->
 
−
# Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71125-8/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25456369 PubMed]
 
−
 
 
−
==KTd {{#subobject:48ff6b|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
KTd: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>T</u>'''halidomide, '''<u>d</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:d87119|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ Sonneveld et al. 2014]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
 
 
−
''Three cohorts are reported; optimal dose of carfilzomib is not described.''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1 & 2, and:
 
−
**''Cohort 1:'' 27 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles
 
−
**''Cohort 2:'' 36 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles
 
−
**''Cohort 3:'' 45 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with stem cell rescue]]
 
−
 
 
−
===References===
 
−
<!-- # '''Abstract:''' Pieter Sonneveld, Emilie Asselberg-Hacker, Sonja Zweegman, Bronno van der Holt, Marie Jose Kersten, Edo Vellenga, Marinus van Marwijk Kooy, Okke de Weerdt, Sarah Lonergan, Antonio Palumbo, Henk Lokhorst. Dose Escalation Phase 2 Trial Of Carfilzomib Combined With Thalidomide and Low-Dose Dexamethason In Newly Diagnosed, Transplant Eligible Patients With Multiple Myeloma. A Trial Of The European Myeloma Network. Blood Nov 2013,122(21)688 [http://www.bloodjournal.org/content/122/21/688 link to abstract] -->
 
−
# Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. [http://www.bloodjournal.org/content/125/3/449 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25398935 PubMed]
 
−
 
 
−
==Lenalidomide & Prednisone {{#subobject:583b2a|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
RP: '''<u>R</u>'''evlimid (Lenalidomide) & '''<u>P</u>'''rednisone
 
−
===Regimen {{#subobject:9d35d3|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.nature.com/leu/journal/v27/n3/full/leu2012271a.html Falco et al. 2012]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''Note: this is a component of the sequential "RP-MPR-RP" protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Prednisone (Sterapred)]] 50 mg PO three times per week
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 100 mg PO once per day as thromboprophylaxis during [[Lenalidomide (Revlimid)]] treatment. Unclear from protocol if this also means off weeks.
 
−
*Antiviral prophylaxis if history of VZV.
 
−
 
 
−
'''28-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#MPR_2|MPR consolidation]]
 
−
 
 
−
===References===
 
−
# Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. [https://www.nature.com/leu/journal/v27/n3/full/leu2012271a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22996335 PubMed]
 
−
 
 
−
==PAD doxil {{#subobject:55d959|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
PAD doxil: '''<u>P</u>'''S-341 (Bortezomib), liposomal '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
 
−
<br>DVD: '''<u>D</u>'''oxil (Liposomal doxorubicin), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone
 
−
<br>VDD: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''oxil (Liposomal doxorubicin), '''<u>D</u>'''examethasone
 
−
===Variant #1 {{#subobject:57cebe|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08884.x/full Berenson et al. 2011]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Pegylated liposomal doxorubicin (Doxil)]] 5 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 40 mg IV once per day on days 1, 4, 8, 11
 
−
 
 
−
'''28-day cycle for up to 8 cycles'''
 
−
 
 
−
===Variant #2 {{#subobject:aaa1e3|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/5/800.long Palumbo et al. 2010]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Pegylated liposomal doxorubicin (Doxil)]] 30 mg/m<sup>2</sup> IV once on day 4
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
 
−
**Cycles 2 to 4: 40 mg PO once per day on days 1 to 4
 
−
 
 
−
====Supportive medications====
 
−
*[[Acyclovir (Zovirax)]] recommended during [[Bortezomib (Velcade)]] therapy
 
−
 
 
−
'''21-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem MEL-100, then auto HSCT]]
 
−
 
 
−
===Variant #3 {{#subobject:e38e22|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/27/30/5015.long Jakubowiak et al. 2009]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Pegylated liposomal doxorubicin (Doxil)]] 30 mg/m<sup>2</sup> IV once on day 4
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycle 1: 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
====Supportive medications====
 
−
*Low-molecular weight heparin 40 mg SC once per day or [[Aspirin]] 81 mg PO once per day for DVT prophylaxis
 
−
*[[Acyclovir (Zovirax)]] 400 mg PO BID for Herpes zoster prophylaxis
 
−
 
 
−
'''21-day cycle for 6 cycles'''
 
−
 
 
−
===References===
 
−
# Jakubowiak AJ, Kendall T, Al-Zoubi A, Khaled Y, Mineishi S, Ahmed A, Campagnaro E, Brozo C, Braun T, Talpaz M, Kaminski MS. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol. 2009 Oct 20;27(30):5015-22. Epub 2009 Sep 8. [http://jco.ascopubs.org/content/27/30/5015.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19738129 PubMed]
 
−
## '''Update:''' Dytfeld D, Griffith KA, Friedman J, Lebovic D, Harvey C, Kaminski MS, Jakubowiak AJ. Superior overall survival of patients with myeloma achieving very good partial response or better to initial treatment with bortezomib, pegylated liposomal doxorubicin, and dexamethasone, predicted after two cycles by a free light chain- and M-protein-based model: extended follow-up of a phase II trial. Leuk Lymphoma. 2011 Jul;52(7):1271-80. [https://www.tandfonline.com/doi/full/10.3109/10428194.2011.567316 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21699382 PubMed]
 
−
# Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. [http://jco.ascopubs.org/content/28/5/800.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20048187 PubMed]
 
−
## '''Update:''' Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. [http://www.bloodjournal.org/content/122/8/1376.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23775712 PubMed]
 
−
# Berenson JR, Yellin O, Chen CS, Patel R, Bessudo A, Boccia RV, Yang HH, Vescio R, Yung E, Mapes R, Eades B, Hilger JD, Wirtschafter E, Hilger J, Nassir Y, Swift RA. A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients. Br J Haematol. 2011 Dec;155(5):580-7. Epub 2011 Sep 26. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08884.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21950583 PubMed]
 
−
 
 
−
==Total Therapy {{#subobject:06fc58|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:1cd95c|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/89/3/789.long Barlogie et al. 1997 (Total Therapy)]
 
−
|style="background-color:#91cf61"|Prospective
 
−
|-
 
−
|[https://www.nejm.org/doi/10.1056/NEJMoa053583 Barlogie et al. 2006 (Total Therapy 2)]
 
−
| style="background-color:#1a9851" |Prospective with randomization
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06639.x/full Barlogie et al. 2007 (Total Therapy 3)]
 
−
|style="background-color:#91cf61"|Prospective
 
−
|-
 
−
|}
 
−
''Total Therapy is a very complicated regimen, you are highly recommended to refer to the original protocols for further details. Total Therapy 3 is replicated here; the references for Total Therapy 2 are provided below but there are no plans to add this regimen here, for now.''
 
−
 
 
−
====Induction therapy, VTD-PACE====
 
−
VTD-PACE: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone, '''<u>P</u>'''latinum (Cisplatin), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide
 
−
 
 
−
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day on days 4 to 7
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 4 to 7
 
−
*[[Cisplatin (Platinol)]] 10 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m<sup>2</sup>)
 
−
*[[Doxorubicin (Adriamycin)]] 10 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m<sup>2</sup>)
 
−
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 1600 mg/m<sup>2</sup>)
 
−
*[[Etoposide (Vepesid)]] 40 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 160 mg/m<sup>2</sup>)
 
−
*Peripheral blood stem cells (PBSC) are usually collected during cycle 1--cycle 2 PBSC collection is done if needed--with a median CD34 count of 29 x 10<sup>6</sup>/kg. 87% of collections yielded at least 20 x 10<sup>6</sup>/kg.
 
−
 
 
−
'''Duration of each cycle not specified; 2 cycles total are given, no more than 8 weeks apart'''
 
−
 
 
−
During the interim period between cycle 1 and cycle 2, as well as after cycle 2 and prior to transplant, this is given once platelets have recovered to at least 50 x 10<sup>9</sup>/L:
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day on days 1 to 21
 
−
 
 
−
'''21-day cycles, given between induction cycles and transplant'''
 
−
 
 
−
In other words, the initial therapy consists of: Induction therapy cycle 1, dexamethasone & thalidomide, induction therapy cycle 2, dexamethasone & thalidomide, then transplant.
 
−
 
 
−
====Supportive medications====
 
−
*As described in Barlogie et al. 2006, which Barlogie et al. 2007 refers to. Note: Barlogie et al. 2007 lists an incorrect title for the reference. See below for the the correct full reference.
 
−
*[[Filgrastim (Neupogen)]] "was administered to support induction and consolidation chemotherapy regimens"
 
−
*"Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed
 
−
*Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide
 
−
 
 
−
====Autologous hematopoietic cell transplant====
 
−
''Full details were not provided in Barlogie et al. 2007. Tandem autologous transplants were done between 2 to 6 months apart.
 
−
*[[Melphalan (Alkeran)]] 200 mg/m2
 
−
 
 
−
During the interim period after transplant 1 and transplant 2, patients receive:
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day on days 1 to 21
 
−
 
 
−
'''21-day cycles, given in the time between and after each transplant'''; if platelets less than 50 x 10<sup>9</sup>/L, proceed to year 1 of maintenance therapy. Otherwise, if platelets are at least 50 x 10<sup>9</sup>/L, proceed to consolidation therapy.
 
−
 
 
−
====Consolidation chemotherapy, VTD-PACE====
 
−
VTD-PACE: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone, '''<u>P</u>'''latinum (Cisplatin), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide
 
−
 
 
−
''Cycle 1 of consolidation starts 1.5 to 4 months after the last transplant. Cycle 2 of consolidation starts 2 to 4 months after cycle 1 of consolidation.''
 
−
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day on days 1 to 4
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
 
−
*[[Cisplatin (Platinol)]] 7.5 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 30 mg/m<sup>2</sup>)
 
−
*[[Doxorubicin (Adriamycin)]] 7.5 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 30 mg/m<sup>2</sup>)
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1200 mg/m<sup>2</sup>)
 
−
*[[Etoposide (Vepesid)]] 30 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 120 mg/m<sup>2</sup>)
 
−
 
 
−
'''2 cycles total are given according to the interval specified above, with the interim therapy below used'''
 
−
 
 
−
During the interim period between cycle 1 and cycle 2, as well as after cycle 2 and prior to maintenance therapy, this is given once platelets have recovered to at least 50 x 10<sup>9</sup>/L:
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21
 
−
 
 
−
'''21-day cycles, given between consolidation cycles and maintenance'''
 
−
 
 
−
In other words, consolidation therapy consists of: Consolidation therapy cycle 1, dexamethasone & thalidomide, consolidation therapy cycle 2, dexamethasone & thalidomide, then maintenance therapy.
 
−
 
 
−
====Supportive medications====
 
−
*As described in Barlogie et al. 2006, which Barlogie et al. 2007 refers to. Note: Barlogie et al. 2007 lists an incorrect title for the reference. See below for the the correct full reference.
 
−
*[[Filgrastim (Neupogen)]] "was administered to support induction and consolidation chemotherapy regimens"
 
−
*"Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed
 
−
*Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide
 
−
 
 
−
====Maintenance chemotherapy, year 1 - VTD====
 
−
VTD: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
−
 
 
−
''Year 1 of maintenance therapy starts 1 to 4 months after consolidation cycle 2.''
 
−
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 28
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 8 to 11
 
−
 
 
−
'''28-day cycle for 1 year''', then proceed to maintenance therapy years 2 to 3
 
−
 
 
−
====Maintenance chemotherapy, years 2 & 3 - TD====
 
−
TD: '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
−
 
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once every other day
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4
 
−
 
 
−
'''28-day cycle for 2 years'''
 
−
 
 
−
===References===
 
−
# '''Total Therapy:''' Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997 Feb 1;89(3):789-93. [http://www.bloodjournal.org/content/89/3/789.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9028309 PubMed]
 
−
## '''Update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834471/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20085933 PubMed]
 
−
# '''Total Therapy 2:''' Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, Fassas A, Zangari M, Hollmig K, Pineda-Roman M, Lee C, Talamo G, Thertulien R, Kiwan E, Krishna S, Fox M, Crowley J. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006 Mar 9;354(10):1021-30. [http://www.nejm.org/doi/full/10.1056/NEJMoa053583 link to original article] '''supportive medication details''' [https://www.ncbi.nlm.nih.gov/pubmed/16525139 PubMed]
 
−
## '''Update:''' Zangari M, van Rhee F, Anaissie E, Pineda-Roman M, Haessler J, Crowley J, Barlogie B. Eight-year median survival in multiple myeloma after total therapy 2: roles of thalidomide and consolidation chemotherapy in the context of Total Therapy 1. Br J Haematol. 2008 May;141(4):433-44. Epub 2008 Mar 26. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2008.06982.x/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649864/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18371114 PubMed]
 
−
## '''Subgroup analysis:''' Barlogie B, Pineda-Roman M, van Rhee F, Haessler J, Anaissie E, Hollmig K, Alsayed Y, Waheed S, Petty N, Epstein J, Shaughnessy JD Jr, Tricot G, Zangari M, Zeldis J, Barer S, Crowley J. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008 Oct 15;112(8):3115-21. Epub 2008 May 20. [http://www.bloodjournal.org/content/112/8/3115.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569166/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18492953 PubMed]
 
−
## '''Update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834471/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20085933 PubMed]
 
−
# '''Total Therapy 3:''' Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of Total Therapy 3. Br J Haematol. 2007 Jul;138(2):176-85. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06639.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17593024 PubMed]
 
−
## '''Update:''' Pineda-Roman M, Zangari M, Haessler J, Anaissie E, Tricot G, van Rhee F, Crowley J, Shaughnessy JD Jr, Barlogie B. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol. 2008 Mar;140(6):625-34. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06921.x/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655432/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18302711 PubMed]
 
−
## '''Update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834471/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20085933 PubMed]
 
−
 
 
−
==VP {{#subobject:8cd2dc|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VP: '''<u>V</u>'''elcade (Bortezomib) & '''<u>P</u>'''rednisone
 
−
 
 
−
===Regimen {{#subobject:19553c|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.nature.com/leu/journal/v30/n6/full/leu201636a.html Larocca et al. 2016]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''Note: doses and schedules were not specified in the abstract.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] SC
 
−
*[[Prednisone (Sterapred)]]
 
−
====Subsequent treatment====
 
−
*[[#Bortezomib_monotherapy_2|Bortezomib maintenance]]
 
−
 
 
−
===References===
 
−
# Larocca A, Bringhen S, Petrucci MT, Oliva S, Falcone AP, Caravita T, Villani O, Benevolo G, Liberati AM, Morabito F, Montefusco V, Passera R, De Rosa L, Omedé P, Vincelli ID, Spada S, Carella AM, Ponticelli E, Derudas D, Genuardi M, Guglielmelli T, Nozzoli C, Aghemo E, De Paoli L, Conticello C, Musolino C, Offidani M, Boccadoro M, Sonneveld P, Palumbo A. A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma. Leukemia. 2016 Jun;30(6):1320-6. [https://www.nature.com/leu/journal/v30/n6/full/leu201636a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26898189 PubMed]
 
−
 
 
−
==VTD-PACE {{#subobject:539ce9|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VTD-PACE: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone, '''<u>P</u>'''latinum (Cisplatin), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide
 
−
 
 
−
===Regimen {{#subobject:b0b58e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06639.x/full Barlogie et al. 2007 (Total Therapy 3)]
 
−
|style="background-color:#91cf61"|Prospective
 
−
|-
 
−
|}
 
−
 
 
−
''Note: this is the induction therapy used in Total Therapy 3. We are not aware of other sources prospectively describing VTD-PACE.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day on days 4 to 7
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 4 to 7
 
−
*[[Cisplatin (Platinol)]] 10 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m<sup>2</sup>)
 
−
*[[Doxorubicin (Adriamycin)]] 10 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m<sup>2</sup>)
 
−
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 1600 mg/m<sup>2</sup>)
 
−
*[[Etoposide (Vepesid)]] 40 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 160 mg/m<sup>2</sup>)
 
−
 
 
−
'''Duration of each cycle not specified; 2 cycles total are given, no more than 8 weeks apart'''
 
−
 
 
−
===References===
 
−
# Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007 Jul;138(2):176-85. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06639.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17593024 PubMed]
 
−
# '''Retrospective:''' '''Abstract:''' Preet Paul Singh, Wilson I. Gonsalves, Vinay Gupta, Francis Buadi, Martha Lacy, Angela Dispenzieri, Morie Gertz, Suzanne R. Hayman, David Dingli, Stephen J. Russell, John Anthony Lust, Steven R. Zeldenrust, Prashant Kapoor, Arleigh Robertson McCurdy, S. Vincent Rajkumar, Shaji Kumar. Clinical outcomes after intensive VDT-PACE therapy for relapsed multiple myeloma. J Clin Oncol 31, 2013 (suppl; abstr 8600) [http://meetinglibrary.asco.org/content/116010-132 link to abstract]
 
−
<section end=1st-line />
 
−
<section begin=1st-consol />
 
−
=Consolidation after first-line therapy=
 
−
''Note that there is no crisp distinction between consolidation and maintenance. Generally regimens that are intended for a long or indefinite duration would be considered maintenance, whereas regimens with a short intended course would be considered consolidation.''
 
−
 
 
−
==Bortezomib monotherapy {{#subobject:dd778e|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Variant #1 {{#subobject:66855e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674665/ Mellqvist et al. 2013 (NMSG 15/05)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Observation|Observation]]
 
−
|style="background-color:#d9ef8b"|Might have superior PFS
 
−
|-
 
−
|}
 
−
''This trial only included bortezomib-naive patients; induction regimen was not specified but the majority received Cy-Dex.''
 
−
====Preceding treatment====
 
−
*All patients underwent autologous hematopoietic cell transplant at least 3 months prior to starting consolidation.
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11 of a 21-day cycle
 
−
**Cycles 3 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15 of a 28-day cycle
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] were administered "according to national guidelines."
 
−
 
 
−
'''22-week course'''
 
−
 
 
−
===Variant #2, 4 out of 5 weeks for 6 months {{#subobject:9a4ece|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/33/33/3921.long Niesvizky et al. 2015 (UPFRONT)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Bortezomib_.26_Dexamethasone|VD]] x 8 versus [[#VMP|VMP]] x 8 versus [[#VTD|VTD]] x 8
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
 
 
−
'''35-day cycle for 5 cycles'''
 
−
 
 
−
===Variant #3, 4 out of 6 weeks for 6 months {{#subobject:e72a4c|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/119/19/4375.long Kumar et al. 2012 (EVOLUTION)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#VDC|VDC]] versus [[#VDC|VDC-mod]] versus [[#RVD|VDR]] versus [[#RVDC|VDCR]]
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 325 mg PO once per day
 
−
**[[Warfarin (Coumadin)]] or [[Enoxaparin (Lovenox)]] could be used based on physician discretion
 
−
*[[:Category:PCP_prophylaxis|PCP prophylaxis]] recommended
 
−
*[[Acyclovir (Zovirax)]] prophylaxis for Herpes zoster recommended
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] could be used "as necessary"
 
−
 
 
−
'''42-day cycle for 4 cycles'''
 
−
 
 
−
===References===
 
−
<!-- Presented in abstract form at the 51st American Society of Hematology (ASH) annual meeting, New Orleans, LA, December 7, 2009; the 52nd ASH annual meeting, Orlando, FL, December 6, 2010; and the 13th International Myeloma Workshop, Paris, France, May 5, 2011.-->
 
−
# '''EVOLUTION:''' Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22422823 PubMed]
 
−
# '''NMSG 15/05:''' Mellqvist UH, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, Steingrimsdottir H, Abildgaard N, Ahlberg L, Blimark C, Dahl IM, Forsberg K, Gedde-Dahl T, Gregersen H, Gruber A, Guldbrandsen N, Haukås E, Carlson K, Kvam AK, Nahi H, Lindås R, Andersen NF, Turesson I, Waage A, Westin J; Nordic Myeloma Study Group. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013 Jun 6;121(23):4647-54. Epub 2013 Apr 24. [http://www.bloodjournal.org/content/121/23/4647.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674665/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23616624 PubMed]
 
−
<!-- Presented at the 53rd American Society of Hematology (ASH) Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011; and the 55th ASH Annual Meeting and Exposition, New Orleans, LA, December 7-10, 2013. -->
 
−
# '''UPFRONT:''' Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. [http://jco.ascopubs.org/content/33/33/3921.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26056177 PubMed]
 
−
 
 
−
==Bortezomib & Melphalan, then auto HSCT {{#subobject:9c28bc|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
Bor-HDM: '''<u>Bor</u>'''tezomib, '''<u>H</u>'''igh '''<u>D</u>'''ose '''<u>M</u>'''elphalan
 
−
===Regimen {{#subobject:0bfd33|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/115/1/32.long Roussel et al. 2009]
 
−
| style="background-color:#91cf61" |Phase II
 
−
|-
 
−
|}
 
−
{{#lst:Autologous HSCT|0bfd33}}
 
−
===References===
 
−
# Roussel M, Moreau P, Huynh A, Mary JY, Danho C, Caillot D, Hulin C, Fruchart C, Marit G, Pégourié B, Lenain P, Araujo C, Kolb B, Randriamalala E, Royer B, Stoppa AM, Dib M, Dorvaux V, Garderet L, Mathiot C, Avet-Loiseau H, Harousseau JL, Attal M; Intergroupe Francophone du Myélome (IFM). Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM). Blood. 2010 Jan 7;115(1):32-7. Epub 2009 Nov 2. [http://www.bloodjournal.org/content/115/1/32.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19884643 PubMed]
 
−
 
 
−
==DCEP {{#subobject:431b08|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
DCEP: '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide, '''<u>P</u>'''latinol (Cisplatin)
 
−
 
 
−
===Regimen {{#subobject:bbd0bf|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/30/4621.long Harousseau et al. 2010 (IFM 2005-01)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|No DCEP
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Bortezomib_.26_Dexamethasone|VD]] x 4 versus [[Multiple_myeloma_-_historical#VAD|VAD]] x 4
 
−
====Chemotherapy====
 
−
*[[Dexamethasone (Decadron)]] 40 mg once per day on days 1 to 4
 
−
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m<sup>2</sup>)
 
−
*[[Etoposide (Vepesid)]] 40 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m<sup>2</sup>)
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 60 mg/m<sup>2</sup>)
 
−
 
 
−
'''28-day cycle for 2 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic cell transplant]]
 
−
 
 
−
===References===
 
−
<!-- Presented at the 48th Annual Meeting of the American Society of Hematology (ASH), December 9-12, 2006, Orlando, FL; the 49th Annual Meeting of the ASH, December 8-11, 2007, Atlanta, GA; the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 30-June 3, 2008, Chicago, IL; and the 2008 Annual Meeting of the American Society of Hematology ASH/ASCO Joint Symposium, December 7, 2008, San Francisco, CA. -->
 
−
# '''IFM 2005-01:''' Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010 Oct 20;28(30):4621-9. Epub 2010 Sep 7. [http://jco.ascopubs.org/content/28/30/4621.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823406 PubMed]
 
−
 
 
−
==KTd {{#subobject:bc0c24|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
KTd: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>T</u>'''halidomide, '''<u>d</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:bc14c4|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ Sonneveld et al. 2014]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|high-dose melphalan with stem cell rescue]].''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**''Cohort 1:'' 27 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
**''Cohort 2:'' 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per week on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle for 4 cycles'''
 
−
 
 
−
===References===
 
−
<!-- # '''Abstract:''' Pieter Sonneveld, Emilie Asselberg-Hacker, Sonja Zweegman, Bronno van der Holt, Marie Jose Kersten, Edo Vellenga, Marinus van Marwijk Kooy, Okke de Weerdt, Sarah Lonergan, Antonio Palumbo, Henk Lokhorst. Dose Escalation Phase 2 Trial Of Carfilzomib Combined With Thalidomide and Low-Dose Dexamethason In Newly Diagnosed, Transplant Eligible Patients With Multiple Myeloma. A Trial Of The European Myeloma Network. Blood Nov 2013,122(21)688 [http://www.bloodjournal.org/content/122/21/688 link to abstract] -->
 
−
# Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. [http://www.bloodjournal.org/content/125/3/449 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25398935 PubMed]
 
−
 
 
−
==Lenalidomide & Prednisone {{#subobject:ceb412|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:7d2a7c|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/5/800.long Palumbo et al. 2010]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem MEL-100, then auto HSCT]]
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Prednisone (Sterapred)]] 50 mg PO once every other day
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 100 mg PO once per day during [[Lenalidomide (Revlimid)]] treatment
 
−
 
 
−
'''28-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]
 
−
 
 
−
===References===
 
−
# Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. [http://jco.ascopubs.org/content/28/5/800.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20048187 PubMed]
 
−
## '''Update:''' Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. [http://www.bloodjournal.org/content/122/8/1376.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23775712 PubMed]
 
−
 
 
−
==Melphalan, then auto HSCT {{#subobject:263542|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Synopsis===
 
−
To be completed. This section will give an overview of this commonly used regimen.
 
−
===Variant #1, 140 mg/m<sup>2</sup> {{#subobject:255748|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/67/5/1298 Barlogie et al. 1986]
 
−
| style="background-color:#ffffbe" |Non-randomized, <20 pts
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1
 
−
 
 
−
'''Stem cells re-infused on day 0'''
 
−
===Variant #2, 200 mg/m<sup>2</sup> {{#subobject:3d1bf6|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/99/3/731.long Moreau et al. 2002 (IFM 9502)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Melphalan_.2B_TBI.2C_then_auto_HSCT|Melphalan & TBI, then auto HSCT]]
 
−
|style="background-color:#d9ef8b"|Might have superior OS
 
−
|-
 
−
|[http://www.bloodjournal.org/content/106/12/3755 Bladé et al. 2005]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VBMCP.2FVBAD|VBMCP/VBAD]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[http://jco.ascopubs.org/content/25/17/2434.full Cavo et al. 2007 (Bologna 96)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[Multiple_myeloma_-_historical#Melphalan.2C_then_auto HSCT.2C_then_Melphalan_.26_Busulfan.2C_then_auto HSCT|Melphalan, then auto HSCT, then Melphalan & Busulfan, then auto HSCT]]
 
−
|style="background-color:#d73027"|Inferior EFS
 
−
|-
 
−
|[http://www.bloodjournal.org/content/115/6/1113 Lokhorst et al. 2009 (HOVON 50/GMMG-HD3)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://ascopubs.org/doi/full/10.1200/jco.2010.32.7312 Björkstrand et al. 2011 (EBMT-NMAM2000)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|MEL200, then auto HSCT, then RIC allo HSCT
 
−
| style="background-color:#fc8d59" |Seems to have inferior OS
 
−
|-
 
−
|[http://www.bloodjournal.org/content/118/22/5752.full Moreau et al. 2011 (IFM 2007-02)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://www.bloodjournal.org/content/119/1/7.long Morgan et al. 2011 (MRC Myeloma IX)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://www.bloodjournal.org/content/120/8/1589.long Rosiñol et al. 2012 (PETHEMA/GEM GEM05MENOS65)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (HOVON-65)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ Lok et al. 2014]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://jco.ascopubs.org/content/32/25/2712.full Roussel et al. 2014]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ Sonneveld et al. 2014]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.nature.com/leu/journal/v29/n8/full/leu201580a.html Mai et al. 2015 (GMMG-MM5)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13994/abstract Mai et al. 2016 (GMMG-HD2)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem melphalan, then auto HSCT]]
 
−
|style="background-color:#eeee01"|Non-inferior EFS
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1611750 Attal et al. 2017 (IFM 2009)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#RVD_2|RVD consolidation]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
''Treatment preceded by varying induction regimens:''
 
−
{| class="wikitable sortable" style="text-align: center"
 
−
!'''Trial'''
 
−
!'''Induction regimen'''
 
−
!'''# of cycles'''
 
−
|-
 
−
|'''IFM 9502
 
−
|[[Multiple_myeloma_-_historical#VAD|VAD]]
 
−
|3
 
−
|-
 
−
|'''Bladé et al. 2005
 
−
|[[Multiple_myeloma_-_historical#VBMCP.2FVBAD|VBMCP/VBAD]]
 
−
|4
 
−
|-
 
−
|'''Bologna 96
 
−
|[[Multiple_myeloma_-_historical#VAD|VAD]]
 
−
|4
 
−
|-
 
−
|rowspan=2|'''HOVON 50/GMMG-HD3
 
−
|[[#TAD|TAD]]
 
−
|3
 
−
|-
 
−
|[[Multiple_myeloma_-_historical#VAD|VAD]]
 
−
|3
 
−
|-
 
−
|rowspan=2|'''IFM2007-02
 
−
|[[#VTD|vtD]]
 
−
|4
 
−
|-
 
−
|[[#Bortezomib_.26_Dexamethasone|VD]]
 
−
|4
 
−
|-
 
−
|rowspan=2|'''MRC Myeloma IX
 
−
|[[#CTD|CTD]]
 
−
|4 to 6
 
−
|-
 
−
|[[#CVAD|CVAD]]
 
−
|4 to 6
 
−
|-
 
−
|rowspan=3|'''PETHEMA/GEM GEM05MENOS65
 
−
|[[#Thal-Dex|TD]]
 
−
|6
 
−
|-
 
−
|VBMCP/VBAD/B
 
−
|6
 
−
|-
 
−
|[[#VTD|VTD]]
 
−
|6
 
−
|-
 
−
|rowspan=2|'''HOVON-65
 
−
|[[#PAD|PAD]]
 
−
|3
 
−
|-
 
−
|[[Multiple_myeloma_-_historical#VAD|VAD]]
 
−
|3
 
−
|-
 
−
|'''Lok et al. 2014
 
−
|[[#VTD|vtD]]
 
−
|4
 
−
|-
 
−
|'''Roussel et al. 2014
 
−
|[[#RVD|RVD]]
 
−
|3
 
−
|-
 
−
|'''Sonneveld et al. 2014
 
−
|[[#KTd|KTd]]
 
−
|4
 
−
|-
 
−
|rowspan=2|'''GMMG-MM5
 
−
|[[#VDC|VCD]]
 
−
|3
 
−
|-
 
−
|[[#PAD|PAd]]
 
−
|3
 
−
|-
 
−
|'''IFM 2009
 
−
|[[#RVD|RVD]]
 
−
|3
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day -2
 
−
 
 
−
'''Stem cells re-infused on day 0'''
 
−
====Subsequent treatment====
 
−
''Treatment followed by varying consolidation and/or maintenance regimens:
 
−
{| class="wikitable sortable" style="text-align: center"
 
−
!'''Trial'''
 
−
!'''Subsequent treatment'''
 
−
!'''Type of regimen'''
 
−
!'''Duration'''
 
−
|-
 
−
|'''IFM 9502
 
−
|[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa]]
 
−
|Maintenance
 
−
|1 year
 
−
|-
 
−
|'''Bladé et al. 2005
 
−
|[[Multiple_myeloma_-_historical#Interferon_alfa_.26_Dexamethasone|IFN & Dexamethasone]]
 
−
|Maintenance
 
−
|Indefinite
 
−
|-
 
−
|'''Bologna 96
 
−
|[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa]]
 
−
|Maintenance
 
−
|Indefinite
 
−
|-
 
−
|rowspan=2|'''HOVON 50/GMMG-HD3
 
−
|[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa]] (if induced with VAD)
 
−
|Maintenance
 
−
|Indefinite
 
−
|-
 
−
|[[#Thalidomide_monotherapy|Thalidomide]] (if induced with TAD)
 
−
|Maintenance
 
−
|Indefinite
 
−
|-
 
−
|'''IFM2007-02
 
−
|Unspecified
 
−
|Unspecified
 
−
|Unspecified
 
−
|-
 
−
|rowspan=2|'''MRC Myeloma IX
 
−
|[[#Thalidomide_monotherapy|Thalidomide]]
 
−
|Maintenance
 
−
|Indefinite
 
−
|-
 
−
|[[Multiple_myeloma_-_historical#Observation|No further treatment]]
 
−
|N/A
 
−
|N/A
 
−
|-
 
−
|rowspan=3|'''PETHEMA/GEM GEM05MENOS65
 
−
|[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa-2b]]
 
−
|Maintenance
 
−
|3 years
 
−
|-
 
−
|[[#Thalidomide_monotherapy|Thalidomide]]
 
−
|Maintenance
 
−
|3 years
 
−
|-
 
−
|[[#VT|TV]]
 
−
|Maintenance
 
−
|3 years
 
−
|-
 
−
|rowspan=2|'''HOVON-65
 
−
|[[#Bortezomib_monotherapy_2|Bortezomib]] (if induced with PAD)
 
−
|Maintenance
 
−
|2 years
 
−
|-
 
−
|[[#Thalidomide_monotherapy|Thalidomide]] (if induced with VAD)
 
−
|Maintenance
 
−
|2 years
 
−
|-
 
−
|'''Lok et al. 2014
 
−
|[[#VTD_2|vtD]]
 
−
|Consolidation
 
−
|2 cycles
 
−
|-
 
−
|'''Roussel et al. 2014
 
−
|[[#RVD_2|RVD]]
 
−
|Consolidation
 
−
|2 cycles
 
−
|-
 
−
|'''Sonneveld et al. 2014
 
−
|[[#KTd_2|KTd]]
 
−
|Consolidation
 
−
|4 cycles
 
−
|-
 
−
|rowspan=2|'''GMMG-MM5
 
−
|MEL200, then auto HSCT (if at least nCR not achieved)
 
−
|Consolidation
 
−
|1 cycle
 
−
|-
 
−
|Lenalidomide
 
−
|Consolidation
 
−
|Not specified in abstract
 
−
|-
 
−
|'''IFM 2009
 
−
|[[#RVD_2|RVD]]
 
−
|Consolidation
 
−
|2 cycles
 
−
|-
 
−
|}
 
−
 
 
−
===References===
 
−
# Barlogie B, Hall R, Zander A, Dicke K, Alexanian R. High-dose melphalan with autologous bone marrow transplantation for multiple myeloma. Blood. 1986 May;67(5):1298-301. [http://www.bloodjournal.org/content/67/5/1298 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/3516252 PubMed]
 
−
# '''IFM 9502:''' Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, Sotto JJ, Guilhot F, Marit G, Doyen C, Jaubert J, Fuzibet JG, François S, Benboubker L, Monconduit M, Voillat L, Macro M, Berthou C, Dorvaux V, Pignon B, Rio B, Matthes T, Casassus P, Caillot D, Najman N, Grosbois B, Bataille R, Harousseau JL; Intergroupe Francophone du Myélome. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood. 2002 Feb 1;99(3):731-5. [http://www.bloodjournal.org/content/99/3/731.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11806971 PubMed]
 
−
# Bladé J, Rosiñol L, Sureda A, Ribera JM, Díaz-Mediavilla J, García-Laraña J, Mateos MV, Palomera L, Fernández-Calvo J, Martí JM, Giraldo P, Carbonell F, Callís M, Trujillo J, Gardella S, Moro MJ, Barez A, Soler A, Font L, Fontanillas M, San Miguel J; Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA). High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005 Dec 1;106(12):3755-9. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3755 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16105975 PubMed]
 
−
# '''Bologna 96:''' Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007 Jun 10;25(17):2434-41. Epub 2007 May 7. [http://jco.ascopubs.org/content/25/17/2434.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17485707 PubMed]
 
−
<!-- Presented in part at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 7, 2008. -->
 
−
# '''HOVON 50/GMMG-HD3:''' Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. [http://www.bloodjournal.org/content/115/6/1113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19880501 PubMed]
 
−
# '''Update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834471/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20085933 PubMed]
 
−
# '''EBMT-NMAM2000:''' Björkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Musto P, Beksac M, Bosi A, Milone G, Corradini P, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Gahrton G. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol. 2011 Aug 1;29(22):3016-22. Epub 2011 Jul 5. Erratum in: J Clin Oncol. 2011 Sep 20;29(27):3721. [http://ascopubs.org/doi/full/10.1200/jco.2010.32.7312 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21730266 PubMed]
 
−
## '''Update:''' Gahrton G, Iacobelli S, Björkstrand B, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Carella AM, Beksac M, Bosi A, Milone G, Corradini P, Schönland S, Friberg K, van Biezen A, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Garderet L, Kröger N; EBMT Chronic Malignancies Working Party Plasma Cell Disorders Subcommittee. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood. 2013 Jun 20;121(25):5055-63. Epub 2013 Mar 12. [http://www.bloodjournal.org/content/121/25/5055.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23482933 PubMed]
 
−
# '''IFM 2007-02:''' Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. [http://www.bloodjournal.org/content/118/22/5752.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21849487 PubMed]
 
−
# '''MRC Myeloma IX:''' Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. [http://www.bloodjournal.org/content/119/1/7.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22021371 PubMed]
 
−
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291601/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22058209 PubMed]
 
−
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. [http://clincancerres.aacrjournals.org/content/19/21/6030.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23995858 PubMed]
 
−
# '''PETHEMA/GEM GEM05MENOS65:''' Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. [http://www.bloodjournal.org/content/120/8/1589.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22791289 PubMed]
 
−
# '''HOVON-65/GMMG-HD4:''' Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. [http://jco.ascopubs.org/content/30/24/2946.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22802322 PubMed]
 
−
## '''Update:''' Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. [https://www.nature.com/articles/leu2017211 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28761118 PubMed]
 
−
# Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous Bortezomib incorporated into the Bortezomib-Thalidomide-Dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. [http://www.haematologica.org/content/99/3/e33.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24532044 PubMed]
 
−
# Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. [http://jco.ascopubs.org/content/32/25/2712.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25024076 PubMed]
 
−
<!-- # '''Abstract:''' Pieter Sonneveld, Emilie Asselberg-Hacker, Sonja Zweegman, Bronno van der Holt, Marie Jose Kersten, Edo Vellenga, Marinus van Marwijk Kooy, Okke de Weerdt, Sarah Lonergan, Antonio Palumbo, Henk Lokhorst. Dose Escalation Phase 2 Trial Of Carfilzomib Combined With Thalidomide and Low-Dose Dexamethason In Newly Diagnosed, Transplant Eligible Patients With Multiple Myeloma. A Trial Of The European Myeloma Network. Blood Nov 2013,122(21)688 [http://www.bloodjournal.org/content/122/21/688 link to abstract] -->
 
−
# Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. [http://www.bloodjournal.org/content/125/3/449 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25398935 PubMed]
 
−
# '''GMMG-MM5:''' Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. [https://www.nature.com/leu/journal/v29/n8/full/leu201580a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25787915 PubMed]
 
−
# '''GMMG-HD2:''' Mai EK, Benner A, Bertsch U, Brossart P, Hänel A, Kunzmann V, Naumann R, Neben K, Egerer G, Ho AD, Hillengass J, Raab MS, Neubauer A, Peyn A, Ko YD, Peter N, Scheid C, Goldschmidt H. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br J Haematol. 2016 Jun;173(5):731-41. Epub 2016 Mar 17. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13994/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26990892 PubMed]
 
−
# '''IFM 2009:''' Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. [http://www.nejm.org/doi/full/10.1056/NEJMoa1611750 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28379796 PubMed]
 
−
 
 
−
==MPR {{#subobject:611aa1|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
MPR: '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>R</u>'''evlimid (Lenalidomide)
 
−
===Variant #1, 0.18/2/10 {{#subobject:eac77a|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1402888 Palumbo et al. 2014 (GIMEMA RV-209)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem Melphalan, then auto HSCT]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior OS
 
−
|-
 
−
|}
 
−
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 
−
====Preceding treatment====
 
−
*[[#Rd|Rd induction]] x 4
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21
 
−
 
 
−
'''28-day cycle for 6 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_monotherapy|Lnalidomide maintenance]] versus [[Multiple_myeloma_-_historical#Observation|no further treatment]]
 
−
 
 
−
===Variant #2 {{#subobject:bd5044|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.nature.com/leu/journal/v27/n3/full/leu2012271a.html Falco et al. 2012]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''Note: this is a component of the sequential "RP-MPR-RP" protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 
−
====Preceding treatment====
 
−
*[[#Lenalidomide_.26_Prednisone|RP induction]] x 4
 
−
====Chemotherapy====
 
−
*[[Melphalan (Alkeran)]] 2 mg PO three times per week
 
−
*[[Prednisone (Sterapred)]] 50 mg PO three times per week
 
−
*[[Lenalidomide (Revlimid)]] 10 or 15 mg PO once per day on days 1 to 21
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 100 mg PO once per day as thromboprophylaxis during [[Lenalidomide (Revlimid)]] treatment. Unclear from protocol if this also means off weeks.
 
−
*Antiviral prophylaxis if history of VZV.
 
−
 
 
−
'''28-day cycle for 6 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_.26_Prednisone_3|RP maintenance]]
 
−
 
 
−
===References===
 
−
# Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. [https://www.nature.com/leu/journal/v27/n3/full/leu2012271a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22996335 PubMed]
 
−
# '''GIMEMA RV-209:''' Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. [http://www.nejm.org/doi/full/10.1056/NEJMoa1402888 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25184862 PubMed]
 
−
 
 
−
==RVD {{#subobject:3d2d57|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
RVD: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone
 
−
<br>VDR: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>R</u>'''evlimid (Lenalidomide)
 
−
<br>VRD: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone
 
−
<br>VRd: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
===Variant #1, 2 cycles post-transplant with lower-dose dex {{#subobject:073d3b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1611750 Attal et al. 2017 (IFM 2009)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic stem cell transplant]]
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
'''21-day cycle for 2 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]
 
−
 
 
−
===Variant #2, 2 cycles post-transplant with higher-dose dex {{#subobject:073d3b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/32/25/2712.full Roussel et al. 2014]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''Two months after hematologic recovery, patients without progressive disease began treatment.''
 
−
====Preceding treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic stem cell transplant]]
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Low_molecular_weight_heparins |Low–molecular weight heparin (LMWH)]] for DVT prophylaxis
 
−
*[[:Category:Antivirals |Antiviral therapy]] with example [[Valacyclovir (Valtrex) | valacyclovir]] given, for herpes zoster prevention
 
−
*[[:Category:Antibacterials |Antibiotic prophylaxis]] with example [[Amoxicillin | amoxicillin]] given, for bacterial infections
 
−
 
 
−
'''21-day cycle for 2 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]
 
−
 
 
−
===Variant #3, 5 cycles, no transplant {{#subobject:073d3b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1611750 Attal et al. 2017 (IFM 2009)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Melphalan.2C_then_auto_HSCT|Melphalan, then auto HSCT]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#RVD|RVD induction]] x 3
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
'''21-day cycle for 5 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]
 
−
 
 
−
===Variant #4, 8 cycles, no transplant {{#subobject:7fe92b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030380/ Jacobus et al. 2016 (E1A05)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|Rd
 
−
|style="background-color:#d3d3d3"|Not reported
 
−
|-
 
−
|}
 
−
''Note: this trial closed early due to poor accrual so only descriptive results are available.''
 
−
====Preceding treatment====
 
−
*Dexamethasone-based induction for 1 to 6 cycles
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
===References===
 
−
# '''Retrospective:''' Nooka AK, Kaufman JL, Muppidi S, Langston A, Heffner LT, Gleason C, Casbourne D, Saxe D, Boise LH, Lonial S. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014 Mar;28(3):690-3. Epub 2013 Nov 13. [https://www.nature.com/leu/journal/v28/n3/full/leu2013335a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24220275 PubMed]
 
−
# Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. [http://jco.ascopubs.org/content/32/25/2712.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25024076 PubMed]
 
−
# '''E1A05:''' Jacobus SJ, Rajkumar SV, Weiss M, Stewart AK, Stadtmauer EA, Callander NS, Dreosti LM, Lacy MQ, Fonseca R. Randomized phase III trial of consolidation therapy with bortezomib-lenalidomide-Dexamethasone (VRd) vs bortezomib-dexamethasone (Vd) for patients with multiple myeloma who have completed a dexamethasone based induction regimen. Blood Cancer J. 2016 Jul 29;6(7):e448. [https://www.nature.com/articles/bcj201655 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030380/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27471864 PubMed]
 
−
# '''IFM 2009:''' Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. [http://www.nejm.org/doi/full/10.1056/NEJMoa1611750 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28379796 PubMed]
 
−
 
 
−
==Tandem melphalan, then auto HSCT {{#subobject:dd75e9|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Variant #1, MEL100, then MEL100 {{#subobject:b2cefd|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/5/800.long Palumbo et al. 2010]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|VGPR or better: 82%
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#PAD_doxil|PAD doxil]] induction x 4. ORR as reported is VGPR or better.''
 
−
====Chemotherapy, first transplant====
 
−
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)
 
−
 
 
−
'''Stem cells re-infused on day 0'''
 
−
 
 
−
====Chemotherapy, second transplant====
 
−
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)
 
−
====Subsequent treatment====
 
−
*[[#Lenalidomide_.26_Prednisone_2|RP maintenance]]
 
−
 
 
−
===Variant #2, MEL140, then MEL200 {{#subobject:509dbc|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/108/10/3289.long Attal et al. 2006 (IFM 99-06)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[Multiple_myeloma_-_historical#VAD|VAD]] x 3 to 4
 
−
====Chemotherapy, first transplant====
 
−
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once (day not specified)
 
−
 
 
−
'''Stem cells re-infused on day 0'''
 
−
 
 
−
====Chemotherapy, second transplant====
 
−
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once (day not specified)
 
−
====Subsequent treatment====
 
−
*[[Multiple_myeloma_-_historical#Observation|Observation]] versus [[#Thalidomide_monotherapy|thalidomide maintenance]]
 
−
 
 
−
===Variant #3, MEL200, then MEL200 {{#subobject:dd954b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/115/6/1113 Lokhorst et al. 2009 (HOVON 50/GMMG-HD3)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3611089/ Krishnan et al. 2011 (BMT CTN 0102)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Melphalan.2C_then_auto HSCT.2C_then_RIC_allo HSCT|MEL200, then auto HSCT, then RIC allo HSCT]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (GMMG-HD4)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1402888 Palumbo et al. 2014 (RV-MM-PI-209)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#MPR_2|MPR consolidation]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract Gay et al. 2015 (EMN-441)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|CRD consolidation
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13994/abstract Mai et al. 2016 (GMMG-HD2)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Melphalan.2C_then_auto_HSCT|Melphalan, then auto HSCT]]
 
−
|style="background-color:#eeee01"|Non-inferior EFS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
{| class="wikitable sortable" style="text-align: center"
 
−
!'''Trial'''
 
−
!'''Induction regimen'''
 
−
!'''# of cycles'''
 
−
|-
 
−
|rowspan=2|'''HOVON 50/GMMG-HD3
 
−
|[[#TAD|TAD]]
 
−
|3
 
−
|-
 
−
|[[Multiple_myeloma_-_historical#VAD|VAD]]
 
−
|3
 
−
|-
 
−
|'''BMT CTN 0102
 
−
|Not specified
 
−
|N/A
 
−
|-
 
−
|rowspan=2|'''GMMG-HD4
 
−
|[[#PAD|PAD]]
 
−
|3
 
−
|-
 
−
|[[Multiple_myeloma_-_historical#VAD|VAD]]
 
−
|3
 
−
|-
 
−
|'''RV-MM-PI-209
 
−
|[[#Rd|Rd]]
 
−
|4
 
−
|-
 
−
|'''EMN-441
 
−
|[[#Rd|Rd]]
 
−
|4
 
−
|-
 
−
|}
 
−
====Chemotherapy, first transplant====
 
−
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day -2
 
−
 
 
−
'''Stem cells re-infused on day 0'''
 
−
 
 
−
====Chemotherapy, second transplant====
 
−
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day -2
 
−
 
 
−
'''Stem cells re-infused on day 0'''
 
−
====Subsequent treatment====
 
−
''Treatment followed by varying consolidation and/or maintenance regimens:
 
−
{| class="wikitable sortable" style="text-align: center"
 
−
!'''Trial'''
 
−
!'''Subsequent regimen'''
 
−
!'''Type of regimen'''
 
−
!'''Duration'''
 
−
|-
 
−
|rowspan=2|'''HOVON 50/GMMG-HD3
 
−
|[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa]] (if induced with VAD)
 
−
|Maintenance
 
−
|Indefinite
 
−
|-
 
−
|[[#Thalidomide_monotherapy|Thalidomide]] (if induced with TAD)
 
−
|Maintenance
 
−
|Indefinite
 
−
|-
 
−
|rowspan=2|'''BMT CTN 0102
 
−
|[[Multiple_myeloma_-_historical#Observation|No further treatment]]
 
−
|N/A
 
−
|N/A
 
−
|-
 
−
|[[#Thal-Dex_2|Thal-Dex]]
 
−
|Maintenance
 
−
|1 year
 
−
|-
 
−
|rowspan=2|'''HOVON-65
 
−
|[[#Bortezomib_monotherapy_2|Bortezomib]] (if induced with PAD)
 
−
|Maintenance
 
−
|2 years
 
−
|-
 
−
|[[#Thalidomide_monotherapy|Thalidomide]] (if induced with VAD)
 
−
|Maintenance
 
−
|2 years
 
−
|-
 
−
|rowspan=2|'''RV-MM-PI-209
 
−
|[[#Lenalidomide_monotherapy|Lenalidomide]]
 
−
|Maintenance
 
−
|Indefinite
 
−
|-
 
−
|[[Multiple_myeloma_-_historical#Observation|No further treatment]]
 
−
|N/A
 
−
|N/A
 
−
|-
 
−
|rowspan=2|'''EMN-441
 
−
|[[#Lenalidomide_monotherapy|Lenalidomide]]
 
−
|Maintenance
 
−
|Indefinite
 
−
|-
 
−
|[[#Lenalidomide_.26_Prednisone_3|Lenalidomide & Prednisone]]
 
−
|Maintenance
 
−
|Indefinite
 
−
|-
 
−
|}
 
−
 
 
−
===Variant #4, MEL200, then MEL200 (split doses) {{#subobject:9ceef8|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/93/1/55.long Barlogie et al. 1999 (Total Therapy)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|83%
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[Multiple_myeloma_-_historical#EDAP|EDAP]] x 1
 
−
====Chemotherapy, first transplant====
 
−
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -3 & -2
 
−
 
 
−
'''Stem cells re-infused on day 0'''
 
−
 
 
−
====Chemotherapy, second transplant====
 
−
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -3 & -2
 
−
 
 
−
'''Stem cells re-infused on day 0'''
 
−
====Subsequent treatment====
 
−
*[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa maintenance]]
 
−
 
 
−
===References===
 
−
# Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999 Jan 1;93(1):55-65. [http://www.bloodjournal.org/content/93/1/55.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9864146 PubMed]
 
−
# '''IFM 99-02:''' Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. [http://www.bloodjournal.org/content/108/10/3289.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16873668 PubMed]
 
−
## '''Update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20085933 PubMed]
 
−
# Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F, Giaccone L, Sorasio R, Omedè P, Baldi I, Bringhen S, Massaia M, Aglietta M, Levis A, Gallamini A, Fanin R, Palumbo A, Storb R, Ciccone G, Boccadoro M. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007 Mar 15;356(11):1110-20. [http://www.nejm.org/doi/full/10.1056/NEJMoa065464 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17360989 PubMed]
 
−
# Rosiñol L, Pérez-Simón JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ, González JD, Díaz-Mediavilla J, Hernández B, García-Frade J, Carrera D, León A, Hernández M, Abellán PF, Bergua JM, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas y Grupo Español de Mieloma (PETHEMA/GEM). A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood. 2008 Nov 1;112(9):3591-3. Epub 2008 Jul 8. [http://www.bloodjournal.org/content/112/9/3591.long link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18612103 PubMed]
 
−
<!-- Presented in part at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 7, 2008. -->
 
−
# '''HOVON 50/GMMG-HD3:''' Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. [http://www.bloodjournal.org/content/115/6/1113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19880501 PubMed]
 
−
# Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. [http://jco.ascopubs.org/content/28/5/800.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20048187 PubMed]
 
−
## '''Update:''' Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. [http://www.bloodjournal.org/content/122/8/1376.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23775712 PubMed]
 
−
# Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG; Blood Marrow Transplant Clinical Trials Network (BMT CTN). Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203. Epub 2011 Sep 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3611089/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21962393 PubMed]
 
−
# '''HOVON-65/GMMG-HD4:''' Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. [http://jco.ascopubs.org/content/30/24/2946.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22802322 PubMed]
 
−
## '''Update:''' Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. [https://www.nature.com/articles/leu2017211 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28761118 PubMed]
 
−
# '''Meta-analysis:''' Armeson KE, Hill EG, Costa LJ. Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transplant. 2013 Apr;48(4):562-7. Epub 2012 Sep 10. Review. [https://www.nature.com/bmt/journal/v48/n4/full/bmt2012173a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22964593 PubMed]
 
−
# '''RV-MM-PI-209:''' Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. [http://www.nejm.org/doi/full/10.1056/NEJMoa1402888 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25184862 PubMed]
 
−
# '''EMN-441:''' Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26596670 PubMed]
 
−
# '''GMMG-HD2:''' Mai EK, Benner A, Bertsch U, Brossart P, Hänel A, Kunzmann V, Naumann R, Neben K, Egerer G, Ho AD, Hillengass J, Raab MS, Neubauer A, Peyn A, Ko YD, Peter N, Scheid C, Goldschmidt H. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br J Haematol. 2016 Jun;173(5):731-41. Epub 2016 Mar 17. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13994/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26990892 PubMed]
 
−
 
 
−
==VMP {{#subobject:028a65|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VMP: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone
 
−
===Regimen {{#subobject:a9c980|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/108/7/2165.long Mateos et al. 2006]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
''Note: this was the phase II portion of this phase I/II study.''
 
−
====Preceding treatment====
 
−
*[[#VMP|VMP induction]]
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4
 
−
 
 
−
'''35-day cycle for 5 cycles'''
 
−
===References===
 
−
# Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Díaz-Mediavilla J, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, de Arriba F, Alegre A, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006 Oct 1;108(7):2165-72. Epub 2006 Jun 13. [http://www.bloodjournal.org/content/108/7/2165.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16772605 PubMed]
 
−
 
 
−
==VTD {{#subobject:c74cc6|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VTD: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
−
===Variant #1, "vTD" {{#subobject:ac81d8|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ Lok et al. 2014]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|Melphalan with autologous hematopoietic stem cell transplantation]]
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg (route not specified) once per day on days 1 to 4
 
−
 
 
−
'''21-day cycle for 2 cycles'''
 
−
 
 
−
===Variant #2 {{#subobject:85c53d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961424-9/fulltext Cavo et al. 2010 (GIMEMA MM-BO2005)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''VTD consolidation is to begin 3 months after the second transplant.''
 
−
====Preceding treatment====
 
−
*VTD induction and [[#Melphalan.2C_then_auto_HSCT|high-dose melphalam with tandem autologous hematopoietic stem cell transplant]]
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 35
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
 
−
 
 
−
====Supportive medications====
 
−
*[[Acyclovir (Zovirax)]] prophylaxis recommended
 
−
 
 
−
'''35-day cycle for 2 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_2|Dexamethasone maintenance]]
 
−
 
 
−
===Variant #3 {{#subobject:9a493a|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/12/2077.long Ladetto et al. 2010 (GIMEMA VEL-03-096)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|Melphalan, then HSCT]], with at least a very good partial response (VGPR)
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day, increased by 50 mg each week, up to a maximum of 200 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
 
−
 
 
−
'''35-day cycle for 4 cycles'''
 
−
 
 
−
===References===
 
−
# '''GIMEMA VEL-03-096:''' Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L, Crippa C, De Rosa L, Pregno P, Grasso M, Liberati AM, Caravita T, Pisani F, Guglielmelli T, Callea V, Musto P, Cangialosi C, Passera R, Boccadoro M, Palumbo A. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010 Apr 20;28(12):2077-84. Epub 2010 Mar 22. [http://jco.ascopubs.org/content/28/12/2077.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20308672 PubMed]
 
−
## '''Update:''' Ferrero S, Ladetto M, Drandi D, Cavallo F, Genuardi E, Urbano M, Caltagirone S, Grasso M, Rossini F, Guglielmelli T, Cangialosi C, Liberati AM, Callea V, Carovita T, Crippa C, De Rosa L, Pisani F, Falcone AP, Pregno P, Oliva S, Terragna C, Musto P, Passera R, Boccadoro M, Palumbo A. Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival. Leukemia. 2015 Mar;29(3):689-95. Epub 2014 Jul 16. [https://www.nature.com/leu/journal/v29/n3/full/leu2014219a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25027515 PubMed]
 
−
# '''GIMEMA MM-BO2005:''' Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961424-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21146205 PubMed]
 
−
## '''Update:''' Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. [http://www.bloodjournal.org/content/120/1/9.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22498745 PubMed]
 
−
# Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous bortezomib incorporated into the bortezomib-thalidomide-dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. [http://www.haematologica.org/content/99/3/e33.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24532044 PubMed]
 
−
 
 
−
=Maintenance after first-line therapy=
 
−
''Note that there is no crisp distinction between consolidation and maintenance. Generally regimens that are intended for a long or indefinite duration would be considered maintenance, whereas regimens with a short intended course would be considered consolidation.''
 
−
 
 
−
==Bortezomib monotherapy {{#subobject:d759b6|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Variant #1, every other week for 2 years {{#subobject:85e781|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (HOVON-65/GMMG-HD4)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Thalidomide_monotherapy|Thalidomide]]
 
−
|style="background-color:#1a9850"|Superior PFS (*)
 
−
|-
 
−
|}
 
−
''Note that in the initial publication, this arm seemed to have an overall survival advantage; this was no longer present in the updated report of 2017; PFS was the primary endpoint.''
 
−
====Preceding treatment====
 
−
*'''HOVON-65:''' [[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with single autologous hematopoietic stem cell transplant]]
 
−
*'''GMMG-HD4:''' [[#Tandem_melphalan.2C_then_auto_HSCT|High-dose melphalan with tandem autologous hematopoietic stem cell transplants]]
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once on day 1
 
−
 
 
−
'''14-day cycle for 2 years'''
 
−
 
 
−
===Variant #2, every other week indefinitely {{#subobject:8ce3fb|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.14536/abstract Berdeja et al. 2017]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|91%
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#BBD|BBD]] x 8
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once on day 1
 
−
 
 
−
'''14-day cycles'''
 
−
 
 
−
===References===
 
−
# '''HOVON-65/GMMG-HD4:''' Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. [http://jco.ascopubs.org/content/30/24/2946.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22802322 PubMed]
 
−
## '''Subgroup analysis:''' Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. [http://www.bloodjournal.org/content/119/4/940.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22160383 PubMed]
 
−
## '''Update:''' Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. [https://www.nature.com/articles/leu2017211 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28761118 PubMed]
 
−
# Berdeja JG, Bauer T, Arrowsmith E, Essell J, Murphy P, Reeves JA Jr, Boccia RV, Donnellan W, Flinn I. Phase II study of bendamustine, bortezomib and dexamethasone (BBD) in the first-line treatment of patients with multiple myeloma who are not candidates for high dose chemotherapy. Br J Haematol. 2017 Apr;177(2):254-262. Epub 2017 Feb 7. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14536/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28169430 PubMed]
 
−
 
 
−
==Carfilzomib monotherapy {{#subobject:cf0af4|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Variant #1, bi-weekly {{#subobject:fdc86d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/124/1/63 Bringhen et al. 2014 (IST-CAR-506)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#CCyd|CCyd]] x 9
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 15, 16
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #2, weekly {{#subobject:54dd57|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.nature.com/articles/leu2017327 Bringhen et al. 2017 (IST-CAR-561)]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
''Note: this is the MTD established for the phase II portion of the trial.''
 
−
====Preceding treatment====
 
−
*[[#CCyd|wKCyd]] x 9
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] 70 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
−
 
 
−
'''28-day cycles'''
 
−
===References===
 
−
<!-- # '''Abstract:''' Palumbo, Antonio; Bringhen, Sara; Villani, Oreste; Siniscalchi, Agostina; Russo, Eleonora; Uccello, Giuseppina; Cerrato, Chiara; Gilestro, Milena; Rossi, Davide; Boccadoro, Mario. Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients. ASH Annual Meeting Abstracts 2012 120: 730 [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/730 link to abstract] -->
 
−
# '''IST-CAR-506:''' Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omedé P, Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3;124(1):63-9. Epub 2014 May 22. [http://www.bloodjournal.org/content/124/1/63 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24855212 PubMed]
 
−
# '''IST-CAR-561:''' Bringhen S, D'Agostino M, De Paoli L, Montefusco V, Liberati AM, Galieni P, Grammatico S, Muccio VE, Esma F, De Angelis C, Musto P, Ballanti S, Offidani M, Petrucci MT, Gaidano G, Corradini P, Palumbo A, Sonneveld P, Boccadoro M. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia. 2018 Apr;32(4):979-985. Epub 2017 Nov 16. [https://www.nature.com/articles/leu2017327 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29263440 PubMed]
 
−
 
 
−
==CRd (Carfilzomib) {{#subobject:9f1904|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CRd: '''<u>C</u>'''arfilzomib, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
<br>KRd: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:df3763|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ Jakubowiak et al. 2012]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''This is the MTD dosing in this phase I/II trial.''
 
−
====Preceding treatment====
 
−
*[[#CRd_.28Carfilzomib.29|CRd]] x 8
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 15, 16
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 20 mg (route not specified) once per week on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle for 16 cycles'''
 
−
====Subsequent treatment====
 
−
*It was recommended that patients proceed to [[#Lenalidomide_monotherapy|lenalidomide maintenance]]
 
−
 
 
−
===References===
 
−
# Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. [http://www.bloodjournal.org/content/120/9/1801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22665938 PubMed]
 
−
 
 
−
==Daratumumab monotherapy {{#subobject:744fd9|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:9dcf90|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1714678 Mateos et al. 2017 (ALCYONE)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#D-VMP|D-VMP]] x 9
 
−
====Chemotherapy====
 
−
*[[Daratumumab (Darzalex)]] 16 mg/kg IV once on day 1
 
−
 
 
−
====Supportive medications====
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO/IV once prior to [[Daratumumab (Darzalex)]]
 
−
 
 
−
'''28-day cycles'''
 
−
===References===
 
−
# '''ALCYONE:''' Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. [http://www.nejm.org/doi/full/10.1056/NEJMoa1714678 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231133 PubMed]
 
−
 
 
−
==Ixazomib monotherapy {{#subobject:af8692|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:214582|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71125-8/abstract Kumar et al. 2014]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#IRd|IRd]] x 12
 
−
====Chemotherapy====
 
−
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
<!-- Presented at ASH 2012 and ASH 2014, Abstract 82: Long-Term Ixazomib Maintenance Is Tolerable and Improves Depth of Response Following Ixazomib-Lenalidomide-Dexamethasone Induction in Patients (Pts) with Previously Untreated Multiple Myeloma (MM): Phase 2 Study Results -->
 
−
# Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71125-8/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25456369 PubMed]
 
−
 
 
−
==Lenalidomide monotherapy {{#subobject:1bb17c|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Variant #1, indefinite 10 mg 21/28 {{#subobject:7a71f8|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/25/28/4459.long Palumbo et al. 2007]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/5/800.long Palumbo et al. 2010]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1112704 Palumbo et al. 2012 (MM-015)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Observation|Placebo]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1402888 Palumbo et al. 2014 (RV-MM-PI-209)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Observation|Observation]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ Stewart et al. 2015 (ECOG E1A06)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract Gay et al. 2015 (EMN-441)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Lenalidomide_.26_Prednisone_3|Lenalidomide & Prednisone]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Lenalidomide_.26_Prednisone_3|Lenalidomide & Prednisone]]
 
−
|style="background-color:#d3d3d3"|Not reported
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/9/1109.long Zweegman et al. 2016 (HOVON87/NMSG18)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Thalidomide_monotherapy|Thalidomide]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*Palumbo et al. 2007 & MM-015: [[#MPR|MPR]] induction x 9
 
−
*Palumbo et al. 2010: [[#Lenalidomide_.26_Prednisone_2|Lenalidomide & Prednisone]] consolidation.
 
−
*RV-MM-PI-209: [[#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan with autologous hematopoietic stem cell transplants]] versus [[#MPR_2|MPR]] consolidation
 
−
*ECOG E1A06: [[#MPR|mPR]] induction x 12
 
−
*EMN-441: [[#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan with autologous hematopoietic cell transplants]] versus CRD consolidation
 
−
*EMN01: [[#CPR|CPR]] versus [[#MPR|MPR]] versus [[#Rd_3|Rd]] induction x 9
 
−
*HOVON87/NMSG18: [[#MPR|MPR]] induction x 9
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21
 
−
 
 
−
====Supportive medications====
 
−
*Varies depending on reference:
 
−
*'''MM-015:''' [[Aspirin]] 75 to 100 mg PO once per day
 
−
*'''Palumbo et al. 2007 and Palumbo et al. 2010:''' [[Aspirin]] 100 mg PO once per day
 
−
*'''ECOG E1A06:''' [[Aspirin]] was required (dose not specified)
 
−
**''Full anticoagulation was used for patients at "higher risk" for DVT''
 
−
*'''EMN01:''' [[Aspirin]] or [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] at physician's discretion (mandatory)
 
−
*'''ECOG E1A06:''' [[Pamidronate (Aredia)]] 90 mg IV once per month recommended for patients with "active bone disease"
 
−
*'''Palumbo et al. 2007:''' [[Ciprofloxacin (Cipro)]] 500 mg PO BID
 
−
 
 
−
'''28-day cycles, given until progression or intolerable toxicity'''
 
−
 
 
−
===Variant #2, indefinite 15 mg per day {{#subobject:afeaa0|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1114138 Attal et al. 2012 (IFM 2005-02)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Observation|Placebo]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|}
 
−
====Consolidation====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
 
 
−
'''28-day cycle for 2 cycles, then'''
 
−
 
 
−
====Maintenance====
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day x 3 months, then increased to 15 mg PO once per day if tolerated
 
−
 
 
−
====Supportive medications====
 
−
*"Thromboprophylaxis was not used"
 
−
 
 
−
'''Given until progression of disease or unacceptable toxicity, or patient choice'''
 
−
 
 
−
===Variant #3, indefinite 30 mg per day {{#subobject:9d6a85|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744390/ McCarthy et al. 2012 (CALGB 100104)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Observation|Placebo]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|}
 
−
 
 
−
''Patients started therapy 100 to 120 days after [[#Melphalan.2C_then_auto_HSCT|autologous hematopoietic cell transplant (AHCT)]].''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 20 mg PO once per day; after 3 months, dose may be increased to 30 mg PO once per day if the patient's ANC remains at least 1000/uL and platelet count is at least 75 x 10<sup>9</sup>/L
 
−
**Dose adjustments can be found in the paper's supplementary appendix
 
−
 
 
−
====Supportive medications====
 
−
*Patients at high risk of deep venous thrombosis (DVT) or pulmonary embolism (PE) received [[Aspirin]], [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]], or [[Warfarin (Coumadin)]] unless contraindicated. High risk patients were defined as people with: history of diabetes, coronary artery disease, "DVT/PE, significant family history, performance status = 2, smoking history, use of oral contraceptives, and[/or] concurrent use of epoetin."
 
−
 
 
−
'''Given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
===Variant #4, 2 years of 25 mg 21/28 {{#subobject:537dbc|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://oncology.jamanetwork.com/article.aspx?articleid=2363017 Korde et al. 2016]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#CRd_.28Carfilzomib.29|CRd]] x 8
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
 
 
−
'''28-day cycle for up to 24 cycles'''
 
−
 
 
−
===Variant #5, 1 year of 10 to 15 mg per day {{#subobject:99cf02|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/32/25/2712.full Roussel et al. 2014]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1611750 Attal et al. 2017 (IFM 2009)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#RVD_2|RVD consolidation]]
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day, escalated to 15 mg PO once per day after 3 months, if tolerated.
 
−
 
 
−
'''12-month course'''
 
−
 
 
−
===Variant #6, indefinite 25 mg 21/28 {{#subobject:2650d7|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ Jakubowiak et al. 2012]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#CRd_.28Carfilzomib.29_2|CRd]] x 24
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, Crippa C, Ciccone G, Omedè P, Ambrosini MT, Gay F, Bringhen S, Musto P, Foà R, Knight R, Zeldis JB, Boccadoro M, Petrucci MT; GIMEMA--Italian Multiple Myeloma Network. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian Multiple Myeloma Network. J Clin Oncol. 2007 Oct 1;25(28):4459-65. Epub 2007 Sep 4. [http://jco.ascopubs.org/content/25/28/4459.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17785703 PubMed]
 
−
# Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. [http://jco.ascopubs.org/content/28/5/800.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20048187 PubMed]
 
−
## '''Update:''' Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. [http://www.bloodjournal.org/content/122/8/1376.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23775712 PubMed]
 
−
# McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Seiler M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1770-81. [http://www.nejm.org/doi/full/10.1056/NEJMoa1114083 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1114083/suppl_file/nejmoa1114083_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744390/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571201 PubMed]
 
−
## '''Update:''' Holstein SA, Jung SH, Richardson PG, Hofmeister CC, Hurd DD, Hassoun H, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, van Besien K, Gentile TG, Isola L, Maziarz RT, Bashey A, Landau H, Martin T, Qazilbash MH, Rodriguez C, McClune B, Schlossman RL, Smith SE, Hars V, Owzar K, Jiang C, Boyd M, Schultz C, Wilson M, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Linker C, Anderson KC, McCarthy PL. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol. 2017 Sep;4(9):e431-e442. Epub 2017 Aug 17. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30140-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28826616 PubMed]
 
−
# Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, Stoppa AM, Hulin C, Benboubker L, Garderet L, Decaux O, Leyvraz S, Vekemans MC, Voillat L, Michallet M, Pegourie B, Dumontet C, Roussel M, Leleu X, Mathiot C, Payen C, Avet-Loiseau H, Harousseau JL; IFM Investigators. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1782-91. [http://www.nejm.org/doi/full/10.1056/NEJMoa1114138 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22571202 PubMed]
 
−
## '''Abstract: Update:''' Michel Attal, MD, Valerie Cances Lauwers, Gerald Marit, Denis Caillot, Thierry Facon, MD, Cyrille Hulin, Philippe Moreau, MD, Claire Mathiot, Murielle Roussel, Catherine Payen, H. Avet-Loiseau and Jean Luc Harousseau. Maintenance Treatment with Lenalidomide After Transplantation for MYELOMA : Final Analysis of the IFM 2005-02. ASH 2010 Abstract 310. [https://ash.confex.com/ash/2010/webprogram/Paper26522.html link to abstract]
 
−
# Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. [http://www.bloodjournal.org/content/120/9/1801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22665938 PubMed]
 
−
# Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. [http://www.nejm.org/doi/full/10.1056/NEJMoa1112704 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22571200 PubMed]
 
−
# Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. [http://jco.ascopubs.org/content/32/25/2712.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25024076 PubMed]
 
−
# Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. [http://www.nejm.org/doi/full/10.1056/NEJMoa1402888 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25184862 PubMed]
 
−
# '''GMMG-MM5:''' Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. [https://www.nature.com/leu/journal/v29/n8/full/leu201580a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25787915 PubMed]
 
−
# '''ECOG E1A06:''' Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. [http://www.bloodjournal.org/content/126/11/1294.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26157076 PubMed]
 
−
# Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26596670 PubMed]
 
−
# Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. [http://www.bloodjournal.org/content/127/9/1102.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26729895 PubMed]
 
−
# Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. [http://www.bloodjournal.org/content/127/9/1109.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26802176 PubMed]
 
−
# '''Abstract: Meta-analysis:''' Michel Attal, Antonio Palumbo, Sarah A. Holstein, Valerie Lauwers-Cances, Maria Teresa Petrucci, Paul G. Richardson, Cyrille Hulin, Patrizia Tosi, Kenneth Carl Anderson, Denis Caillot, Valeria Magarotto, Philippe Moreau, Gerald Marit, Zhinuan Yu, Philip L. McCarthy. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): A meta-analysis (MA) of overall survival (OS). J Clin Oncol 34, 2016 (suppl; abstr 8001) [http://meetinglibrary.asco.org/content/168948-176 link to abstract]
 
−
<!--
 
−
# '''Abstract:''' Korde, Neha; Zingone, Adriana; Kwok, Mary; Manasanch, Elisabet E.; Costello, Rene; Zuchlinski, Diamond; Mulquin, Marcia; Maric, Irina; Calvo, Katherine R; Braylan, Raul C.; Yuan, Constance; Tembhare, Prashant Ramesh; Stetler-Stevenson, Maryalice; Arthur, Diane C; Raffeld, Mark; Xi, Liqiang; Choyke, Peter; Kurdziel, Karen; Lindenberg, Liza; Steinberg, Seth M.; Roschewski, Mark; Landgren, Ola. Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone (CRd) in Newly Diagnosed Multiple Myeloma (MM) Patients ASH Annual Meeting Abstracts 2012 120: 732 [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/732 link to abstract] -->
 
−
# Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O. Treatment With carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 2015 Sep;1(6):746-54. [http://oncology.jamanetwork.com/article.aspx?articleid=2363017 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26181891 PubMed]
 
−
# '''IFM 2009:''' Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. [http://www.nejm.org/doi/full/10.1056/NEJMoa1611750 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28379796 PubMed]
 
−
 
 
−
==Lenalidomide & Prednisone {{#subobject:6261f9|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Variant #1, prednisone 25 mg every other day {{#subobject:2cd1c5|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Lenalidomide_monotherapy|Lenalidomide]]
 
−
|style="background-color:#d3d3d3"|Not reported
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#CPR|CPR]] x 9 versus [[#MPR|MPR]] x 9 versus [[#Rd_3|Rd]] x 9
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21
 
−
*[[Prednisone (Sterapred)]] 25 mg PO once every other day
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] or [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] at physician's discretion (mandatory)
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #2, prednisone 25 mg TIW {{#subobject:5276c5|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.nature.com/leu/journal/v27/n3/full/leu2012271a.html Falco et al. 2012]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#MPR_2|MPR consolidation]] x 6
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21
 
−
*[[Prednisone (Sterapred)]] 25 mg PO three times per week
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 100 mg PO once per day as thromboprophylaxis during [[Lenalidomide (Revlimid)]] treatment. Unclear from protocol if this also means off weeks.
 
−
*Antiviral prophylaxis if history of VZV.
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #3, prednisone 50 mg every other day {{#subobject:2acd15|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract Gay et al. 2015 (EMN-441)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Lenalidomide_monotherapy|Lenalidomide]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan with autologous hematopoietic stem cell transplants]] versus CRD consolidation
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21
 
−
*[[Prednisone (Sterapred)]] 50 mg PO once every other day
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. [https://www.nature.com/leu/journal/v27/n3/full/leu2012271a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22996335 PubMed]
 
−
# '''EMN-441:''' Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26596670 PubMed]
 
−
# '''EMN01:''' Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. [http://www.bloodjournal.org/content/127/9/1102.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26729895 PubMed]
 
−
 
 
−
==Rd {{#subobject:945256|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone
 
−
===Regimen {{#subobject:ef4eb4|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext Durie et al. 2016 (SWOG S0777)]
 
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Rd|Rd]] x 6 versus [[#RVD|VRd]] x 8
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycles'''
 
−
===References===
 
−
# '''SWOG S0777:''' Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527. Epub 2016 Dec 22. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28017406 PubMed]
 
−
 
 
−
==RVD {{#subobject:416bec|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
RVD: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone
 
−
<br>VDR: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>R</u>'''evlimid (Lenalidomide)
 
−
<br>VRD: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone
 
−
<br>VRd: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
===Variant #1, 3-year course {{#subobject:8392a1|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879104/ Nair et al. 2010 (2006-66)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*VTD-PACE consolidation (per Total Therapy 3 protocol)
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 20, then 5 mg PO once per day on days 21 to 28
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Year 1: 1.0 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
**Years 2 & 3: 1.0 mg/m<sup>2</sup> IV once per week
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
 
 
−
'''3-year course'''
 
−
===Variant #2, Indefinite {{#subobject:b97d68|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324254/ Richardson et al. 2010]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#RVD_2|RVD]] x 4 to 8 cycles
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg (or previously tolerated dose) PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (or previously tolerated dose) IV once per day on days 1 & 8
 
−
*[[Dexamethasone (Decadron)]] 20 mg (or previously tolerated dose) PO once per day on days 1, 2, 8, 9
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 81 mg or 325 mg PO once per day
 
−
*[[:Category:Antivirals |Antiviral therapy]], such as [[Acyclovir (Zovirax)]] 400 mg PO once per day
 
−
*[[:Category:Bisphosphonates|Bisphosphonate]]
 
−
 
 
−
'''21-day cycles'''
 
−
===References===
 
−
# '''2006-66:''' Nair B, van Rhee F, Shaughnessy JD Jr, Anaissie E, Szymonifka J, Hoering A, Alsayed Y, Waheed S, Crowley J, Barlogie B. Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance. Blood. 2010 May 27;115(21):4168-73. Epub 2010 Feb 2. [http://www.bloodjournal.org/content/115/21/4168.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879104/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20124509 PubMed]
 
−
# Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, Delaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine DL, Anderson KC. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010 Aug 5;116(5):679-86. Epub 2010 Apr 12. [http://www.bloodjournal.org/content/116/5/679.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324254/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20385792 PubMed]
 
−
# '''Retrospective:''' Nooka AK, Kaufman JL, Muppidi S, Langston A, Heffner LT, Gleason C, Casbourne D, Saxe D, Boise LH, Lonial S. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014 Mar;28(3):690-3. Epub 2013 Nov 13. [https://www.nature.com/leu/journal/v28/n3/full/leu2013335a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24220275 PubMed]
 
−
 
 
−
==Thalidomide monotherapy {{#subobject:9f2412|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Variant #1, 3 years of 100 mg/d {{#subobject:5b0623|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|rowspan=2|[https://www.nature.com/leu/journal/v31/n9/full/leu201735a.html Rosiñol et al. 2017 (PETHEMA/GEM GEM05MENOS65)]
 
−
|rowspan=2 style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Interferon_alfa|Interferon alfa-2b]]
 
−
|style="background-color:#d3d3d3"|Not reported
 
−
|-
 
−
|[[#VT|TV]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior PFS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous HSCT]]
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
 
 
−
'''Up to 3 years'''
 
−
 
 
−
===Variant #2, indefinite 100 mg/d {{#subobject:596043|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2806%2968338-4/fulltext Palumbo et al. 2006]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ Stewart et al. 2015 (ECOG E1A06)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/9/1109.long Zweegman et al. 2016 (HOVON87/NMSG18)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Lenalidomide_monotherapy|Lenalidomide]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*'''Palumbo et al. 2006:''' [[#MPT|MPT]] x 6
 
−
*'''ECOG E1A06:''' [[#MPT|MPT]] x 12
 
−
*'''HOVON87/NMSG18:''' [[#MPT|MPT]] x 9
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
 
 
−
====Supportive medications====
 
−
*Per ECOG E1A06, [[Aspirin]] was required (dose not specified)
 
−
**Per ECOG E1A06, full anticoagulation was used for patients at "higher risk" for DVT
 
−
*Per ECOG E1A06, [[Pamidronate (Aredia)]] 90 mg IV once per month recommended for patients with "active bone disease"
 
−
 
 
−
'''Continued until evidence of relapse or refractory disease'''
 
−
 
 
−
===Variant #3, 2 years of 50 mg/d {{#subobject:c09c56|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (HOVON-65/GMMG-HD4)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Bortezomib_monotherapy_2|Bortezomib]]
 
−
|style="background-color:#d73027"|Inferior PFS (*)
 
−
|-
 
−
|}
 
−
''Note that in the initial publication, this arm seemed to have an overall survival disadvantage; this was no longer present in the updated report of 2017; PFS was the primary endpoint. Observed efficacy is for induction PAD, then transplant, then maintenance bortezomib compared with induction VAD, then transplant, then maintenance thalidomide. Treatment starts 4 weeks after the final autologous hematopoietic stem cell transplant.''
 
−
====Preceding treatment====
 
−
*'''HOVON-65:''' [[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]
 
−
*'''GMMG-HD4:''' [[#Tandem_melphalan.2C_then_auto_HSCT|High-dose melphalan with tandem autologous hematopoietic stem cell transplants]]
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day
 
−
 
 
−
'''2-year course'''
 
−
 
 
−
===Variant #4, indefinite with lead-in {{#subobject:24fe5b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/119/1/7.long Morgan et al. 2012 (MRC Myeloma IX)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Observation|Observation]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*'''Intensive treatment pathway:''' [[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic stem cell transplant]]
 
−
*'''Non-intensive treatment pathway:''' [[#CTD|CTDa]] versus [[Multiple_myeloma_-_historical#MP|MP]]
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] as follows:
 
−
**Weeks 1 to 4: 50 mg PO once per day
 
−
**Week 5 onwards: 100 mg PO once per day
 
−
 
 
−
'''Continued until progression'''
 
−
 
 
−
===Variant #5, indefinite 400 mg/d {{#subobject:767bfd|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/108/10/3289.long Attal et al. 2006 (IFM 99-02)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Observation|Observation]]
 
−
|style="background-color:#1a9850"|Superior OS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*VAD x 3 to 4 and [[#Tandem_melphalan.2C_then_auto_HSCT|high-dose melphalan with tandem autologous hematopoietic stem cell transplant]]
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 400 mg PO once per day
 
−
**Dose reductions to a minimum of 50 mg PO once per day were allowed
 
−
 
 
−
'''Continued until progression'''
 
−
 
 
−
===Variant #6, indefinite 50 mg/d {{#subobject:dbd3f3|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/19/3160.long Wijermans et al. 2010 (HOVON 49)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|[http://www.bloodjournal.org/content/115/6/1113 Lokhorst et al. 2009 (HOVON 50/GMMG-HD3)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*'''HOVON 49:''' [[#MPT|MPT]] x 8
 
−
*'''HOVON 50/GMMG-HD3:''' [[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]] or [[#Tandem_melphalan.2C_then_auto_HSCT|high-dose melphalan with tandem autologous hematopoietic stem cell transplants]]; this was not a randomization but was pre-determined by the treating center
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day
 
−
 
 
−
====Supportive medications====
 
−
*'''HOVON 49:''' [[:Category:Bisphosphonates|Bisphosphonate]] use recommended with [[Pamidronate (Aredia)]] or [[Clodronate (Bonefos)]]; "a maximum treatment period of 2 years was recommended in patients without active disease."
 
−
*'''HOVON 49:''' During maintenance therapy, "low-dose [[Aspirin]] was advised"
 
−
 
 
−
'''Continued until progression'''
 
−
 
 
−
===Variant #7, 18 months of 400 mg/d {{#subobject:962746|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.nature.com/bmt/journal/v37/n9/full/1705339a.html Sahebi et al. 2006]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic stem cell transplant]]
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day, escalated by 50 mg once per week to a target dose of 400 mg PO once per day
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Bisphosphonates|Bisphosphonate]] once per month
 
−
*Vitamin B6
 
−
 
 
−
'''18 months of treatment or 6 months past CR, whichever comes first'''
 
−
 
 
−
===References===
 
−
# Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network (GIMEMA). Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006 Mar 11;367(9513):825-31. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2806%2968338-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16530576 PubMed]
 
−
## '''Update:''' Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14. Epub 2008 May 27. [http://www.bloodjournal.org/content/112/8/3107.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18505783 PubMed]
 
−
# Sahebi F, Spielberger R, Kogut NM, Fung H, Falk PM, Parker P, Krishnan A, Rodriguez R, Nakamura R, Nademanee A, Popplewell L, Frankel P, Ruel C, Tin R, Ilieva P, Forman SJ, Somlo G. Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma. Bone Marrow Transplant. 2006 May;37(9):825-9. [https://www.nature.com/bmt/journal/v37/n9/full/1705339a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16565743 PubMed]
 
−
# Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. [http://www.bloodjournal.org/content/108/10/3289.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16873668 PubMed]
 
−
## '''Update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834471/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20085933 PubMed]
 
−
# '''**RETRACTED**''' Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB, Omri HE, Elloumi M, Belaaj H, Jeddi R, Aissaouï L, Ksouri H, Hassen AB, Msadek F, Saad A, Hsaïri M, Boukef K, Amouri A, Louzir H, Dellagi K, Abdeladhim AB; Tunisian Multiple Myeloma Study Group. Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood. 2008 Feb 15;111(4):1805-10. Epub 2007 Sep 17. [http://www.bloodjournal.org/content/111/4/1805.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17875806 PubMed] '''**RETRACTED**'''
 
−
<!-- Presented in part at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 7, 2008. -->
 
−
# '''HOVON 50/GMMG-HD3:''' Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. [http://www.bloodjournal.org/content/115/6/1113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19880501 PubMed]
 
−
# '''HOVON 49:''' Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P; Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010 Jul 1;28(19):3160-6. Epub 2010 Jun 1. [http://jco.ascopubs.org/content/28/19/3160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20516439 PubMed]
 
−
# '''MRC Myeloma IX:''' Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. [http://www.bloodjournal.org/content/119/1/7.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22021371 PubMed]
 
−
# '''HOVON-65/GMMG-HD4:''' Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. [http://jco.ascopubs.org/content/30/24/2946.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22802322 PubMed]
 
−
## '''Update:''' Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. [https://www.nature.com/articles/leu2017211 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28761118 PubMed]
 
−
# Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. [http://www.bloodjournal.org/content/126/11/1294.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26157076 PubMed]
 
−
# Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. [http://www.bloodjournal.org/content/127/9/1109.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26802176 PubMed]
 
−
# Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. [https://www.nature.com/leu/journal/v31/n9/full/leu201735a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28111466 PubMed]
 
−
 
 
−
==Thal-Dex {{#subobject:3906a8|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
TD: '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
−
<br>Thal-Dex: '''<u>Thal</u>'''idomide, '''<u>Dex</u>'''amethasone
 
−
===Regimen {{#subobject:e146e3|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1002/ajh.23274/full Maiolino et al. 2012]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_2|Dexamethasone]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic stem cell transplant]]
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
 
−
 
 
−
'''28-day cycle for 12 months or until disease progression'''
 
−
 
 
−
===References===
 
−
# Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG; Blood Marrow Transplant Clinical Trials Network (BMT CTN). Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203. Epub 2011 Sep 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3611089/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21962393 PubMed]
 
−
<!-- This work was presented in part at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, 2008 and at the XII International Myeloma Workshop, Washington, DC, 2009. -->
 
−
# Maiolino A, Hungria VT, Garnica M, Oliveira-Duarte G, Oliveira LC, Mercante DR, Miranda EC, Quero AA, Peres AL, Barros JC, Tanaka P, Magalhães RP, Rego EM, Lorand-Metze I, Lima CS, Renault IZ, Braggio E, Chiattone C, Nucci M, de Souza CA; Brazilian Multiple Myeloma Study Group (BMMSG/GEMOH). Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. Am J Hematol. 2012 Oct;87(10):948-52. Epub 2012 Jun 23. [https://onlinelibrary.wiley.com/doi/10.1002/ajh.23274/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22730113 PubMed]
 
−
 
 
−
==Thalidomide & Prednisolone {{#subobject:6f8a22|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:96e048|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/27/11/1788.long Spencer et al. 2009]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Prednisolone_monotherapy|Prednisolone]]
 
−
|style="background-color:#1a9850"|Superior OS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & auto HSCT]]
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day, increased to 200 mg PO once per day after 14 days (if tolerated)
 
−
*[[Prednisolone (Millipred)]] 50 mg PO once every other day
 
−
 
 
−
'''Thalidomide stopped after 12 months; prednisolone given until disease progression'''
 
−
 
 
−
===References===
 
−
<!-- Presented in part at the 48th Annual Meeting of the American Society of Hematology, Orlando, FL, December 9-12, 2006; and at the XIth International Myeloma Workshop, Kos Island, Greece, June 25-30, 2007. -->
 
−
# Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009 Apr 10;27(11):1788-93. Epub 2009 Mar 9. [http://jco.ascopubs.org/content/27/11/1788.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19273705 PubMed]
 
−
 
 
−
==Thalidomide & Prednisone {{#subobject:c74709|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:ff7fc7|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
!style="width: 20%"|[[Levels_of_Evidence#Toxicity|Toxicity]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587317/ Stewart et al. 2013 (NCICCTG Myeloma 10 Trial)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Observation|Observation]]
 
−
|style="background-color:#1a9851"|Improved PFS
 
−
|style="background-color:#ffffbe"|Decreased QOL
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day
 
−
*[[Prednisone (Sterapred)]] 50 mg PO once every other day
 
−
 
 
−
====Supportive medications====
 
−
*"[[:Category:Bisphosphonates|Bisphosphonates]], histamine-2 blockers, and laxatives were recommended"
 
−
*"Anticoagulant and antiplatelet medications were not mandated"
 
−
 
 
−
'''Four years or until disease progression'''
 
−
 
 
−
===References===
 
−
# Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, Reiman T, Roy J, Shustik C, Kovacs MJ, Rubinger M, Cantin G, Song K, Tompkins KA, Marcellus DC, Lacy MQ, Sussman J, Reece D, Brundage M, Harnett EL, Shepherd L, Chapman JA, Meyer RM. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. Blood. 2013 Feb 28;121(9):1517-23. Epub 2013 Jan 7. [http://www.bloodjournal.org/content/121/9/1517.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587317/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23297129 PubMed]
 
−
 
 
−
==VP {{#subobject:ee2988|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VP: '''<u>V</u>'''elcade (Bortezomib) & '''<u>P</u>'''rednisone
 
−
===Regimen {{#subobject:763da1|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext Mateos et al. 2010 (GEM2005)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#VT|VT]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#VMP|VMP]] x 6 versus [[#VTP|VTP]] x 6
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Prednisone (Sterapred)]] 50 mg PO once every other day
 
−
 
 
−
====Supportive medications====
 
−
*Patients with bone disease received [[:Category:Bisphosphonates|bisphosphonates]]
 
−
*Prophylactic [[Acyclovir (Zovirax)]] was recommended.
 
−
 
 
−
'''3-month cycle for up to 3 years'''
 
−
 
 
−
===References===
 
−
# '''GEM2005:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739218 PubMed]
 
−
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. [http://www.bloodjournal.org/content/120/13/2581 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22889759 PubMed]
 
−
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. [http://www.bloodjournal.org/content/124/12/1887 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25102853 PubMed]
 
−
 
 
−
==VT {{#subobject:e94510|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VT: '''<u>V</u>'''elcade (Bortezomib) & '''<u>T</u>'''halidomide
 
−
<br>TV: '''<u>T</u>'''halidomide & '''<u>V</u>'''elcade (Bortezomib)
 
−
===Variant #1, 1.3/50 x 2 y {{#subobject:8a32ae|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/28/34/5101.long Palumbo et al. 2010]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 
−
====Preceding treatment====
 
−
*[[#VMPT|VMPT]] x 9
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once on day 1
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day
 
−
 
 
−
'''14-day cycle for up to 2 years or until disease progression or relapse'''
 
−
===Variant #2, 1.3/50 x 3 y {{#subobject:8eb947|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext Mateos et al. 2010 (GEM2005)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#VP_2|VP]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 
−
====Preceding treatment====
 
−
*[[#VMP|VMP]] x 6 versus [[#VTP|VTP]] x 6
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day
 
−
 
 
−
====Supportive medications====
 
−
*Patients with bone disease received [[:Category:Bisphosphonates|bisphosphonates]]
 
−
*Prophylactic [[Acyclovir (Zovirax)|aciclovir]] was recommended.
 
−
*Thromboprophylaxis with either [[aspirin]] or [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]]
 
−
 
 
−
'''3-month cycle for up to 3 years'''
 
−
===Variant #3, 1.3/100 {{#subobject:61320d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.nature.com/leu/journal/v31/n9/full/leu201735a.html Rosiñol et al. 2017 (PETHEMA/GEM GEM05MENOS65)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Interferon_alfa|Interferon alfa-2b]]<br> [[#Thalidomide_monotherapy|Thalidomide]]
 
−
|style="background-color:#91cf60"|Seems to have superior PFS
 
−
|-
 
−
|}
 
−
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 
−
====Preceding treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous HCT]]
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
 
 
−
'''3-month cycle for up to 3 years'''
 
−
===References===
 
−
# '''GEM2005:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739218 PubMed]
 
−
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. [http://www.bloodjournal.org/content/120/13/2581 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22889759 PubMed]
 
−
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. [http://www.bloodjournal.org/content/124/12/1887 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25102853 PubMed]
 
−
# Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. [http://jco.ascopubs.org/content/28/34/5101.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20940200 PubMed]
 
−
## '''Post-hoc analysis:''' Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. [http://www.bloodjournal.org/content/116/23/4745.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20807892 PubMed]
 
−
## '''Subset analysis:''' Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. [http://www.bloodjournal.org/content/118/22/5759.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21951682 PubMed]
 
−
## '''Update:''' Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. [http://jco.ascopubs.org/content/32/7/634.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24449241 PubMed]
 
−
# '''PETHEMA/GEM GEM05MENOS65:''' Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. [https://www.nature.com/leu/journal/v31/n9/full/leu201735a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28111466 PubMed]
 
−
<section end=1st-consol />
 
−
<section begin=rrmm />
 
−
=Relapsed or refractory, randomized data=
 
−
 
 
−
==Bortezomib monotherapy {{#subobject:eadacb|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Variant #1, 1 mg/m<sup>2</sup>, 21-day cycle x 8 {{#subobject:77fac1|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2004.05188.x/full Jagannath et al. 2004 (CREST)]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|Bortezomib +/- Dexamethasone
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.12198/full Petrucci et al. 2013]
 
−
| style="background-color:#91cf61" |Phase II
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|}
 
−
''Note: Petrucci et al. 2013 was a re-treatment trial; the dose used was the same as in the initial treatment (1.0 or 1.3 mg/m<sup>2</sup>).''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*CREST: Patients with PD after 2 cycles or SD after 4 cycles could escalate to [[#Bortezomib_.26_Dexamethasone_2|bortezomib & dexamethasone]]
 
−
 
 
−
===Variant #2, 1.3 mg/m<sup>2</sup>, 21-day cycle x 8 (IV) {{#subobject:cd7b63|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2004.05188.x/full Jagannath et al. 2004 (CREST)]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|Low-dose Bortezomib +/- Dexamethasone
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa043445 Richardson et al. 2005 (APEX)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_3|High-dose dexamethasone]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS (*)
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70081-X/fulltext Moreau et al. 2011 (MMY-3021)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|Subcutaneous Bortezomib +/- Dexamethasone
 
−
|style="background-color:#eeee01"|Non-inferior ORR
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.12198/full Petrucci et al. 2013]
 
−
| style="background-color:#91cf61" |Phase II
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737504/ Orlowski et al. 2015]
 
−
|style="background-color:#1a9851"|Randomized Phase II (C)
 
−
|Bortezomib & Siltuximab
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''Note: Petrucci et al. 2013 was a re-treatment trial; the dose used was the same as in the initial treatment (1.0 or 1.3 mg/m<sup>2</sup>).''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Bisphosphonates|Bisphosphonate]] IV therapy once every 3 to 4 weeks unless contraindicated
 
−
 
 
−
'''21-day cycle for 8 cycles (see note)'''
 
−
====Subsequent treatment====
 
−
*CREST: Patients with PD after 2 cycles or SD after 4 cycles could escalate to [[#Bortezomib_.26_Dexamethasone_2|bortezomib & dexamethasone]]
 
−
*APEX: [[#Bortezomib_monotherapy_4|Bortezomib consolidation]]
 
−
*MMY-3021: Patients with suboptimal response after 4 cycles could escalate to [[#Bortezomib_.26_Dexamethasone_2|bortezomib & dexamethasone]]; patients who were "evolving" towards CR after 8 cycles could receive 2 additional cycles
 
−
*Orlowski et al. 2015: [[#Bortezomib_monotherapy_5|Bortezomib maintenance]]
 
−
 
 
−
===Variant #3, 1.3 mg/m<sup>2</sup>, 21-day cycle x 8 (SC) {{#subobject:16fb4f|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70081-X/fulltext Moreau et al. 2011 (MMY-3021)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|Intravenous Bortezomib +/- Dexamethasone
 
−
|style="background-color:#eeee01"|Non-inferior ORR
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
**Subcutaneous injections are 2.5 mg/mL (3.5 mg bortezomib reconstituted in 1.4 mL NS)
 
−
**SC injections are in the thighs or abdomen, with injection sites rotated between proximal/distal right/left thigh and upper/lower right/left abdominal quadrants
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] "according to established guidelines"
 
−
 
 
−
'''21-day cycle for 8 cycles (see note)'''
 
−
====Subsequent treatment====
 
−
*Patients with suboptimal response after 4 cycles could escalate to [[#Bortezomib_.26_Dexamethasone_2|bortezomib & dexamethasone]]; patients who were "evolving" towards CR after 8 cycles could receive 2 additional cycles
 
−
 
 
−
===Variant #4, indefinite 21-day cycles {{#subobject:e26d0e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa030288 Richardson et al. 2003 (SUMMIT)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://jco.ascopubs.org/content/25/25/3892.long Orlowski et al. 2007]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Bortezomib_.26_Doxorubicin_liposomal|Bortezomib & Doxorubicin liposomal]]
 
−
|style="background-color:#d73027"|Inferior TTP
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2008.07409.x/full Mikhael et al. 2008]
 
−
|style="background-color:#91cf61"|Phase IIIb
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70398-X/fulltext Dimopoulos et al. 2013 (VANTAGE 088)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Bortezomib_.26_Vorinostat|Bortezomib & Vorinostat]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior PFS
 
−
|-
 
−
|}
 
−
''Note: '''SUMMIT''' and '''Mikhael et al. 2008''' specified a total of 8 cycles, but those who were deriving clinical benefit could continue beyond this. In '''SUMMIT''' and '''Mikhael et al. 2008''', patients with PD after 2 cycles or SD after 4 cycles could escalate to [[#Bortezomib_.26_Dexamethasone_2|bortezomib & dexamethasone]].''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
 
 
−
'''21-day cycles'''
 
−
 
 
−
===Variant #5, 1.6 mg/m<sup>2</sup>, 35-day cycle x 10 {{#subobject:59c4b8|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23606/full Hainsworth et al. 2008]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
 
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
 
−
 
 
−
'''35-day cycle for up to 10 cycles'''
 
−
 
 
−
===References===
 
−
# Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. [http://www.nejm.org/doi/full/10.1056/NEJMoa030288 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12826635 PubMed]
 
−
## '''Subgroup Analysis:''' Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. [http://www.haematologica.org/content/91/7/929.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16818280 PubMed]
 
−
# Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004 Oct;127(2):165-72. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2004.05188.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15461622 PubMed]
 
−
## '''Subgroup Analysis:''' Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. [http://www.haematologica.org/content/91/7/929.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16818280 PubMed]
 
−
## '''Update:''' Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Esseltine DL, Anderson KC. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol. 2008 Nov;143(4):537-40. Epub 2008 Sep 6. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2008.07359.x/full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18783399 PubMed]
 
−
# '''APEX:''' Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005 Jun 16;352(24):2487-98. [http://www.nejm.org/doi/full/10.1056/NEJMoa043445 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15958804 PubMed]
 
−
## '''Update:''' Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Miguel JS, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007 Nov 15;110(10):3557-60. Epub 2007 Aug 9. [http://www.bloodjournal.org/content/110/10/3557.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17690257 PubMed]
 
−
# Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. Epub 2007 Aug 6. [http://jco.ascopubs.org/content/25/25/3892.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17679727 PubMed]
 
−
## '''Update:''' Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016 Jul 1;122(13):2050-6. Epub 2016 May 18. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.30026/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27191689 PubMed]
 
−
# Hainsworth JD, Spigel DR, Barton J, Farley C, Schreeder M, Hon J, Greco FA. Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network. Cancer. 2008 Aug 15;113(4):765-71. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23606/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18543319 PubMed]
 
−
# Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, Petrucci MT, Musto P, Komarnicki M, Stewart AK. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009 Jan;144(2):169-75. Epub 2008 Nov 19. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2008.07409.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19036114 PubMed]
 
−
# '''MMY-3021:''' Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 May;12(5):431-40. Epub 2011 Apr 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70081-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21507715 PubMed]
 
−
## '''Update:''' Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, Feng H, Cakana A, Deraedt W, Moreau P. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012 Dec;97(12):1925-8. Epub 2012 Jun 11. [http://www.haematologica.org/content/97/12/1925.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685287/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22689676 PubMed]
 
−
## '''Subgroup analysis:''' Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Rekhtman G, Masliak Z, Robak P, Esseltine DL, Feng H, Deraedt W, van de Velde H, Arnulf B. Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study. Haematologica. 2015 May;100(5):e207-10. Epub 2015 Jan 16. [http://www.haematologica.org/content/100/5/e207.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420234/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25596270 PubMed]
 
−
# Petrucci MT, Giraldo P, Corradini P, Teixeira A, Dimopoulos MA, Blau IW, Drach J, Angermund R, Allietta N, Broer E, Mitchell V, Bladé J. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol. 2013 Mar;160(5):649-59. Epub 2013 Jan 7. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.12198/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2323914 PubMed]
 
−
# '''VANTAGE 088:''' Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, Rosinol L, Williams C, Blacklock H, Goldschmidt H, Hungria V, Spencer A, Palumbo A, Graef T, Eid JE, Houp J, Sun L, Vuocolo S, Anderson KC. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013 Oct;14(11):1129-1140. Epub 2013 Sep 19. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70398-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24055414 PubMed]
 
−
# Orlowski RZ, Gercheva L, Williams C, Sutherland H, Robak T, Masszi T, Goranova-Marinova V, Dimopoulos MA, Cavenagh JD, Špička I, Maiolino A, Suvorov A, Bladé J, Samoylova O, Puchalski TA, Reddy M, Bandekar R, van de Velde H, Xie H, Rossi JF. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol. 2015 Jan;90(1):42-9. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737504/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25294016 PubMed]
 
−
 
 
−
==Bortezomib & Dexamethasone {{#subobject:899402|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
BD: '''<u>B</u>'''ortezomib, '''<u>D</u>'''examethasone
 
−
<br>Bd: '''<u>B</u>'''ortezomib, low-dose '''<u>d</u>'''examethasone
 
−
<br>Bort-Dex: '''<u>Bort</u>'''ezomib, '''<u>Dex</u>'''amethasone
 
−
<br>Vd: '''<u>V</u>'''elcade (Bortezomib), low-dose '''<u>d</u>'''examethasone
 
−
<br>VD: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone
 
−
 
 
−
===Variant #1, indefinite 21-day then 28-day cycles {{#subobject:a29ce5 |Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900953/ Jakubowiak et al. 2016 (CA204-009)]
 
−
|style="background-color:#1a9851"|Randomized Phase II (C)
 
−
|[[#EBd|EBd]]
 
−
|style="background-color:#fee08b"|Might have inferior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Cycles 1 to 8: 1.3 mg/m<sup>2</sup> SC/IV once per day on days 1, 4, 8, 11
 
−
**Cycle 9 onwards: 1.3 mg/m<sup>2</sup> SC/IV once per day on days 1, 8, 15
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 8: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
**Cycle 9 onwards: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16
 
−
 
 
−
'''21-day cycle for 8 cycles, then 28-day cycles'''
 
−
 
 
−
===Variant #2, SC 21-day cycles (8 total) {{#subobject:c5b78f|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70081-X/fulltext Moreau et al. 2011 (MMY-3021)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|IV Bort-Dex
 
−
|style="background-color:#eeee01"|Non-inferior ORR
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1606038 Palumbo et al. 2016 (CASTOR)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#DVd_2|DVd]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*MMY-3021: [[#Bortezomib_monotherapy_3|Bortezomib]] x 4
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
'''21-day cycle for 8 cycles (see note)'''
 
−
 
 
−
''In '''MMY-3021''', patients who were "evolving" towards CR after 8 cycles could receive 2 additional cycles.''
 
−
 
 
−
===Variant #3, 21-day followed by 42-day cycles (12 total) {{#subobject:c68433|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70440-1/fulltext San-Miguel et al. 2014 (PANORAMA 1)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Bortezomib.2C_Dexamethasone.2C_Panobinostat|Bortezomib, Dexamethasone, Panobinostat]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy, Phase 1====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
 
 
−
''Patients who had clinical benefit per the modified European Group for Blood and Marrow Transplantation [EBMT] criteria on day 1 of cycle 8 proceeded to phase 2 treatment:''
 
−
 
 
−
====Chemotherapy, Phase 2====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per week days 1, 8, 22, 29
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 8, 9, 22, 23, 29, 30
 
−
 
 
−
'''42-day cycle for 4 cycles'''
 
−
 
 
−
===Variant #4, 21-day cycles, response-adapted {{#subobject:47b011|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492844/ Hjorth et al. 2012 (NMSG 17/07)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Thal-Dex_3|Thal-Dex]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729908/ Dimopoulos et al. 2013 (CR013165)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|Not evaluable
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
====Supportive medications====
 
−
*"Antithrombotic prophylaxis and [[Acyclovir (Zovirax)|acyclovir]] prophylaxis were not mandatory according to the study protocol but used routinely in an increasing proportion of participating centers during the study period."
 
−
 
 
−
'''21-day cycles, to be continued until progression or best response, which would then be followed by 1 to 2 additional cycles'''
 
−
 
 
−
===Variant #5, IV 21-day cycles (8 total) {{#subobject:5d8a03|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2004.05188.x/full Jagannath et al. 2004 (CREST)]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|Low-dose Bort-Dex
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70081-X/fulltext Moreau et al. 2011 (MMY-3021)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|SC Bort-Dex
 
−
|style="background-color:#eeee01"|Non-inferior ORR
 
−
|-
 
−
|[https://link.springer.com/article/10.1007%2Fs00277-017-3065-z Kropff et al. 2017 (CR015247)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#VDC_2|VCD]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*CREST: [[#Bortezomib_monotherapy_3|Bortezomib]] x 2 to 4 cycles
 
−
*MMY-3021: [[#Bortezomib_monotherapy_3|bortezomib]] x 4
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
'''21-day cycle for 8 cycles (see note)'''
 
−
 
 
−
''In '''MMY-3021''', patients who were "evolving" towards CR after 8 cycles could receive 2 additional cycles.''
 
−
 
 
−
===Variant #6, low-dose IV 21-day cycles (8 total) {{#subobject:823e44|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2004.05188.x/full Jagannath et al. 2004 (CREST)]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|Standard-dose Bort-Dex
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Bortezomib_monotherapy_3|Bortezomib]] x 2 to 4 cycles
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
 
 
−
===Variant #7, IV indefinite 21-day cycles {{#subobject:0e7bc2|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa030288 Richardson et al. 2003 (SUMMIT)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#8c6bb1" |RR: 35%
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2008.07409.x/full Mikhael et al. 2008 (MMY-3001)]
 
−
|style="background-color:#91cf61"|Phase IIIb
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#bfd3e6" |ORR: 67%
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00464-7/fulltext Dimopoulos et al. 2015 (ENDEAVOR)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Carfilzomib_.26_Dexamethasone|Kd]]
 
−
| style="background-color:#d73027" |Inferior OS (*)
 
−
|-
 
−
|}
 
−
''Note: SUMMIT & MMY-3001 specified a total of 8 cycles, but those who were deriving clinical benefit could continue beyond this. Efficacy for ENDEAVOR based on the 2017 update.''
 
−
====Preceding treatment====
 
−
*SUMMIT & MMY-3001: [[#Bortezomib_monotherapy_3|Bortezomib]] x 2 to 4 cycles
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO/IV once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
'''21-day cycles'''
 
−
 
 
−
===Variant #8, SC indefinite 21-day cycles {{#subobject:6696bc|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00464-7/fulltext Dimopoulos et al. 2015 (ENDEAVOR)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Carfilzomib_.26_Dexamethasone|Kd]]
 
−
| style="background-color:#d73027" |Inferior OS (*)
 
−
|-
 
−
|}
 
−
''Note: efficacy based on the 2017 update.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO/IV once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
'''21-day cycles'''
 
−
 
 
−
===Variant #9, indefinite 35-day cycles {{#subobject:ed7a2d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://ar.iiarjournals.org/content/31/6/2297.long Fukushima et al. 2011]
 
−
|style="background-color:#91cf61"|Phase II
 
−
| style="background-color:#e0ecf4" |ORR: 77%
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
 
−
 
 
−
'''35-day cycles, to be continued until complete response, progression of disease, or severe adverse events'''
 
−
 
 
−
===References===
 
−
# '''SUMMIT:''' Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. [http://www.nejm.org/doi/full/10.1056/NEJMoa030288 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12826635 PubMed]
 
−
# '''CREST:''' Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004 Oct;127(2):165-72. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2004.05188.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15461622 PubMed]
 
−
## '''Subgroup Analysis:''' Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. [http://www.haematologica.org/content/91/7/929.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16818280 PubMed]
 
−
## '''Update:''' Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Esseltine DL, Anderson KC. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol. 2008 Nov;143(4):537-40. Epub 2008 Sep 6. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2008.07359.x/full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18783399 PubMed]
 
−
# '''MMY-3001:''' Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, Petrucci MT, Musto P, Komarnicki M, Stewart AK. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009 Jan;144(2):169-75. Epub 2008 Nov 19. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2008.07409.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19036114 PubMed]
 
−
# '''MMY-3021:''' Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 May;12(5):431-40. Epub 2011 Apr 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70081-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21507715 PubMed]
 
−
## '''Update:''' Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, Feng H, Cakana A, Deraedt W, Moreau P. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012 Dec;97(12):1925-8. Epub 2012 Jun 11. [http://www.haematologica.org/content/97/12/1925.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685287/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22689676 PubMed]
 
−
## '''Subgroup analysis:''' Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Rekhtman G, Masliak Z, Robak P, Esseltine DL, Feng H, Deraedt W, van de Velde H, Arnulf B. Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study. Haematologica. 2015 May;100(5):e207-10. Epub 2015 Jan 16. [http://www.haematologica.org/content/100/5/e207.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420234/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25596270 PubMed]
 
−
# Fukushima T, Nakamura T, Iwao H, Nakajima A, Miki M, Sato T, Sakai T, Sawaki T, Fujita Y, Tanaka M, Masaki Y, Nakajima H, Motoo Y, Umehara H. Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events. Anticancer Res. 2011 Jun;31(6):2297-302. [http://ar.iiarjournals.org/content/31/6/2297.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21737655 PubMed]
 
−
# '''NMSG 17/07:''' Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A; Nordic Myeloma Study Group (NMSG). Thalidomide and dexamethasone vs bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol. 2012 Jun;88(6):485-96. Epub 2012 Mar 30. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.2012.01775.x link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492844/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22404182 PubMed]
 
−
# '''CR013165:''' Dimopoulos MA, Beksac M, Benboubker L, Roddie H, Allietta N, Broer E, Couturier C, Mazier MA, Angermund R, Facon T. Phase 2 study of bortezomib-dexamethasone alone or with added cyclophosphamide or lenalidomide for sub-optimal response as second-line treatment for patients with multiple myeloma. Haematologica. 2013 Aug;98(8):1264-72. Epub 2013 May 28. [http://www.haematologica.org/content/98/8/1264.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729908/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23716559 PubMed]
 
−
<!-- Presented in abstract form at the American Society of Hematology Annual Meeting, Atlanta, GA, December 8-11, 2012. -->
 
−
# '''PANORAMA 1:''' San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Bladé J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. Epub 2014 Sep 18. Erratum in: Lancet Oncol. 2015 Jan;16(1):e6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70440-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25242045 PubMed]
 
−
## '''Subgroup analysis:''' Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. Epub 2015 Dec 2. [http://www.bloodjournal.org/content/127/6/713.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760132/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26631116 PubMed]
 
−
## '''Update:''' San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Binlich F, Richardson PG. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016 Nov;3(11):e506-e515. Epub 2016 Oct 14. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30147-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27751707 PubMed]
 
−
# '''ENDEAVOR:''' Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. Epub 2015 Dec 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00464-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26671818 PubMed]
 
−
## '''Subgroup analysis:''' Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017 Jun;31(6):1368-1374. Epub 2016 Dec 27. [https://www.nature.com/articles/leu2016390 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467042/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28025582 PubMed]
 
−
## '''Update:''' Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1327-1337. Epub 2017 Aug 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30578-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28843768 PubMed]
 
−
# '''CA204-009:''' Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016 Jun 9;127(23):2833-40. Epub 2016 Apr 18. [http://www.bloodjournal.org/content/127/23/2833.long link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900953/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27091875 PubMed]
 
−
<!-- # ASCO 2016 Abstract LBA4 -->
 
−
# '''CASTOR:''' Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. [http://www.nejm.org/doi/full/10.1056/NEJMoa1606038 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1606038/suppl_file/nejmoa1606038_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27557302 PubMed]
 
−
# '''CR015247:''' Kropff M, Vogel M, Bisping G, Schlag R, Weide R, Knauf W, Fiechtner H, Kojouharoff G, Kremers S, Berdel WE. Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study. Ann Hematol. 2017 Nov;96(11):1857-1866. Epub 2017 Sep 14. [https://link.springer.com/article/10.1007%2Fs00277-017-3065-z link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28905189 PubMed]
 
−
 
 
−
==Bortezomib, Dexamethasone, Panobinostat {{#subobject:PYR1|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:PYV1|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/122/14/2331.full Richardson et al. 2013 (PANORAMA 2)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70440-1/fulltext San-Miguel et al. 2014 (PANORAMA 1)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Bortezomib_.26_Dexamethasone_2|Bortezomib & Dexamethasone]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy, phase 1====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
*[[Panobinostat (Farydak)]] 20 mg PO once per day on days 1, 3, 5, 8, 10, 12
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
 
 
−
''Patients who had clinical benefit per the modified European Group for Blood and Marrow Transplantation [EBMT] criteria on day 1 of cycle 8 proceeded to phase 2 treatment:''
 
−
 
 
−
====Chemotherapy, phase 2====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 22, 29
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 8, 9, 22, 23, 29, 30
 
−
*[[Panobinostat (Farydak)]] 20 mg PO once per day on days 1, 3, 5, 8, 10, 12, 22, 24, 26, 29, 31, 33
 
−
 
 
−
'''42-day cycles'''
 
−
 
 
−
''Patients in '''PANORAMA 1''' received 4 cycles; '''PANORAMA 2''' continued treatment until progression of disease, unacceptable toxicity, or death.''
 
−
 
 
−
===References===
 
−
# Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C, Mukhopadhyay S, Ondovik MS, Khan M, Paley CS, Lonial S. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013 Oct 3;122(14):2331-7. [http://www.bloodjournal.org/content/122/14/2331.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23950178 PubMed]
 
−
<!-- Presented in abstract form at the American Society of Hematology Annual Meeting, Atlanta, GA, December 8-11, 2012. -->
 
−
# '''PANORAMA 1:''' San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Bladé J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. Epub 2014 Sep 18. Erratum in: Lancet Oncol. 2015 Jan;16(1):e6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70440-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25242045 PubMed]
 
−
## '''Subgroup analysis:''' Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. Epub 2015 Dec 2. [http://www.bloodjournal.org/content/127/6/713.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760132/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26631116 PubMed]
 
−
## '''Update:''' San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Binlich F, Richardson PG. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016 Nov;3(11):e506-e515. Epub 2016 Oct 14. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30147-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27751707 PubMed]
 
−
 
 
−
==Bortezomib & Doxorubicin liposomal {{#subobject:2a0373|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:bef7d6|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/25/25/3892.long Orlowski et al. 2007]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Bortezomib_monotherapy_3|Bortezomib]]
 
−
|style="background-color:#1a9850"|Superior TTP
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11
 
−
*[[Pegylated liposomal doxorubicin (Doxil)]] 30 mg/m<sup>2</sup> IV over at least 1 hour once on day 4, given after [[Bortezomib (Velcade)]]
 
−
 
−
====Supportive medications====
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] were used according to established guidelines
 
−
 
 
−
'''21-day cycle for up to 8 cycles'''
 
−
 
 
−
''Treatment given until progression of disease, or unacceptable toxicity; treatment could be continued beyond 8 cycles if it was tolerated.''
 
−
 
 
−
===References===
 
−
# Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. Epub 2007 Aug 6. [http://jco.ascopubs.org/content/25/25/3892.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17679727 PubMed]
 
−
## '''Update:''' Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016 Jul 1;122(13):2050-6. Epub 2016 May 18. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.30026/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27191689 PubMed]
 
−
 
 
−
==Bortezomib & Vorinostat {{#subobject:2a5b7f|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:a5c93b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70398-X/fulltext Dimopoulos et al. 2013 (VANTAGE 088)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Bortezomib_monotherapy_3|Bortezomib]]
 
−
|style="background-color:#91cf60"|Seems to have superior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11
 
−
*[[Vorinostat (Zolinza)]] 400 mg PO once per day on days 1 to 14
 
−
 
 
−
'''21-day cycles'''
 
−
 
 
−
===References===
 
−
# '''VANTAGE 088:''' Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, Rosinol L, Williams C, Blacklock H, Goldschmidt H, Hungria V, Spencer A, Palumbo A, Graef T, Eid JE, Houp J, Sun L, Vuocolo S, Anderson KC. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013 Oct;14(11):1129-1140. Epub 2013 Sep 19. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70398-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24055414 PubMed]
 
−
 
 
−
==Carfilzomib monotherapy {{#subobject:36c1ce|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Variant #1, 20/27 dosing, variant #1 {{#subobject:270a70|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220126/ Hájek et al. 2016 (FOCUS)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Cyclophosphamide_.26_Dexamethasone|Cyclophosphamide & Dexamethasone]]<br> [[#Cyclophosphamide_.26_Prednisone|CP]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have ORRs greater than 20%.''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV over 10 minutes once per day on days 1 & 2, then 27 mg/m<sup>2</sup> IV over 10 minutes once per day on days 8, 9, 15, 16
 
−
**Cycles 2 to 9: 27 mg/m<sup>2</sup> IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16
 
−
**Cycle 10 onwards: 27 mg/m<sup>2</sup> IV over 10 minutes once per day on days 1, 2, 15, 16
 
−
 
 
−
====Supportive medications====
 
−
*IV and PO hydration required for cycle 1
 
−
*[[Dexamethasone (Decadron)]] 4 mg PO/IV prior to each cycle 1 dose
 
−
*[[Ciprofloxacin (Cipro)]] 500 mg PO once per day during cycle 1
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #2, 20/27 dosing, variant #2 {{#subobject:51e1ba|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785611/ Watanabe et al. 2016]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
| style="background-color:#88419d; color:white |ORR: 22.5%
 
−
|-
 
−
|}
 
−
''This is the maximum predetermined dose, there was no MTD; ORR is reported for the phase II portion.''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1 & 2, then 27 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16
 
−
**Cycle 2 onwards: 27 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
 
 
−
====Supportive medications====
 
−
*IV and PO hydration required for cycle 1, then as needed
 
−
*[[Dexamethasone (Decadron)]] 4 mg PO/IV prior to each cycle 1 dose, then as needed
 
−
*Prophylactic antibiotics (not specified) in cycle 1
 
−
*[[Acyclovir (Zovirax)]] for patients with history of herpes infection, in cycle 1
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #3, 20/56 dosing {{#subobject:2563a9|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624439/ Lendvai et al. 2014]
 
−
|style="background-color:#91cf61"|Phase II
 
−
| style="background-color:#9ebcda" |ORR: 55%
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2, then 56 mg/m<sup>2</sup> IV over 30 minutes once per day on days 8, 9, 15, 16
 
−
**Cycle 2 onwards: 56 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16
 
−
 
 
−
====Supportive medications====
 
−
*Normal saline pre- and post-hydration, tapered over subsequent cycles (see text for details)
 
−
*[[Dexamethasone (Decadron)]] 8 mg (route not specified) mandated with each cycle 1 dose, then optional
 
−
*[[Palonosetron (Aloxi)]] 250 mcg (route not specified) mandated with each cycle 1 dose, then optional
 
−
*[[Acyclovir (Zovirax)]] 400 mg PO once per day
 
−
 
 
−
'''28-day cycles'''
 
−
===Variant #4, 20/27 dosing, with BSA cap {{#subobject:166b4f|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123327/ Vij et al. 2012a (PX-171-004 bortezomib-naive)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
| style="background-color:#9ebcda" |ORR: 42-52%
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123387/ Siegel et al. 2012 (PX-171-003-A1)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
| style="background-color:#88419d; color:white |ORR: 24%
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> (body surface area capped at 2.2 m<sup>2</sup>) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
 
−
**Cycle 2 onwards: 27 mg/m<sup>2</sup> (body surface area capped at 2.2 m<sup>2</sup>) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
 
−
**Note: Neither Vij et al. 2012a nor Siegel et al. 2012 specify that carfilzomib is capped at a body surface area of 2.2 m2, but the [[Carfilzomib (Kyprolis)]] package insert specifies that: "The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m<sup>2</sup> should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%."
 
−
 
 
−
====Supportive medications====
 
−
*[[Dexamethasone (Decadron)]] 4 mg PO/IV before all doses in cycle 1 (Vij et al. 2012a also administered one dose of dexamethasone 4 mg before the first increased dose of carfilzomib 27 mg/m<sup>2</sup>). Restart dexamethasone premedication if patients experience infusion reactions: "fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina."
 
−
*"All patients were to receive oral and intravenous fluids before dosing to assure adequate hydration."
 
−
 
 
−
====Dose modifications====
 
−
*"Carfilzomib was withheld for grade 3 or 4 hematologic or nonhematologic toxicities and resumed at reduced doses of 15 mg/m<sup>2</sup> in cycle 1 or 20 mg/m<sup>2</sup> in cycle 2 and above on resolution."
 
−
 
 
−
'''28-day cycle for up to 12 cycles'''
 
−
 
 
−
===Variant #5, 20/20 dosing {{#subobject:0b775a|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2012.09232.x/full Vij et al. 2012b (PX-171-004 bortezomib-exposed)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
| style="background-color:#88419d; color:white |ORR: 17%
 
−
|-
 
−
|[http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(12)00148-6/fulltext Jagannath et al. 2012 (PX-171-003-A0)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
| style="background-color:#88419d; color:white |ORR: 17%
 
−
|-
 
−
|}
 
−
''Note: Patients enrolled in PX-171-004 could continue therapy beyond 12 cycles on PX-171-010; results of this extension study have not been published, to our knowledge.''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
 
 
−
'''28-day cycle for up to 12 cycles (see note)'''
 
−
 
 
−
===Variant #6, 15/20/27 dosing, for renal impairment {{#subobject:bdffd3|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!Study
 
−
![[Levels_of_Evidence#Evidence|Evidence]]
 
−
| style="background-color:#88419d; color:white |ORR: 17%
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740399/ Badros et al. 2013 (PX-171-005)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
| style="background-color:#8c6bb1" |ORR: 25.5%
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 15 mg/m<sup>2</sup> IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
 
−
**Cycle 2: 20 mg/m<sup>2</sup> IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
 
−
**Cycle 3 onwards: 27 mg/m<sup>2</sup> IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
 
−
 
 
−
====Supportive medications====
 
−
*[[Dexamethasone (Decadron)]] 4 mg (route not specified) before all doses in cycle 1. Continue dexamethasone premedication if patients experience "treatment-related fever, chills, and/or dyspnea."
 
−
*"All patients were "required to be well hydrated."
 
−
 
 
−
'''28-day cycle for 12 cycles or longer if deriving clinical benefit'''
 
−
====Subsequent treatment====
 
−
*Patients with less than PR after 2 cycles or less than CR after 4 cycles were allowed to escalate to [[#Carfilzomib_.26_Dexamethasone|carfilzomib & dexamethasone]]
 
−
 
 
−
===References===
 
−
# '''PX-171-004 bortezomib-naive:''' Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012 Jun 14;119(24):5661-70. Epub 2012 May 3. [http://www.bloodjournal.org/content/119/24/5661.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123327/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22555973 PubMed]
 
−
# '''PX-171-004 bortezomib-exposed:''' Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, Bahlis N, Belch A, Kunkel LA, Wear S, Wong AF, Wang M. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012 Sep;158(6):739-48. Epub 2012 Jul 30. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2012.09232.x/full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22845873 PubMed]
 
−
# '''PX-171-003-A0:''' Jagannath S, Vij R, Stewart AK, Trudel S, Jakubowiak AJ, Reiman T, Somlo G, Bahlis N, Lonial S, Kunkel LA, Wong A, Orlowski RZ, Siegel DS. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):310-8. [http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(12)00148-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23040437 PubMed]
 
−
# '''PX-171-003-A1:''' Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012 Oct 4;120(14):2817-25. Epub 2012 Jul 25. [http://www.bloodjournal.org/content/120/14/2817.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123387/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22833546 PubMed] '''Pivotal trial for accelerated FDA approval'''
 
−
## '''Subset analysis:''' Jakubowiak AJ, Siegel DS, Martin T, Wang M, Vij R, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Harrison BL, Wong AF, Orlowski RZ, Jagannath S. Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. Leukemia. 2013 Dec;27(12):2351-6. Epub 2013 May 14. [https://www.nature.com/leu/journal/v27/n12/full/leu2013152a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865533/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23670297 PubMed]
 
−
# '''PX-171-005:''' Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, Lee S, Wong AF, Niesvizky R. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013 Aug;27(8):1707-14. Epub 2013 Jan 31. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740399/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23364621 PubMed]
 
−
# Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, Tsakos I, Redling K, Koehne G, Chung DJ, Schaffer WL, Giralt SA. A phase 2 single-center study of carfilzomib 56 mg/m<sup>2</sup> with or without low-dose dexamethasone in relapsed multiple myeloma. Blood. 2014 Aug 7;124(6):899-906. Epub 2014 Jun 24. [http://www.bloodjournal.org/content/124/6/899 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624439/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24963043 PubMed]
 
−
# Watanabe T, Tobinai K, Matsumoto M, Suzuki K, Sunami K, Ishida T, Ando K, Chou T, Ozaki S, Taniwaki M, Uike N, Shibayama H, Hatake K, Izutsu K, Ishikawa T, Shumiya Y, Kashihara T, Iida S. A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma. Br J Haematol. 2016 Mar;172(5):745-56. Epub 2016 Jan 5. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13900/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785611/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26732066 PubMed]
 
−
# '''FOCUS:''' Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. [https://www.nature.com/leu/journal/v31/n1/full/leu2016176a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220126/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27416912 PubMed]
 
−
 
 
−
==Carfilzomib & Dexamethasone {{#subobject:0823d6|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
Kd: '''<u>K</u>'''yprolis (Carfilzomib) & low-dose '''<u>d</u>'''examethasone
 
−
===Variant #1, 20/27 {{#subobject:9a649a|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30354-1/fulltext Moreau et al. 2018 (ARROW)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|Weekly Kd
 
−
| style="background-color:#d73027" |Inferior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV over 10 minutes once per day on days 1 & 2, then 27 mg/m<sup>2</sup> IV over 10 minutes once per day on days 8, 9, 15, 16
 
−
**Cycle 2 onwards: 27 mg/m<sup>2</sup> IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 8: 40 mg PO/IV once per day on days 1, 8, 15, 22
 
−
**Cycle 10 onwards: 40 mg PO/IV once per day on days 1, 8, 15
 
−
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #2, 20/56 dosing {{#subobject:9bd940|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00464-7/fulltext Dimopoulos et al. 2015 (ENDEAVOR)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Bortezomib_.26_Dexamethasone_2|Vd]]
 
−
|style="background-color:#1a9850"|Superior OS (*)
 
−
|-
 
−
|}
 
−
''Note: efficacy based on the 2017 update.''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2, then 56 mg/m<sup>2</sup> IV over 30 minutes once per day on days 8, 9, 15, 16
 
−
**Cycle 2 onwards: 56 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #3, 20/70 dosing (weekly) {{#subobject:5322cb|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929927/ Berenson et al. 2016 (CHAMPION-1)]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30354-1/fulltext Moreau et al. 2018 (ARROW)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|Twice-weekly Kd
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV over 30 minutes once on day 1, then 70 mg/m<sup>2</sup> IV over 30 minutes once per day on days 8 & 15
 
−
**Cycle 2 onwards: 70 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 8: 40 mg PO/IV once per day on days 1, 8, 15, 22
 
−
**Cycle 10 onwards: 40 mg PO/IV once per day on days 1, 8, 15
 
−
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #4, 27 dosing {{#subobject:2b988e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740399/ Badros et al. 2013 (PX-171-005)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Carfilzomib_monotherapy_2|Carfilzomib]] x 2 to 4 cycles (carfilzomib dose escalation attained during this period)
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] 27 mg/m<sup>2</sup> IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
 
−
*[[Dexamethasone (Decadron)]] 20 mg (route not specified) once per day on days 1, 2, 8, 9, 15, 16, '''given first'''
 
−
 
 
−
'''28-day cycle for 12 cycles or longer if deriving clinical benefit'''
 
−
 
 
−
===References===
 
−
# '''PX-171-005:''' Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, Lee S, Wong AF, Niesvizky R. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013 Aug;27(8):1707-14. Epub 2013 Jan 31. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740399/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23364621 PubMed]
 
−
# '''ENDEAVOR:''' Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. Epub 2015 Dec 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00464-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26671818 PubMed]
 
−
## '''Subgroup analysis:''' Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017 Jun;31(6):1368-1374. Epub 2016 Dec 27. [https://www.nature.com/articles/leu2016390 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467042/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28025582 PubMed]
 
−
## '''Update:''' Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1327-1337. Epub 2017 Aug 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30578-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28843768 PubMed]
 
−
# '''CHAMPION-1:''' Berenson JR, Cartmell A, Bessudo A, Lyons RM, Harb W, Tzachanis D, Agajanian R, Boccia R, Coleman M, Moss RA, Rifkin RM, Patel P, Dixon S, Ou Y, Anderl J, Aggarwal S, Berdeja JG. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016 Jun 30;127(26):3360-8. Epub 2016 May 12. [http://www.bloodjournal.org/content/127/26/3360.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929927/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27207788 PubMed]
 
−
# '''ARROW:''' Moreau P, Mateos MV, Berenson JR, Weisel K, Lazzaro A, Song K, Dimopoulos MA, Huang M, Zahlten-Kumeli A, Stewart AK. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (ARROW): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018 Jul;19(7):953-964. Epub 2018 Jun 1. Erratum in: Lancet Oncol. 2018 Aug;19(8):e382. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30354-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29866475 PubMed]
 
−
 
 
−
==Cyclophosphamide & Prednisone {{#subobject:969973|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CP: '''<u>C</u>'''yclophosphamide & '''<u>P</u>'''rednisone
 
−
<br>CyPred: '''<u>Cy</u>'''clophosphamide & '''<u>Pred</u>'''nisone
 
−
===Variant #1 {{#subobject:bcd1ee|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220126/ Hájek et al. 2016 (FOCUS)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Carfilzomib_monotherapy_2|Carfilzomib]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''Note: cyclophosphamide was described as optional for the control arm but 95% of patients received it.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day
 
−
*[[Prednisone (Sterapred)]] 30 mg PO once every other day
 
−
 
 
−
'''Continued until progression'''
 
−
 
 
−
===Variant #2 {{#subobject:0a11f4|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pubmed/11476912 de Weerdt et al. 2001]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day
 
−
*[[Prednisone (Sterapred)]] 10 to 20 mg PO once per day
 
−
 
 
−
'''Continued until progression or intolerance'''
 
−
 
 
−
===References===
 
−
# de Weerdt O, van de Donk NW, Veth G, Bloem AC, Hagenbeek A, Lokhorst HM. Continuous low-dose cyclophosphamide-prednisone is effective and well tolerated in patients with advanced multiple myeloma. Neth J Med. 2001 Aug;59(2):50-6. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11476912 PubMed]
 
−
# Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. [https://www.nature.com/leu/journal/v31/n1/full/leu2016176a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220126/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27416912 PubMed]
 
−
 
 
−
==CRd (Carfilzomib) {{#subobject:dec1da|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CRd: '''<u>C</u>'''arfilzomib, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
<br>KRd: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
 
 
−
===Variant #1 {{#subobject:de433f|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
!style="width: 20%"|[[Levels_of_Evidence#Toxicity|Toxicity]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1411321 Stewart et al. 2014 (ASPIRE)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Rd_3|Rd]]
 
−
|style="background-color:#1a9850"|Superior OS (*)
 
−
|style="background-color:#1a9850"|Superior GHS/QoL
 
−
|-
 
−
|}
 
−
''Efficacy based on the 2018 update.''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV over 10 minutes once per day on days 1 & 2, then 27 mg/m<sup>2</sup> IV over 10 minutes once per day on days 8, 9, 15, 16
 
−
**Cycles 2 to 12: 27 mg/m<sup>2</sup> IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16
 
−
**Cycles 13 to 18: 27 mg/m<sup>2</sup> IV over 10 minutes once per day on days 1, 2, 15, 16
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*[[Valacyclovir (Valtrex)]] (dose not specified) or equivalent [[:Category:Antivirals|antiviral]] while taking [[Lenalidomide (Revlimid)]]
 
−
*[[Aspirin]] (dose not specified) or other [[:Category:Anticoagulants|anticoagulant]] or [[:Category:Antiplatelet_agents|antiplatelet]] medication such as [[Clopidogrel (Plavix)]], [[:Category:Low_molecular_weight_heparins|low-molecular-weight heparin]] or [[Warfarin (Coumadin)]] while taking [[Lenalidomide (Revlimid)]]
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] while taking [[Dexamethasone (Decadron)]]
 
−
*[[Lansoprazole (Prevacid)]] (dose not specified) or other [[:Category:Proton_pump_inhibitors|proton pump inhibitor]] while taking [[Dexamethasone (Decadron)]]
 
−
*A prophylactic antibiotic ([[Ciprofloxacin (Cipro)]], [[Amoxicillin]], [[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] are given as examples)
 
−
 
 
−
'''28-day cycles until progression or intolerable side effects (Carfilzomib stopped after 18 cycles)'''
 
−
 
 
−
===Variant #2 {{#subobject:b40f55|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814729/ Wang et al. 2013]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1 & 2, then 27 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16
 
−
**Cycles 2 to 12: 27 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
**Cycles 13 to 18: 27 mg/m<sup>2</sup> IV once per day on days 1, 2, 15, 16
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycle for up to 18 cycles, longer duration allowed at discretion of investigator'''
 
−
 
 
−
''Patients with at least SD after 4 cycles received up to 12 cycles; patients with at least SD after 12 cycles received up to 18 cycles.''
 
−
 
 
−
===References===
 
−
# Wang M, Martin T, Bensinger W, Alsina M, Siegel DS, Kavalerchik E, Huang M, Orlowski RZ, Niesvizky R. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood. 2013 Oct 31;122(18):3122-8. Epub 2013 Sep 6. [http://www.bloodjournal.org/content/122/18/3122.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814729/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24014245 PubMed]
 
−
# '''ASPIRE:''' Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. [http://www.nejm.org/doi/full/10.1056/NEJMoa1411321 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25482145 PubMed]
 
−
## '''Subgroup analysis:''' Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016 Sep 1;128(9):1174-80. Epub 2016 Jul 20. [http://www.bloodjournal.org/content/128/9/1174.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009511/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27439911 PubMed]
 
−
## '''HRQoL analysis:''' Stewart AK, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Buchanan J, Cocks K, Yang X, Xing B, Zojwalla N, Tonda M, Moreau P, Palumbo A. Health-related quality-of-life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma. J Clin Oncol. 2016 Nov 10;34(32):3921-3930. [http://ascopubs.org/doi/full/10.1200/JCO.2016.66.9648 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27601539 PubMed]
 
−
## '''Update:''' Siegel DS, Dimopoulos MA, Ludwig H, Facon T, Goldschmidt H, Jakubowiak A, San-Miguel J, Obreja M, Blaedel J, Stewart AK. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018 Mar 10;36(8):728-734. Epub 2018 Jan 17. [http://ascopubs.org/doi/full/10.1200/JCO.2017.76.5032 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29341834 PubMed]
 
−
 
 
−
==Cyclophosphamide & Dexamethasone {{#subobject:2c713a|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:5a653e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220126/ Hájek et al. 2016 (FOCUS)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Carfilzomib_monotherapy_2|Carfilzomib]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''Note: cyclophosphamide was described as optional for the control arm but 95% of patients received it.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 6 mg PO once every other day
 
−
 
 
−
'''Continued until progression'''
 
−
 
 
−
===References===
 
−
# Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. [https://www.nature.com/leu/journal/v31/n1/full/leu2016176a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220126/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27416912 PubMed]
 
−
 
 
−
==DRd {{#subobject:0e17f7|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
DRd: '''<u>D</u>'''aratumumab, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
===Regimen {{#subobject:5cbf82|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054695/ Plesner et al. 2016]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1607751 Dimopoulos et al. 2016 (POLLUX)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Rd_3|Rd]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Daratumumab (Darzalex)]] as follows:
 
−
**Cycles 1 & 2: 16 mg/kg IV once per week
 
−
**Cycles 3 to 6: 16 mg/kg IV once every two weeks
 
−
**Cycle 7 onwards: 16 mg/kg IV once per cycle
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
**'''POLLUX:''' Patients with CrCl of 30 to 60 mL/min/1.73m<sup>2</sup> received 10 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on days 1, 8, 15, 22
 
−
**'''POLLUX:''' Patients older than 75 years or underweight (BMI less than 18.5) could receive 20 mg PO once per week
 
−
 
 
−
'''28-day cycle for up to 24 months (Plesner et al. 2014) or until progression (POLLUX)'''
 
−
 
 
−
===References===
 
−
<!-- # '''Abstract:''' Torben Plesner, MD, Hendrik-Tobias Arkenau, MD, Henk M. Lokhorst, MD PhD, Peter Gimsing, MD, PhD, Jakub Krejcik, MD, Charlotte Lemech, MD, Monique C. Minnema, MD PhD, Ulrik Lassen, MD PhD, Jacob P. Laubach, MD, Tahamtan Ahmadi, MD, PhD, Howard Yeh, MD, Mary E Guckert, MSN, RN, Huaibao Feng, Nikolai Constantin Brun, MD PhD, Steen Lisby, Linda Basse, MD DMSc, Antonio Palumbo, MD. Safety and Efficacy of Daratumumab with Lenalidomide and Dexamethasone in Relapsed or Relapsed, Refractory Multiple Myeloma. ASH 2014 Abstract 84. [https://ash.confex.com/ash/2014/webprogram/Paper74400.html link to abstract]. -->
 
−
# Plesner T, Arkenau HT, Gimsing P, Krejcik J, Lemech C, Minnema MC, Lassen U, Laubach JP, Palumbo A, Lisby S, Basse L, Wang J, Sasser AK, Guckert ME, de Boer C, Khokhar NZ, Yeh H, Clemens PL, Ahmadi T, Lokhorst HM, Richardson PG. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood. 2016 Oct 6;128(14):1821-8. Epub 2016 Aug 16. [http://www.bloodjournal.org/content/128/14/1821.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054695/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27531679 PubMed]
 
−
# '''POLLUX:''' Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. [http://www.nejm.org/doi/full/10.1056/NEJMoa1607751 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1607751/suppl_file/nejmoa1607751_protocol.pdf link to original protocol] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27705267 PubMed]
 
−
 
 
−
==DVd {{#subobject:5770be|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
DVd: '''<u>D</u>'''aratumumab, '''<u>V</u>'''elcade (Bortezomib), low-dose '''<u>d</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:18a80b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1606038 Palumbo et al. 2016 (CASTOR)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Bortezomib_.26_Dexamethasone_2|Vd]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Daratumumab (Darzalex)]] as follows:
 
−
**Cycles 1 to 3: 16 mg/kg IV once per week
 
−
**Cycles 4 to 8: 16 mg/kg IV once on day 1
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO/IV once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
**Can be dose-reduced to 20 mg PO/IV once per week for patients greater than 75 years, with BMI less than 18.5, or with previous side effects
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Daratumumab_monotherapy_3|Daratumumab]] maintenance
 
−
 
 
−
===References===
 
−
<!-- # ASCO 2016 Abstract LBA4 -->
 
−
# '''CASTOR:''' Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. [http://www.nejm.org/doi/full/10.1056/NEJMoa1606038 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1606038/suppl_file/nejmoa1606038_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27557302 PubMed]
 
−
 
 
−
==EBd {{#subobject:165bf3|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
EBd: '''<u>E</u>'''lotuzumab, '''<u>B</u>'''ortezomib, low-dose '''<u>d</u>'''examethasone
 
−
===Regimen {{#subobject:ad710b |Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900953/ Jakubowiak et al. 2016]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|[[#Bortezomib_.26_Dexamethasone_2|Bd]]
 
−
|style="background-color:#d9ef8b"|Might have superior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Elotuzumab (Empliciti)]] as follows:
 
−
**Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15
 
−
**Cycles 3 to 8: 10 mg/kg IV once per day on days 1 & 11
 
−
**Cycle 9 onwards: 10 mg/kg IV once per day on days 1 & 15
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Cycles 1 to 8: 1.3 mg/m<sup>2</sup> SC/IV once per day on days 1, 4, 8, 11
 
−
**Cycle 9 onwards: 1.3 mg/m<sup>2</sup> SC/IV once per day on days 1, 8, 15
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 & 2:
 
−
***20 mg PO once per day on days 2, 4, 5, 9, 11, 12
 
−
***8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to [[Elotuzumab (Empliciti)]] on days 1, 8, 15
 
−
**Cycles 3 to 8:
 
−
***20 mg PO once per day on days 2, 4, 5, 8, 9, 12
 
−
***8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to [[Elotuzumab (Empliciti)]] on days 1 & 11
 
−
**Cycle 9 onwards:
 
−
***20 mg PO once per day on days 2, 8, 9, 16
 
−
***8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to [[Elotuzumab (Empliciti)]] on days 1 & 15
 
−
 
 
−
====Supportive medications====
 
−
*[[Diphenhydramine (Benadryl)]] 25 to 50 mg (route not specified) 30 to 90 minutes prior to [[Elotuzumab (Empliciti)]]
 
−
*[[Ranitidine (Zantac)]] 50 mg (route not specified) 30 to 90 minutes prior to [[Elotuzumab (Empliciti)]]
 
−
*[[Acetaminophen (Tylenol)]] 650 to 1000 mg PO 30 to 90 minutes prior to [[Elotuzumab (Empliciti)]]
 
−
 
 
−
'''21-day cycle for 8 cycles, then 28-day cycles'''
 
−
 
 
−
===References===
 
−
# Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016 Jun 9;127(23):2833-40. Epub 2016 Apr 18. [http://www.bloodjournal.org/content/127/23/2833.long link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900953/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27091875 PubMed]
 
−
 
 
−
==ELd {{#subobject:b79daa |Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
ELd: '''<u>E</u>'''lotuzumab, '''<u>L</u>'''enalidomide, low-dose '''<u>d</u>'''examethasone
 
−
===Variant #1 {{#subobject:f2d044 |Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1505654 Lonial et al. 2015 (ELOQUENT-2)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Rd_3|Ld]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS (*)
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(15)00197-0/abstract Richardson et al. 2015 (1703 Study)]
 
−
|style="background-color:#1a9851"|Randomized Phase Ib/II (E)
 
−
|Elotuzumab 20 mg, Lenalidomide, Dexamethasone
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''Note: the complex dexamethasone instructions for '''ELOQUENT-2''' were not described in the abstract of '''Richardson et al. 2015'''. Efficacy reported for '''ELOQUENT-2''' is based on the 2017 update.''
 
−
====Chemotherapy====
 
−
*[[Elotuzumab (Empliciti)]] as follows:
 
−
**Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15, 22
 
−
**Cycle 3 onwards: 10 mg/kg IV once per day on days 1 & 15
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on weeks without elotuzumab; 28 mg PO and 8 mg IV on days when [[Elotuzumab (Empliciti)]] is administered
 
−
**According to the elotuzumab package insert, the 28 mg PO dose should be given between 3 and 24 hours before elotuzumab; the 8 mg IV dose should be given 45 to 90 minutes before elotuzumab.
 
−
 
 
−
====Supportive medications====
 
−
*Mandatory premedications 30 to 90 minutes prior to [[Elotuzumab (Empliciti)]]:
 
−
**[[Diphenhydramine (Benadryl)]] 25 to 50 mg (route not specified) or its equivalent
 
−
**[[Ranitidine (Zantac)]] 50 mg (route not specified) or its equivalent
 
−
**[[Acetaminophen (Tylenol)]] 650 to 1000 mg (route not specified) or its equivalent
 
−
*"Thromboembolic prophylaxis (e.g., aspirin, low-molecular-weight heparin, or vitamin K antagonists) was administered according to institutional guidelines or at the discretion of the investigator."
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #2 {{#subobject:949377|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(15)00197-0/abstract Richardson et al. 2015 (1703 Study)]
 
−
|style="background-color:#1a9851"|Randomized Phase Ib/II (E)
 
−
|Elotuzumab 10 mg, Lenalidomide, Dexamethasone
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Elotuzumab (Empliciti)]] as follows:
 
−
**Cycles 1 & 2: 20 mg/kg IV once per day on days 1, 8, 15, 22
 
−
**Cycle 3 onwards: 20 mg/kg IV once per day on days 1 & 15
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# '''Phase I:''' Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, Kaufman JL, Leleu X, Tsao LC, Westland C, Singhal AK, Jagannath S. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012 Jun 1;30(16):1953-9. [http://jco.ascopubs.org/content/30/16/1953.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22547589 PubMed]
 
−
## '''Abstract: Update:''' Paul G. Richardson, Sundar Jagannath, MD, Philippe Moreau, MD, Andrzej Jakubowiak, MD, PhD, Marc S Raab, MD, PhD, Thierry Facon, MD, Ravi Vij, MBBS, MD, Darrell White, MD, Donna E. Reece, MD, Lotfi Benboubker, MD, PhD, Jeffrey Zonder, MD, L. Claire Tsao, PhD, Kenneth C. Anderson, MD, Eric Bleickardt, MD, Anil K Singhal, MD and Sagar Lonial, MD. Final Results for the 1703 Phase 1b/2 Study of Elotuzumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. ASH 2014 Abstract 302 [https://ash.confex.com/ash/2014/webprogram/Paper74278.html link to abstract]
 
−
# '''ELOQUENT-2:''' Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. [http://www.nejm.org/doi/full/10.1056/NEJMoa1505654 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26035255 PubMed]
 
−
## '''Update:''' Dimopoulos MA, Lonial S, White D, Moreau P, Palumbo A, San-Miguel J, Shpilberg O, Anderson K, Grosicki S, Spicka I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Bleickardt E, Poulart V, Sheng J, Sy O, Katz J, Singhal A, Richardson P. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017 Sep;178(6):896-905. Epub 2017 Jul 5. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14787/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28677826 PubMed]
 
−
<!-- # '''Abstract:''' Richardson, Paul G., Jagannath, Sundar, Moreau, Philippe, Jakubowiak, Andrzej, Raab, Marc S, Facon, Thierry, Vij, Ravi, White, Darrell J., Reece, Donna, Benboubker, Lotfi, Zonder, Jeffrey A., Deng, Wei, Kroog, Glenn, Singhal, Anil K, Lonial, Sagar. A Phase 2 Study of Elotuzumab (Elo) in Combination with Lenalidomide and Low-Dose Dexamethasone (Ld) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R MM): Updated Results. ASH Annual Meeting Abstracts 2012 120: 202 -->
 
−
# Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T, Vij R, White D, Reece DE, Benboubker L, Zonder J, Tsao LC, Anderson KC, Bleickardt E, Singhal AK, Lonial S; 1703 study investigators. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015 Dec;2(12):e516-27. Epub 2015 Nov 16. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(15)00197-0/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26686406 PubMed]
 
−
 
 
−
==IRd {{#subobject:PYR3|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
IRd: '''<u>I</u>'''xazomib, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:PYV3|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1516282 Moreau et al. 2016 (TOURMALINE-MM1)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Rd_3|Rd]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500972/ Hou et al. 2017 (TOURMALINE-MM1 China Continuation)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Rd_3|Rd]]
 
−
|style="background-color:#1a9850"|Superior OS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15, taken at least one hour before or at least two hours after food
 
−
*[[Lenalidomide (Revlimid)]] as follows:
 
−
**Normal renal function: 25 mg PO once per day on days 1 to 21
 
−
**CrCl of less than or equal to 60 mL/min/1.73m<sup>2</sup> or less than or equal to 50 mL/min/1.73m<sup>2</sup> (depends on local practice): 10 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*Thromboprophylaxis required
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
<!-- # Richardson PG, Baz R, Wang M, Jakubowiak AJ, Laubach JP, Harvey RD, Talpaz M, Berg D, Liu G, Yu J, Gupta N, Di Bacco A, Hui AM, Lonial S. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014 Aug 14;124(7):1038-46. [http://www.bloodjournal.org/content/124/7/1038 link to original article][https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574453/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24920586 PubMed]
 
−
# '''Abstract:''' Philippe Moreau, MD, Tamás Masszi, MD, Norbert Grzasko, MD, PhD, Nizar J Bahlis, MD, Markus Hansson, Ludek Pour, MD, Irwindeep Sandhu, MD, Peter Ganly, BMBCh, PhD, Bartrum W Baker, MBChB, FRACP, FRCPA, Sharon Jackson, MBChB, FRACP, FRCPA, Anne-Marie Stoppa, MD, David R Simpson, MBChB, FRACP, FRCPA, Peter Gimsing, MD, DMSci, Antonio Palumbo, Laurent Garderet, MD, Michele Cavo, Shaji K. Kumar, MD, Cyrille Touzeau, MD, Francis Buadi, MD, Jacob P. Laubach, MD, Jianchang Lin, PhD, Deborah Berg, RN, MSN, Alessandra DiBacco, PhD, Ai-Min Hui, MD, PhD and Paul G. Richardson, MD. Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (NCT01564537). ASH Annual Meeting 2015 Abstract 727 [https://ash.confex.com/ash/2015/webprogram/Paper79829.html link to abstract] -->
 
−
# '''TOURMALINE-MM1:''' Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Apr 28;374(17):1621-1634. [http://www.nejm.org/doi/full/10.1056/NEJMoa1516282 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27119237 PubMed]
 
−
## '''Subgroup analysis:''' Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, Ganly P, Palumbo A, Cavo M, Langer C, Pluta A, Nagler A, Kumar S, Ben-Yehuda D, Rajkumar SV, San-Miguel J, Berg D, Lin J, van de Velde H, Esseltine DL, di Bacco A, Moreau P, Richardson PG. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017 Dec 14;130(24):2610-2618. Epub 2017 Oct 20. [http://www.bloodjournal.org/content/130/24/2610.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29054911 PubMed]
 
−
# '''TOURMALINE-MM1 China Continuation:''' Hou J, Jin J, Xu Y, Wu D, Ke X, Zhou D, Lu J, Du X, Chen X, Li J, Liu J, Gupta N, Hanley MJ, Li H, Hua Z, Wang B, Zhang X, Wang H, van de Velde H, Richardson PG, Moreau P. Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study. J Hematol Oncol. 2017 Jul 6;10(1):137. [https://jhoonline.biomedcentral.com/articles/10.1186/s13045-017-0501-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500972/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28683766 PubMed]
 
−
 
 
−
==Ixazomib & Dexamethasone {{#subobject:af43a2|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Variant #1 {{#subobject:55fb47|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558585/ Kumar et al. 2015]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114487/ Kumar et al. 2016]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|Ixazomib 4 mg & Dexamethasone
 
−
|style="background-color:#d9ef8b"|Might have superior ORR
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Ixazomib (Ninlaro)]] 5.5 mg PO once per day on days 1, 8, 15
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 8, 9, 15, 16
 
−
 
 
−
====Supportive medications====
 
−
*Herpes zoster prophylaxis
 
−
 
 
−
'''28-day cycles until progression'''
 
−
 
 
−
===Variant #2 {{#subobject:0ec76c|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114487/ Kumar et al. 2016]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|Ixazomib 5.5 mg & Dexamethasone
 
−
|style="background-color:#fee08b"|Might have inferior ORR
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 8, 9, 15, 16
 
−
 
 
−
====Supportive medications====
 
−
*Herpes zoster prophylaxis
 
−
 
 
−
'''28-day cycles until progression'''
 
−
 
 
−
===References===
 
−
# Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015 Aug 14;5:e338. [https://www.nature.com/bcj/journal/v5/n8/full/bcj201560a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558585/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26275080 PubMed]
 
−
# Kumar SK, LaPlant BR, Reeder CB, Roy V, Halvorson AE, Buadi F, Gertz MA, Bergsagel PL, Dispenzieri A, Thompson MA, Crawley J, Kapoor P, Mikhael J, Stewart K, Hayman SR, Hwa YL, Gonsalves W, Witzig TE, Ailawadhi S, Dingli D, Go RS, Lin Y, Rivera CE, Rajkumar SV, Lacy MQ. Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib. Blood. 2016 Nov 17;128(20):2415-2422. [http://www.bloodjournal.org/content/128/20/2415.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114487/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27702799 PubMed]
 
−
 
 
−
==Lenalidomide monotherapy {{#subobject:ea18d8|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:96b9ec|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895441/ Richardson et al. 2006]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|Lenalidomide 15 mg PO BID
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[http://www.bloodjournal.org/content/114/4/772.long Richardson et al. 2009]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|}
 
−
''This regimen is essentially of historical interest, as neither dosing of lenalidomide is in common use now.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 30 mg PO once per day on days 1 to 21
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
''Patients in '''Richardson et al. 2006''' with SD or progression after 2 cycles were escalated to [[#Rd_3|RD]].''
 
−
 
 
−
===References===
 
−
# Richardson P, Jagannath S, Hussein M, Berenson J, Singhal S, Irwin D, Williams SF, Bensinger W, Badros AZ, Vescio R, Kenvin L, Yu Z, Olesnyckyj M, Zeldis J, Knight R, Anderson KC. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009 Jul 23;114(4):772-8. Epub 2009 May 26. [http://www.bloodjournal.org/content/114/4/772.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19471019 PubMed]
 
−
# Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. [http://www.bloodjournal.org/content/108/10/3458.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895441/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/16840727 PubMed]
 
−
 
 
−
==Pomalidomide & Dexamethasone {{#subobject:06b435|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
PD: '''<u>P</u>'''omalidomide, '''<u>D</u>'''examethasone
 
−
<br>PomDex: '''<u>Pom</u>'''alidomide, '''<u>Dex</u>'''amethasone
 
−
<br>Pom + LoDEX: '''<u>Pom</u>'''alidomide, '''<u>Lo</u>'''w-dose '''<u>Dex</u>'''amethasone
 
−
 
 
−
===Variant #1, 4 mg 21/28 {{#subobject:ed2ee6|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70380-2/fulltext San Miguel et al. 2013 (MM-003)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_3|Dexamethasone]]
 
−
|style="background-color:#1a9850"|Superior OS (*)
 
−
|-
 
−
|[http://www.bloodjournal.org/content/121/11/1968.long Leleu et al. 2013 (IFM 2009-02)]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|Pom-Dex (28/28)
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962162/ Richardson et al. 2014]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|[[#Pomalidomide_monotherapy|Pomalidomide]]
 
−
|style="background-color:#91cf60"|Seems to have superior PFS
 
−
|-
 
−
|[http://www.bloodjournal.org/content/125/9/1411.long Leleu et al. 2015 (IFM 2010-02)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/21/2561.long Baz et al. 2016]
 
−
|style="background-color:#1a9851"|Randomized Phase I/II (C)
 
−
|[[#PomCyDex|PomCyDex]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior ORR rate
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009959/ Dimopoulos et al. 2016 (STRATUS)]
 
−
|style="background-color:#91cf61"|Phase IIIb
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|}
 
−
''Note: efficacy reported for MM-003 is based on the 2015 update.''
 
−
====Chemotherapy====
 
−
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Age less than or equal to 75: 40 mg PO once per day on days 1, 8, 15, 22
 
−
**Age greater than 75: 20 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*San Miguel et al. 2013: Thromboprohpylaxis required. "Choice of thromboprophylaxis and use of myeloid and erythroid growth factors was left to the physician's discretion."
 
−
*Leleu et al. 2013: Thromboprophylaxis "at the physician's discretion"
 
−
*Richardson et al. 2014: [[Aspirin]] 81 to 100 mg once per day unless contraindicated
 
−
*Baz et al. 2016: [[Aspirin]] 81 mg once per day unless contraindicated
 
−
*'''STRATUS''': Thromboprophylaxis with low-dose [[Aspirin]], [[:Category:Low_molecular_weight_heparins||LMWH]], or equivalent was required
 
−
*Leleu et al. 2013: [[Filgrastim (Neupogen) | G-CSF]] allowed beginning with cycle 2 and on
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #2, 4 mg continuous {{#subobject:306c08|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291492/ Lacy et al. 2011]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[http://www.bloodjournal.org/content/121/11/1968.long Leleu et al. 2013 (IFM 2009-02)]
 
−
|style="background-color:#1a9851"|Randomized phase II, >20 patients (E)
 
−
|Pom-Dex (21/28)
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 28
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on day 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*Lacy et al. 2011: [[Aspirin]] 325 mg PO once per day
 
−
**[[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]] could be substituted at physician discretion
 
−
*Leleu et al. 2013: Thromboprophylaxis "at the physician's discretion"
 
−
*Leleu et al. 2013: [[Filgrastim (Neupogen) | G-CSF]] allowed beginning with cycle 2 and on
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #3, 2 mg continuous {{#subobject:567775|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/27/30/5008.long Lacy et al. 2009]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978257/ Lacy et al. 2010]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291492/ Lacy et al. 2011]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day on days 1 to 28
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on day 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 325 mg PO once per day
 
−
**[[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]] could be substituted at physician discretion
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Kyle RA, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009 Oct 20;27(30):5008-14. Epub 2009 Aug 31. [http://jco.ascopubs.org/content/27/30/5008.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19720894 PubMed]
 
−
# Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV, Buadi F. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010 Nov;24(11):1934-9. Epub 2010 Sep 9. [https://www.nature.com/leu/journal/v24/n11/full/leu2010190a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978257/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20827286 PubMed]
 
−
# Lacy MQ, Allred JB, Gertz MA, Hayman SR, Short KD, Buadi F, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Stewart AK, Laumann K, Mandrekar SJ, Reeder C, Rajkumar SV, Mikhael JR. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011 Sep 15;118(11):2970-5. Epub 2011 Jun 20. [http://www.bloodjournal.org/content/118/11/2970.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291492/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21690557 PubMed]
 
−
# '''IFM 2009-02:''' Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, Mathiot C, Petillon MO, Macro M, Roussel M, Pegourie B, Kolb B, Stoppa AM, Hennache B, Bréchignac S, Meuleman N, Thielemans B, Garderet L, Royer B, Hulin C, Benboubker L, Decaux O, Escoffre-Barbe M, Michallet M, Caillot D, Fermand JP, Avet-Loiseau H, Facon T. Pomalidomide plus low dose dexamethasone is active and well tolerated in bortezomib and lenalidomide refractory multiple myeloma: IFM 2009-02. Blood. 2013 Mar 14;121(11):1968-1975. Epub 2013 Jan 14. [http://www.bloodjournal.org/content/121/11/1968.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23319574 PubMed]
 
−
# '''MM-003:''' San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-66. Epub 2013 Sep 3. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70380-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24007748 PubMed]
 
−
## '''Update:''' Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, Moreau P, Banos A, Oriol A, Garderet L, Cavo M, Ivanova V, Alegre A, Martinez-Lopez J, Chen C, Spencer A, Knop S, Bahlis NJ, Renner C, Yu X, Hong K, Sternas L, Jacques C, Zaki MH, San Miguel JF. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015 Oct;100(10):1327-33. Epub 2015 Aug 6. [http://www.haematologica.org/content/100/10/1327.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591765/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26250580 PubMed]
 
−
# Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. [http://www.bloodjournal.org/content/123/12/1826.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962162/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24421329 PubMed]
 
−
# '''IFM 2010-02:''' Leleu X, Karlin L, Macro M, Hulin C, Garderet L, Roussel M, Arnulf B, Pegourie B, Kolb B, Stoppa AM, Brechiniac S, Marit G, Thielemans B, Onraed B, Mathiot C, Banos A, Lacotte L, Tiab M, Dib M, Fuzibet JG, Petillon MO, Rodon P, Wetterwald M, Royer B, Legros L, Benboubker L, Decaux O, Escoffre-Barbe M, Caillot D, Fermand JP, Moreau P, Attal M, Avet-Loiseau H, Facon T; Intergroupe Francophone du Myélome (IFM). Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood. 2015 Feb 26;125(9):1411-7. Epub 2015 Jan 9. [http://www.bloodjournal.org/content/125/9/1411.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25575538 PubMed]
 
−
<!-- Presented in part at the annual meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2014. -->
 
−
# Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. [http://www.bloodjournal.org/content/127/21/2561.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26932802 PubMed]
 
−
# '''STRATUS:''' Dimopoulos MA, Palumbo A, Corradini P, Cavo M, Delforge M, Di Raimondo F, Weisel KC, Oriol A, Hansson M, Vacca A, Blanchard MJ, Goldschmidt H, Doyen C, Kaiser M, Petrini M, Anttila P, Cafro AM, Raymakers R, San-Miguel J, de Arriba F, Knop S, Röllig C, Ocio EM, Morgan G, Miller N, Simcock M, Peluso T, Herring J, Sternas L, Zaki MH, Moreau P. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016 Jul 28;128(4):497-503. Epub 2016 May 25. [http://www.bloodjournal.org/content/128/4/497.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009959/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27226434 PubMed]
 
−
 
 
−
==Pomalidomide monotherapy {{#subobject:0e409f|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:a946bf|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962162/ Richardson et al. 2014]
 
−
|style="background-color:#1a9851"|Randomized Phase II (C)
 
−
|[[#Pomalidomide_.26_Dexamethasone|POM+LoDEX (PD)]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 81 to 100 mg per day unless contraindicated
 
−
 
 
−
'''28-day cycles until disease progression or unacceptable toxicity'''
 
−
 
 
−
===References===
 
−
# Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. [http://www.bloodjournal.org/content/123/12/1826.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962162/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24421329 PubMed]
 
−
 
 
−
==PomCyDex {{#subobject:e75204|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
PomCyDex: '''<u>Pom</u>'''alidomide, '''<u>Cy</u>'''clophosphamide, '''<u>Dex</u>'''amethasone
 
−
 
 
−
===Regimen {{#subobject:abacf6|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/127/21/2561.long Baz et al. 2016]
 
−
|style="background-color:#1a9851"|Randomized Phase I/II (E)
 
−
|[[#Pomalidomide_.26_Dexamethasone|PomDex]]
 
−
|style="background-color:#91cf60"|Seems to have superior ORR rate
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21
 
−
*[[Cyclophosphamide (Cytoxan)]] 400 mg PO once per day on days 1, 8, 15
 
−
*[[Dexamethasone (Decadron)]] 40 mg (20 mg for patients greater than 75 years old) PO once per day on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 81 mg once per day unless contraindicated
 
−
 
 
−
'''28-day cycles until disease progression or unacceptable toxicity'''
 
−
 
 
−
===References===
 
−
<!-- Presented in part at the annual meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2014. -->
 
−
# Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. [http://www.bloodjournal.org/content/127/21/2561.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26932802 PubMed]
 
−
 
 
−
==Rd {{#subobject:d6803b|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone
 
−
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone
 
−
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone
 
−
<br>Len-Dex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone
 
−
===Variant #1, Len @ 25 mg 21/28 {{#subobject:107197|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
!style="width: 20%"|[[Levels_of_Evidence#Toxicity|Toxicity]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1411321 Stewart et al. 2014 (ASPIRE)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#CRd_.28Carfilzomib.29_3|KRd]]
 
−
|style="background-color:#d73027"|Inferior OS (*)
 
−
|style="background-color:#d73027"|Inferior GHS/QoL
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1505654 Lonial et al. 2015 (ELOQUENT-2)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#ELd|ELd]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior OS (*)
 
−
|
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1516282 Moreau et al. 2016 (TOURMALINE-MM1)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#IRd|IRd]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1607751 Dimopoulos et al. 2016 (POLLUX)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#DRd|DRd]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500972/ Hou et al. 2017 (TOURMALINE-MM1 China Continuation)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#IRd|IRd]]
 
−
|style="background-color:#d73027"|Inferior OS
 
−
|
 
−
|-
 
−
|}
 
−
''Efficacy reported for '''ELOQUENT-2''' is based on the 2017 update. Efficacy reported for '''ASPIRE''' is based on the 2018 update.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
**'''POLLUX:''' Patients with CrCl of 30 to 60 mL/min/1.73m<sup>2</sup> received 10 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on days 1, 8, 15, 22
 
−
**'''POLLUX:''' Patients older than 75 years or underweight (BMI less than 18.5) could receive 20 mg PO once per week
 
−
 
 
−
====Supportive medications====
 
−
''Best described by '''ASPIRE''':''
 
−
*[[Valacyclovir (Valtrex)]] (dose not specified) or equivalent [[:Category:Antivirals|antiviral]] while taking [[Lenalidomide (Revlimid)]]
 
−
*[[Aspirin]] (dose not specified) or other [[:Category:Anticoagulants|anticoagulant]] or [[:Category:Antiplatelet_agents|antiplatelet]] medication such as [[Clopidogrel (Plavix)]], [[:Category:Low_molecular_weight_heparins|low-molecular-weight heparin]] or [[Warfarin (Coumadin)]] while taking [[Lenalidomide (Revlimid)]]
 
−
*[[:Category:Bisphosphonates|Bisphosphonates]] while taking [[Dexamethasone (Decadron)]]
 
−
*[[Lansoprazole (Prevacid)]] (dose not specified) or other [[:Category:Proton_pump_inhibitors|proton pump inhibitor]] while taking [[Dexamethasone (Decadron)]]
 
−
*A prophylactic antibiotic ([[Ciprofloxacin (Cipro)]], [[Amoxicillin]], [[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] are given as examples)
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #2, Len @ 25 mg 21/28, with high-dose dex lead-in {{#subobject:60e23c|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa070596 Weber et al. 2007 (MM-009)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_3|Dexamethasone]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS (*)
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa070594 Dimopoulos et al. 2007 (MM-010)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_3|Dexamethasone]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|}
 
−
''Note: efficacy of '''MM-009''' is based on the 2009 pooled update.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
**Cycle 5 onwards: 40 mg PO once per day on days 1 to 4
 
−
 
 
−
'''28-day cycles until progression or intolerable side effects'''
 
−
 
 
−
===Variant #3, Len @ 30 mg 21/28 {{#subobject:94d1ca|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895441/ Richardson et al. 2006]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|Dexamethasone & twice-daily Lenalidomide
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''This regimen is essentially of historical interest.''
 
−
====Preceding treatment====
 
−
*[[#Lenalidomide_monotherapy_2|Lenalidomide]] x 2 cycles
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 30 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18
 
−
 
 
−
'''28-day cycles until progression'''
 
−
 
 
−
===Variant #4, Len @ 15 mg 21/28 ("RevLite") {{#subobject:f184d5|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.14562/full Quach et al. 2017 (RevLite)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 4: 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
 
−
**Cycle 5 onwards: 20 mg PO once per day on days 1 to 4
 
−
 
 
−
'''28-day cycles until progression'''
 
−
 
 
−
===References===
 
−
# Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. [http://www.bloodjournal.org/content/108/10/3458.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895441/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/16840727 PubMed]
 
−
# '''MM-010:''' Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007 Nov 22;357(21):2123-32. [http://www.nejm.org/doi/full/10.1056/NEJMoa070594 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18032762 PubMed]
 
−
## '''Update:''' Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. [https://www.nature.com/leu/journal/v23/n11/full/leu2009147a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19626046 PubMed]
 
−
# '''MM-009:''' Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007 Nov 22;357(21):2133-42. [http://www.nejm.org/doi/full/10.1056/NEJMoa070596 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18032763 PubMed]
 
−
## '''Update:''' Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. [https://www.nature.com/leu/journal/v23/n11/full/leu2009147a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19626046 PubMed]
 
−
# '''ASPIRE:''' Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. [http://www.nejm.org/doi/full/10.1056/NEJMoa1411321 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25482145 PubMed]
 
−
## '''Subgroup analysis:''' Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016 Sep 1;128(9):1174-80. Epub 2016 Jul 20. [http://www.bloodjournal.org/content/128/9/1174.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009511/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27439911 PubMed]
 
−
## '''HRQoL analysis:''' Stewart AK, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Buchanan J, Cocks K, Yang X, Xing B, Zojwalla N, Tonda M, Moreau P, Palumbo A. Health-related quality-of-life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma. J Clin Oncol. 2016 Nov 10;34(32):3921-3930. [http://ascopubs.org/doi/full/10.1200/JCO.2016.66.9648 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27601539 PubMed]
 
−
## '''Update:''' Siegel DS, Dimopoulos MA, Ludwig H, Facon T, Goldschmidt H, Jakubowiak A, San-Miguel J, Obreja M, Blaedel J, Stewart AK. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018 Mar 10;36(8):728-734. Epub 2018 Jan 17. [http://ascopubs.org/doi/full/10.1200/JCO.2017.76.5032 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29341834 PubMed]
 
−
# '''ELOQUENT-2:''' Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. [http://www.nejm.org/doi/full/10.1056/NEJMoa1505654 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26035255 PubMed]
 
−
## '''Update:''' Dimopoulos MA, Lonial S, White D, Moreau P, Palumbo A, San-Miguel J, Shpilberg O, Anderson K, Grosicki S, Spicka I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Bleickardt E, Poulart V, Sheng J, Sy O, Katz J, Singhal A, Richardson P. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017 Sep;178(6):896-905. Epub 2017 Jul 5. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14787/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28677826 PubMed]
 
−
<!-- # '''Abstract:''' Philippe Moreau, MD, Tamás Masszi, MD, Norbert Grzasko, MD, PhD, Nizar J Bahlis, MD, Markus Hansson, Ludek Pour, MD, Irwindeep Sandhu, MD, Peter Ganly, BMBCh, PhD, Bartrum W Baker, MBChB, FRACP, FRCPA, Sharon Jackson, MBChB, FRACP, FRCPA, Anne-Marie Stoppa, MD, David R Simpson, MBChB, FRACP, FRCPA, Peter Gimsing, MD, DMSci, Antonio Palumbo, Laurent Garderet, MD, Michele Cavo, Shaji K. Kumar, MD, Cyrille Touzeau, MD, Francis Buadi, MD, Jacob P. Laubach, MD, Jianchang Lin, PhD, Deborah Berg, RN, MSN, Alessandra DiBacco, PhD, Ai-Min Hui, MD, PhD and Paul G. Richardson, MD. Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (NCT01564537). ASH Annual Meeting 2015 Abstract 727 [https://ash.confex.com/ash/2015/webprogram/Paper79829.html link to abstract] -->
 
−
# '''TOURMALINE-MM1:''' Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Apr 28;374(17):1621-1634. [http://www.nejm.org/doi/full/10.1056/NEJMoa1516282 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27119237 PubMed]
 
−
## '''Subgroup analysis:''' Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, Ganly P, Palumbo A, Cavo M, Langer C, Pluta A, Nagler A, Kumar S, Ben-Yehuda D, Rajkumar SV, San-Miguel J, Berg D, Lin J, van de Velde H, Esseltine DL, di Bacco A, Moreau P, Richardson PG. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017 Dec 14;130(24):2610-2618. Epub 2017 Oct 20. [http://www.bloodjournal.org/content/130/24/2610.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29054911 PubMed]
 
−
# '''POLLUX:''' Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. [http://www.nejm.org/doi/full/10.1056/NEJMoa1607751 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1607751/suppl_file/nejmoa1607751_protocol.pdf link to original protocol] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27705267 PubMed]
 
−
# '''RevLite:''' Quach H, Fernyhough L, Henderson R, Corbett G, Baker B, Browett P, Blacklock H, Forsyth C, Underhill C, Cannell P, Trotman J, Neylon A, Harrison S, Link E, Swern A, Cowan L, Dimopoulos MA, Miles Prince H. Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study. Br J Haematol. 2017 May;177(3):441-448. Epub 2017 Feb 15. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14562/full link to original article]'''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28197996 PubMed]
 
−
# '''TOURMALINE-MM1 China Continuation:''' Hou J, Jin J, Xu Y, Wu D, Ke X, Zhou D, Lu J, Du X, Chen X, Li J, Liu J, Gupta N, Hanley MJ, Li H, Hua Z, Wang B, Zhang X, Wang H, van de Velde H, Richardson PG, Moreau P. Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study. J Hematol Oncol. 2017 Jul 6;10(1):137. [https://jhoonline.biomedcentral.com/articles/10.1186/s13045-017-0501-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500972/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28683766 PubMed]
 
−
 
 
−
==Thal-Dex {{#subobject:13f920|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
TD: '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
−
<br>Thal-Dex: '''<u>Thal</u>'''idomide, '''<u>Dex</u>'''amethasone
 
−
===Variant #1 {{#subobject:c91582|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/30/20/2475.long Garderet et al. 2012 (MMVAR/IFM 2005-04)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#VTD_3|VTD]]
 
−
|style="background-color:#d73027"|Inferior TTP
 
−
|-
 
−
|}
 
−
''Intended for patients who have relapsed after an autologous stem-cell transplant''
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4 of a 21-day cycle
 
−
 
 
−
====Supportive medications====
 
−
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day for primary prophylaxis; [[Warfarin (Coumadin)]] for secondary prophylaxis
 
−
 
 
−
'''One year of treatment'''
 
−
 
 
−
===Variant #2 {{#subobject:518b17|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492844/ Hjorth et al. 2012 (NMSG 17/07)]
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[#Bortezomib_.26_Dexamethasone_2|Bort-Dex]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day, increased by 50 mg every 3 weeks to a maximum of 200 mg PO once per day "unless sufficient response was achieved by a lower dose"
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
 
−
 
 
−
====Supportive medications====
 
−
*"Antithrombotic prophylaxis and acyclovir prophylaxis were not mandatory according to the study protocol but used routinely in an increasing proportion of participating centers during the study period."
 
−
 
 
−
'''21-day cycles, to be continued until progression or best response, which would then be followed by 1 to 2 additional cycles'''
 
−
 
 
−
===References===
 
−
# '''NMSG 17/07:''' Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A; Nordic Myeloma Study Group (NMSG). Thalidomide and dexamethasone vs bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol. 2012 Jun;88(6):485-96. Epub 2012 Mar 30. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.2012.01775.x link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492844/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22404182 PubMed]
 
−
<!-- Presented at the 37th Annual Meeting of the European Group for Blood and Marrow Transplantation, Paris, France, April, 3-6, 2011. -->
 
−
# '''MMVAR/IFM 2005-04:''' Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, Masszi T, Fontan J, Michallet M, Gratwohl A, Milone G, Doyen C, Pegourie B, Hajek R, Casassus P, Kolb B, Chaleteix C, Hertenstein B, Onida F, Ludwig H, Ketterer N, Koenecke C, van Os M, Mohty M, Cakana A, Gorin NC, de Witte T, Harousseau JL, Morris C, Gahrton G. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012 Jul 10;30(20):2475-82. Epub 2012 May 14. Erratum in: J Clin Oncol. 2012 Sep 20;30(27):3429. [http://jco.ascopubs.org/content/30/20/2475.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22585692 PubMed]
 
−
 
 
−
==VDC {{#subobject:d412fd|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide
 
−
<br>VCD: '''<u>V</u>'''elcade (Bortezomib), '''<u>C</u>'''yclophosphamide, '''<u>D</u>'''examethasone
 
−
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone
 
−
===Variant #1 {{#subobject:c1252d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://link.springer.com/article/10.1007%2Fs00277-017-3065-z Kropff et al. 2017 (CR015247)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Bortezomib_.26_Dexamethasone_2|VD]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''Treatment details are from the [https://clinicaltrials.gov/show/NCT00813150 NCT record].''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day
 
−
 
 
−
'''21-day cycle for up to 8 cycles'''
 
−
 
 
−
===Variant #2 {{#subobject:f35a43|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13653/full de Waal et al. 2015]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''Treatment intended for bortezomib-naive patients.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Cycles 1 to 3: 1.3 mg/m<sup>2</sup> IV/SC once per day on days 1, 4, 8, 11
 
−
**Cycles 4 to 6: 1.6 mg/m<sup>2</sup> IV/SC once per day on days 1, 8, 15, 22
 
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day (continuous)
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 3: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
**Cycles 4 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
 
−
 
 
−
====Supportive medications====
 
−
*Pneumococccal and anti-fungal prophylaxis "according to local protocols"
 
−
*[[Valacyclovir (Valtrex)]] (dose not specified) for herpes prophylaxis
 
−
 
 
−
'''21-day cycle for 3 cycles then 35-day cycle for 3 cycles'''
 
−
====Subsequent treatment====
 
−
*Patients with PR/CR: [[#Bortezomib_.26_Cyclophosphamide|Bortezomib & cyclophosphamide maintenance]]
 
−
 
 
−
===Variant #3 {{#subobject:d34841|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06656.x/full Kropff et al. 2007]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
 
 
−
''Treatment intended for bortezomib-naive patients.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Cycles 1 to 3: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
**Cycles 4 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day (continuous)
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 3: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
**Cycles 4 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
 
−
 
 
−
'''21-day cycle for 3 cycles then 35-day cycle for 3 cycles'''
 
−
 
 
−
===References===
 
−
# Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, Dechow T, Kröger N, Salwender H, Metzner B, Sezer O, Engelhardt M, Wolf HH, Einsele H, Volpert S, Heinecke A, Berdel WE, Kienast J; Deutsche Studiengruppe Multiples Myelom,. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007 Aug;138(3):330-7. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06656.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17614819 PubMed]
 
−
# de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13653/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26358087 PubMed]
 
−
# '''CR015247:''' Kropff M, Vogel M, Bisping G, Schlag R, Weide R, Knauf W, Fiechtner H, Kojouharoff G, Kremers S, Berdel WE. Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study. Ann Hematol. 2017 Nov;96(11):1857-1866. Epub 2017 Sep 14. [https://link.springer.com/article/10.1007%2Fs00277-017-3065-z link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28905189 PubMed]
 
−
 
 
−
==VTD {{#subobject:96881b|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VTD: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:5ad72e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/30/20/2475.long Garderet et al. 2012 (MMVAR/IFM 2005-04)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[#Thal-Dex_3|TD]]
 
−
|style="background-color:#1a9850"|Superior TTP
 
−
|-
 
−
|}
 
−
 
 
−
''Intended for patients who have relapsed after an autologous stem-cell transplant''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] as follows:
 
−
**Cycles 1 to 8: 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11 of a 21-day cycle
 
−
**Cycles 9 to 12: 1.3 mg/m<sup>2</sup> IV bolus once per week on days 1, 8, 15, 22 of a 42-day cycle
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4 of a 21-day cycle
 
−
 
 
−
====Supportive medications====
 
−
*[[Enoxaparin (Lovenox)]] 40 mg SC once per day for primary prophylaxis; [[Warfarin (Coumadin)]] for secondary prophylaxis
 
−
*Herpes zoster prophylaxis highly recommended
 
−
 
 
−
'''One year of treatment'''
 
−
 
 
−
===References===
 
−
<!-- Presented at the 37th Annual Meeting of the European Group for Blood and Marrow Transplantation, Paris, France, April, 3-6, 2011. -->
 
−
# '''MMVAR/IFM 2005-04:''' Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, Masszi T, Fontan J, Michallet M, Gratwohl A, Milone G, Doyen C, Pegourie B, Hajek R, Casassus P, Kolb B, Chaleteix C, Hertenstein B, Onida F, Ludwig H, Ketterer N, Koenecke C, van Os M, Mohty M, Cakana A, Gorin NC, de Witte T, Harousseau JL, Morris C, Gahrton G. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012 Jul 10;30(20):2475-82. Epub 2012 May 14. Erratum in: J Clin Oncol. 2012 Sep 20;30(27):3429. [http://jco.ascopubs.org/content/30/20/2475.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22585692 PubMed]
 
−
 
 
−
=Relapsed or refractory, non-randomized or retrospective data=
 
−
 
 
−
==BBD {{#subobject:adb507|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
BBD: '''<u>B</u>'''endamustine, '''<u>B</u>'''ortezomib, '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:cc2b7d|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924931/ Ludwig et al. 2013]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bendamustine]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 4
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] 20 mg (route not specified) once per day on days 1, 4, 8, 11
 
−
 
 
−
'''28-day cycle for up to 8 cycles'''
 
−
 
 
−
===References===
 
−
# Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, Greil R, Seebacher A, Pour L, Weißmann A, Adam Z. Bendamustine-bortezomib-dexamethasone is an active and well tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood. 2014 Feb 13;123(7):985-91. Epub 2013 Nov 13. [http://www.bloodjournal.org/content/123/7/985.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924931/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24227817 PubMed]
 
−
 
 
−
==BLD {{#subobject:e8445|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
BLD: '''<u>B</u>'''endamustine, '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:edc866|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392072/ Lentzsch et al. 2012]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
 
 
−
''Dosages listed are the determined maximally tolerated doses (MTD) of this phase I/II trial.''
 
−
====Chemotherapy====
 
−
*[[Bendamustine]] 75 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg (no route specified) once per week
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 325 mg PO once per day
 
−
*"Gastroprotectant" ([[:Category:H2-receptor antagonists|H2-blocker]] or [[:Category:Proton pump inhibitors|PPI]])
 
−
 
 
−
'''28-day cycle for up to 8 cycles'''
 
−
 
 
−
===References===
 
−
<!-- Preliminary results were presented at the 53rd Annual Meeting of the American Society of Hematology, December 12, 2011, Orlando, FL. -->
 
−
# Lentzsch S, O'Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, Burt S, Boyiadzis M, Roodman GD, Mapara MY, Agha M, Waas J, Shuai Y, Normolle D, Zonder JA. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012 May 17;119(20):4608-13. Epub 2012 Mar 26. [http://www.bloodjournal.org/content/119/20/4608.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392072/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22451423 PubMed]
 
−
 
 
−
==Bortezomib-HyperCAD {{#subobject:00a88b|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
Bortezomib-HyperCAD: Bortezomib, '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
 
−
===Regimen {{#subobject:48e7e9|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(16)30628-0/fulltext Saraceni et al. 2018]
 
−
|style="background-color:#ffffbe"|Retrospective
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1 & 4
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV q12h on days 1 to 4 (8 doses; total dose per cycle: 2400 mg/m<sup>2</sup>)
 
−
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 4 (total dose per cycle: 36 mg/m<sup>2</sup>)
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
 
−
 
 
−
====Supportive Medications====
 
−
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 5 or 6
 
−
*[[Mesna (Mesnex)]] 350 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 4
 
−
*Antiviral prophylaxis with [[Acyclovir (Valtrex)]] daily (dose not specified)
 
−
*"Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"
 
−
 
 
−
'''Duration of each cycle not specified; for most patients, treatment cycles were administered every 4 weeks'''
 
−
 
 
−
===References===
 
−
# '''Retrospective:''' Saraceni MM, Scott E, Maziarz RT, Siegel MB, Bassale S, Jiing S, Medvedova E. Modified hyperCVAD versus bortezomib-hyperCAD in patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e77-e84. [https://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(16)30628-0/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29169873 PubMed]
 
−
 
 
−
==Bortezomib, Thalidomide, Dexamethasone, Panobinostat {{#subobject:6c61d0|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:1bf613|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30165-X/fulltext Popat et al. 2016 (MUK-six)]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
''Note: this is the dose used in the phase II portion of the trial.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1 & 8
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 8, 9
 
−
*[[Panobinostat (Farydak)]] 20 mg PO once per day on days 1, 3, 5, 8, 10, 12
 
−
 
 
−
'''21-day cycle for 16 cycles'''
 
−
 
 
−
===References===
 
−
# Popat R, Brown SR, Flanagan L, Hall A, Gregory W, Kishore B, Streetly M, Oakervee H, Yong K, Cook G, Low E, Cavenagh J; Myeloma UK Early Phase Clinical Trial Network.. Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial. Lancet Haematol. 2016 Dec;3(12):e572-e580. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30165-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27843120 PubMed]
 
−
 
 
−
==BTD {{#subobject:95a10c|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
BTD: '''<u>B</u>'''endamustine, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:57e4a5|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13435/full Schey et al. 2015 (MUK''one'')]
 
−
|style="background-color:#1a9851"|Randomized Phase II (E)
 
−
|BTD with higher-dose benadmustine
 
−
|style="background-color:#d3d3d3"|See below
 
−
|-
 
−
|}
 
−
''This study involved two doses of bendamustine but the higher dose was too toxic, leading to premature closure. Note that while this study was randomized, it was "not powered to directly compare the two arms for statistically significant superiority." Dosage listed is the lower dose.''
 
−
====Chemotherapy====
 
−
*[[Bendamustine]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21
 
−
**'''Note: abstract says days 1 to 21 but body of paper says days 1 to 28'''
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*Thromboprophylaxis (not specified)
 
−
*Anti-infective prophylaxis (not specified)
 
−
 
 
−
'''28-day cycle for 6 to 9 cycles (2 cycles past best response)'''
 
−
 
 
−
===References===
 
−
# Schey S, Brown SR, Tillotson AL, Yong K, Williams C, Davies F, Morgan G, Cavenagh J, Cook G, Cook M, Orti G, Morris C, Sherratt D, Flanagan L, Gregory W, Cavet J; Myeloma UK Early Phase Clinical Trial Network. Bendamustine, thalidomide and dexamethasone combination therapy for relapsed/refractory myeloma patients: results of the MUKone randomized dose selection trial. Br J Haematol. 2015 Aug;170(3):336-48. Epub 2015 Apr 20. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13435/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25891006 PubMed]
 
−
 
 
−
==Carfilzomib & Panobinostat {{#subobject:9d99ab|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:69e42c|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420216/ Berdeja et al. 2015]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV once on days 1 & 2, then 45 mg/m<sup>2</sup> IV over 30 minutes once per day on days 8, 9, 15, 16
 
−
**Cycle 2 onwards: 45 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
*[[Panobinostat (Farydak)]] 30 mg PO once per day on days 1, 3, 5, 15, 17, 19
 
−
 
−
'''28-day cycles until progression or intolerance'''
 
−
 
 
−
===References===
 
−
# Berdeja JG, Hart LL, Mace JR, Arrowsmith ER, Essell JH, Owera RS, Hainsworth JD, Flinn IW. Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma. Haematologica. 2015 May;100(5):670-6. Epub 2015 Feb 20. [http://www.haematologica.org/content/100/5/670 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420216/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25710456 PubMed]
 
−
 
 
−
==CPD {{#subobject:c7d038|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CPD: '''<u>C</u>'''arfilzomib, '''<u>P</u>'''omalidomide, '''<u>D</u>'''examethasone
 
−
<br>KPD: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>P</u>'''omalidomide, '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:1a0484|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643003/ Shah et al. 2015]
 
−
|style="background-color:#91cf61"|Phase I (*)
 
−
|-
 
−
|}
 
−
''Note, although this is described as a Phase I trial, an additional 20 patients were enrolled at the MTD, which is the dose reported here.''
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] as follows:
 
−
**Cycle 1: 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2, then 27 mg/m<sup>2</sup> IV over 30 minutes once per day on days 8, 9, 15, 16
 
−
**Cycles 2 to 6: 27 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16
 
−
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 4: 40 mg PO/IV once per week on days 1, 8, 15, 22
 
−
**Cycles 5 to 6: 20 mg PO/IV once per week on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*"[[:Category:Antivirals|Anti-viral therapy]]"
 
−
*[[Aspirin]] 81 mg PO once per day
 
−
**[[:Category:Low molecular weight heparins|Low molecular weight heparin]] was used in patients intolerant of aspirin
 
−
 
 
−
'''28-day cycle for 6 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#CPD_2|CPD maintenance]]
 
−
 
 
−
===References===
 
−
<!-- # '''Abstract:''' Jatin J. Shah, MD, Edward A. Stadtmauer, MD, Rafat Abonour, MD, Adam D. Cohen, MD, William I. Bensinger, MD, Cristina Gasparetto, MD, Jonathan L. Kaufman, MD, Suzanne Lentzsch, MD, Dan T. Vogl, MD, Robert Z. Orlowski, MD, PhD, Erica L. Kim, MPH, Marti McKinley, BSN, MBA, Brian G.M. Durie, MD. A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma. 2013 ASH Annual Meeting abstract 690. [http://www.myelomabeacon.com/resources/mtgs/ash2013/abs/690/ link to abstract] [http://myeloma.org/pdfs/Shah-74-3909.pdf link to presentation] '''contains verified protocol''' -->
 
−
# Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015 Nov 12;126(20):2284-90. Epub 2015 Sep 17. [http://www.bloodjournal.org/content/126/20/2284.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643003/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26384354 PubMed]
 
−
 
 
−
==CPR {{#subobject:cbf3b8|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CPR: '''<u>C</u>'''yclophosphamide, '''<u>P</u>'''rednisone, '''<u>R</u>'''evlimid (Lenalidomide)
 
−
<br>REP: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>E</u>'''ndoxan (Cyclophosphamide), '''<u>P</u>'''rednisone
 
−
===Variant #1, "REP" {{#subobject:ea6c95|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/128/19/2297.long Nijhof et al. 2016 (REPEAT)]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
''Details are for the MTD/phase II portion of the published phase I/II trial.''
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day
 
−
*[[Prednisone (Sterapred)]] 20 mg PO once per day
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Variant #2, "CPR" {{#subobject:a8e16f|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13100/full Reece et al. 2014]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
 
 
−
''Details are for the phase II portion of the published phase I/II trial.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO on days 1, 8, 15
 
−
*[[Prednisone (Sterapred)]] 100 mg PO once every other day
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Reece DE, Masih-Khan E, Atenafu EG, Jimenez-Zepeda VH, Anglin P, Chen C, Kukreti V, Mikhael JR, Trudel S. Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide for the treatment of patients with relapsed and refractory multiple myeloma. Br J Haematol. 2015 Jan;168(1):46-54. Epub 2014 Aug 22. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13100/full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25146584 PubMed]
 
−
# Nijhof IS, Franssen LE, Levin MD, Bos GM, Broijl A, Klein SK, Koene HR, Bloem AC, Beeker A, Faber LM, van der Spek E, Ypma PF, Raymakers R, van Spronsen DJ, Westerweel PE, Oostvogels R, van Velzen J, van Kessel B, Mutis T, Sonneveld P, Zweegman S, Lokhorst HM, van de Donk NW. Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma. Blood. 2016 Nov;128(19), 2297-2306. Epub 2016 Sep 19. [http://www.bloodjournal.org/content/128/19/2297.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27647864 PubMed]
 
−
 
 
−
==CRD (Cyclophosphamide) {{#subobject:c9ad0a|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CRD: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:81692e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2010.08250.x/full Schey et al. 2010]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
''This is the MTD of this phase I/II trial.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg PO once per day on days 1 & 8
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 8 to 11
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 75 mg PO once per day
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Schey SA, Morgan GJ, Ramasamy K, Hazel B, Ladon D, Corderoy S, Jenner M, Phekoo K, Boyd K, Davies FE. The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study. Br J Haematol. 2010 Aug;150(3):326-33. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2010.08250.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20553268 PubMed]
 
−
 
 
−
==CTD {{#subobject:5d7a75|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:57a0c2|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pubmed/15048060 Dimopoulos et al. 2004]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 150 mg/m<sup>2</sup> PO every 12 hours (before meals) on days 1 to 5
 
−
*[[Thalidomide (Thalomid)]] as follows:
 
−
**Cycles 1 to 3: 400 mg PO every evening on days 1 to 5 and 14 to 18
 
−
**Cycle 4 onwards: 400 mg PO every evening on days 1 to 5
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 3: 20 mg PO every morning after breakfast on days 1 to 5 and 14 to 18
 
−
**Cycle 4 onwards: 20 mg PO every morning after breakfast on days 1 to 5
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Dimopoulos MA, Hamilos G, Zomas A, Gika D, Efstathiou E, Grigoraki V, Poziopoulos C, Xilouri I, Zorzou MP, Anagnostopoulos N, Anagnostopoulos A. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematol J. 2004;5(2):112-7. [https://www.ncbi.nlm.nih.gov/pubmed/15048060 PubMed]
 
−
 
 
−
==Daratumumab monotherapy {{#subobject:d45aea|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:fc9461|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1506348 Lokhorst et al. 2015 (GEN501 part 2)]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01120-4/fulltext Lonial et al. 2016 (SIRIUS)]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''Note: although '''SIRIUS''' was a randomized phase II trial, the randomization was to choose the dose for further assessment in an expansion cohort; the dose chosen (16 mg/kg from the start) is the one reported here:''
 
−
====Chemotherapy====
 
−
*[[Daratumumab (Darzalex)]] as follows:
 
−
**Weeks 1 to 8: 16 mg/kg IV once per week
 
−
**Weeks 9 to 24: 16 mg/kg IV once every 2 weeks
 
−
**Weeks 25 and on: 16 mg/kg IV once every 4 weeks
 
−
**Per the package insert, daratumumab infusion should complete within 15 hours. In Lokhorst et al. 2015, daratumumab was given over 8 hours.
 
−
 
 
−
====Supportive medications====
 
−
''This is a combination of what is listed in the daratumumab package insert and Lokhorst et al. 2015. There were protocol amendments in Lokhorst et al. 2015; listed medications are what was eventually used.''
 
−
*Prior to all daratumumab infusions:
 
−
**[[Methylprednisolone (Solumedrol)]] 100 mg IV prior to every dose of daratumumab. Per the package insert, after the second dose of daratumumab, dose may be reduced to 60 mg IV. Per Lokhorst et al. 2015, after the fourth dose of daratumumab, dose "could be reduced to 50 mg."
 
−
**[[Acetaminophen (Tylenol)]] (paracetamol) 1000 mg (package insert: 650 to 1000 mg) PO 1 to 2 hours prior to daratumumab
 
−
**Antihistamine: [[Clemastine (Tavist)]] 1 mg IV, [[Cetirizine (Zyrtec)]] 10 mg PO, [[Diphenhydramine (Benadryl)]] 25 to 50 mg PO/IV, or equivalent 1 to 2 hours prior to daratumumab
 
−
*Post-treatment medications:
 
−
**[[Methylprednisolone (Solumedrol)]] 20 to 25 mg (package insert: 20 mg) PO or equivalent one and two days after every daratumumab infusion
 
−
**Package insert: "For patients with a history of obstructive pulmonary disorder, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids."
 
−
*Package insert: "Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week of starting DARZALEX and continue for 3 months following treatment"
 
−
 
 
−
'''Given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
===References===
 
−
<!-- # '''Abstract:''' Plesner, Torben, Lokhorst, Henk, Gimsing, Peter, Nahi, Hareth, Lisby, Steen, Richardson, Paul G. Daratumumab, a CD38 Monoclonal Antibody in Patients with Multiple Myeloma - Data From a Dose-Escalation Phase I/II Study. ASH Annual Meeting Abstracts 2012 120: 73 [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/73 link to abstract] -->
 
−
# Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. [http://www.nejm.org/doi/full/10.1056/NEJMoa1506348 link to original article] '''contains verified protocol''' [http://www.nejm.org/doi/full/10.1056/NEJMoa1506348/suppl_file/nejmoa1506348_appendix.pdf link to supplementary appendix] [http://www.nejm.org/doi/full/10.1056/NEJMoa1506348/suppl_file/nejmoa1506348_protocol.pdf link to study protocol] [https://www.ncbi.nlm.nih.gov/pubmed/26308596 PubMed]
 
−
<!-- # '''Abstract:''' Sagar Lonial, Brendan M. Weiss, Saad Zafar Usmani, Seema Singhal, Ajai Chari, Nizar J. Bahlis, Andrew Belch, Amrita Y. Krishnan, Robert A. Vescio, María-Victoria Mateos, Amitabha Mazumder, Robert Z. Orlowski, Heather J Sutherland, Joan Blade, Emma Catherine Scott, Huaibao Feng, Imran Khan, Clarissa M. Uhlar, Tahamtan Ahmadi, Peter Michael Voorhees. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). 2015 ASCO Annual Meeting abstract LBA8512. [http://meetinglibrary.asco.org/content/150339-156 link to abstract] -->
 
−
# '''SIRIUS:''' Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Bladé J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-60. Epub 2016 Jan 7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01120-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26778538 PubMed]
 
−
# '''Pooled update:''' Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, Lokhorst HM, Voorhees PM, Richardson PG, Chari A, Sasser AK, Axel A, Feng H, Uhlar CM, Wang J, Khan I, Ahmadi T, Nahi H. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. Epub 2016 May 23. [http://www.bloodjournal.org/content/128/1/37.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937359/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27216216 PubMed]
 
−
 
 
−
==DCEP {{#subobject:6dd02a|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
DCEP: '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide, '''<u>P</u>'''latinol (Cisplatin)
 
−
 
 
−
===Variant #1 {{#subobject:bba45e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.nature.com/bmt/journal/v28/n9/full/1703240a.html Lazzarino et al. 2001]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''Note: this protocol is reported as a mobilization regimen prior to high dose autologous transplant; all patients had received prior therapy.''
 
−
====Chemotherapy====
 
−
*[[Dexamethasone (Decadron)]] 40 mg once per day on days 1 to 4
 
−
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m<sup>2</sup>)
 
−
*[[Etoposide (Vepesid)]] 40 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m<sup>2</sup>)
 
−
*[[Cisplatin (Platinol)]] 10 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 40 mg/m<sup>2</sup>)
 
−
 
 
−
====Supportive medications====
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 48 hours after chemotherapy and continuing through stem cell collection
 
−
 
 
−
'''One course'''
 
−
 
 
−
===Variant #2 {{#subobject:3b5550|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pubmed/17436400 Dadacaridou et al. 2007]
 
−
|style="background-color:#ffffbe"|Phase II, <20 patients reported
 
−
|-
 
−
|}
 
−
''These limited details are based on the abstract's description only. Full article was not available for review.''
 
−
====Chemotherapy====
 
−
*[[Dexamethasone (Decadron)]] 40 mg IV bolus once per day on days 1 to 4
 
−
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m<sup>2</sup>)
 
−
*[[Etoposide (Vepesid)]] 40 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m<sup>2</sup>)
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup>/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 60 mg/m<sup>2</sup>)
 
−
 
 
−
====Supportive medications====
 
−
*[[Filgrastim (Neupogen) | G-CSF]] SC once per day, starting on day 5, to continue until neutrophil recovery
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Lazzarino M, Corso A, Barbarano L, Alessandrino EP, Cairoli R, Pinotti G, Ucci G, Uziel L, Rodeghiero F, Fava S, Ferrari D, Fiumanò M, Frigerio G, Isa L, Luraschi A, Montanara S, Morandi S, Perego D, Santagostino A, Savarè M, Vismara A, Morra E. DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) is an effective regimen for peripheral blood stem cell collection in multiple myeloma. Bone Marrow Transplant. 2001 Nov;28(9):835-9. [https://www.nature.com/bmt/journal/v28/n9/full/1703240a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11781643 PubMed]
 
−
# Dadacaridou M, Papanicolaou X, Maltesas D, Megalakaki C, Patos P, Panteli K, Repousis P, Mitsouli-Mentzikof C. Dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) for relapsed or refractory multiple myeloma patients. J BUON. 2007 Jan-Mar;12(1):41 to 4. [https://www.ncbi.nlm.nih.gov/pubmed/17436400 PubMed]
 
−
 
 
−
==DTPACE {{#subobject:e5c635|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
DTPACE: '''<u>D</u>'''examethasone, '''<u>T</u>'''halidomide, '''<u>P</u>'''latinol (Cisplatin), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide
 
−
 
 
−
===Regimen {{#subobject:02d8a9|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/21/14/2732.long Lee et al. 2003]
 
−
|style="background-color:#91cf61"|Prospective
 
−
|-
 
−
|}
 
−
To be completed
 
−
====Chemotherapy====
 
−
*[[Dexamethasone (Decadron)]]
 
−
*[[Thalidomide (Thalomid)]]
 
−
*[[Cisplatin (Platinol)]]
 
−
*[[Doxorubicin (Adriamycin)]]
 
−
*[[Cyclophosphamide (Cytoxan)]]
 
−
*[[Etoposide (Vepesid)]]
 
−
 
 
−
===References===
 
−
# Lee CK, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J, van Rhee F, Cottler-Fox M, Muwalla F, Tricot G. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol. 2003 Jul 15;21(14):2732-9. Erratum in: J Clin Oncol. 2008 Apr 20;26(12): 2066. [http://jco.ascopubs.org/content/21/14/2732.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12860952 PubMed]
 
−
 
 
−
==FRD {{#subobject:69c2ac|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
FRD: '''<u>F</u>'''arydak (Panobinostat), '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone
 
−
===Regimen {{#subobject:fe3761|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodadvances.org/content/1/19/1575 Chari et al. 2017]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Panobinostat (Farydak)]] 20 mg PO once per day on days 1, 3, 5, 15, 17, 19
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on days 1, 8, 15
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Chari A, Cho HJ, Dhadwal A, Morgan G, La L, Zarychta K, Catamero D, Florendo E, Stevens N, Verina D, Chan E, Leshchenko V, Laganà A, Perumal D, Mei AH, Tung K, Fukui J, Jagannath S, Parekh S. A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma. Blood Adv. 2017 Aug 21;1(19):1575-1583. eCollection 2017 Aug 22. [http://www.bloodadvances.org/content/1/19/1575 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728465/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29296798 PubMed]
 
−
 
 
−
==Hyper-CVAD {{#subobject:0df285|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
Hyper-CVAD: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
 
−
===Variant #1 {{#subobject:62dcd6|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1096-8652(199606)52:2%3C77::AID-AJH2%3E3.0.CO;2-2/abstract Dimopoulos et al. 1996]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
''To be completed.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]]
 
−
*[[Vincristine (Oncovin)]]
 
−
*[[Doxorubicin (Adriamycin)]]
 
−
*[[Dexamethasone (Decadron)]]
 
−
 
 
−
===Variant #2, modified {{#subobject:2fd9df|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(16)30628-0/fulltext Saraceni et al. 2018]
 
−
|style="background-color:#ffffbe"|Retrospective
 
−
|-
 
−
|}
 
−
''Note that vincristine is a flat dose.''
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV q12h on days 1 to 4 (8 doses; total dose per cycle: 2400 mg/m<sup>2</sup>)
 
−
*[[Vincristine (Oncovin)]] 0.4 mg/day IV continuous infusion on days 1 to 4 (total dose per cycle: 1.6 mg)
 
−
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 4 (total dose per cycle: 36 mg/m<sup>2</sup>)
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
 
−
 
 
−
====Supportive Medications====
 
−
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 5 or 6
 
−
*[[Mesna (Mesnex)]] 350 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 4
 
−
*Antiviral prophylaxis with [[Valacyclovir (Valtrex)]] daily (dose not specified)
 
−
*"Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"
 
−
 
 
−
'''Duration of each cycle not specified; for most patients, treatment cycles were administered every 4 weeks'''
 
−
 
 
−
===References===
 
−
# Dimopoulos MA, Weber D, Kantarjian H, Delasalle KB, Alexanian R. HyperCVAD for VAD-resistant multiple myeloma. Am J Hematol. 1996 Jun;52(2):77-81. [https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1096-8652(199606)52:2%3C77::AID-AJH2%3E3.0.CO;2-2/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8638645 PubMed]
 
−
# '''Retrospective:''' Saraceni MM, Scott E, Maziarz RT, Siegel MB, Bassale S, Jiing S, Medvedova E. Modified hyperCVAD versus bortezomib-hyperCAD in patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e77-e84. [https://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(16)30628-0/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29169873 PubMed]
 
−
 
 
−
==Ixazomib monotherapy {{#subobject:3fe8c1|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:37950f|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558585/ Kumar et al. 2015]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Ixazomib (Ninlaro)]] 5.5 mg PO once per day on days 1, 8, 15
 
−
 
 
−
'''28-day cycles'''
 
−
====Subsequent treatment====
 
−
*Patients with no minor response by end of cycle 2, no PR by end of cycle 4, or progression: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]
 
−
 
 
−
===References===
 
−
# '''Phase 1:''' Kumar SK, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, Hui AM, Gupta N, Di Bacco A, Yu J, Shou Y, Niesvizky R. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014 Aug 14;124(7):1047-55. Epub 2014 Jun 5. [http://www.bloodjournal.org/content/124/7/1047.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468583/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24904120 PubMed]
 
−
# '''Phase 1:''' Richardson PG, Baz R, Wang M, Jakubowiak AJ, Laubach JP, Harvey RD, Talpaz M, Berg D, Liu G, Yu J, Gupta N, Di Bacco A, Hui AM, Lonial S. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014 Aug 14;124(7):1038-46. Epub 2014 Jun 11. [http://www.bloodjournal.org/content/124/7/1038.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574453/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24920586 PubMed]
 
−
# Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015 Aug 14;5:e338. [https://www.nature.com/bcj/journal/v5/n8/full/bcj201560a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558585/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26275080 PubMed]
 
−
 
 
−
==PAD {{#subobject:0f85ca|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
PAD: '''<u>P</u>'''S-341 (Bortezomib), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
 
−
<br>''Note that this regimen is sometimes called VAD but this can create a lot of confusion with the [[Multiple_myeloma_-_historical#VAD|"original" VAD which uses '''<u>V</u>'''incristine]].''
 
−
<br>VAD: '''<u>V</u>'''elcade (Bortezomib), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:34e46e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30049-7/fulltext Cook et al. 2016 (BSBMT/UKMF Myeloma X)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
''Note: length of cycle is not reported in the manuscript, but presumably is 28 days, similar to other PAD regimens.''
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 4
 
−
**Could be given as a 4-day continuous infusion or as bolus injections
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
 
−
**Cycles 2 to 4: 40 mg PO once per day on days 1 to 4
 
−
 
 
−
'''2 to 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Melphalan.2C_then_auto_HSCT_2|High-dose melphalan & autologous hematopoietic cell transplant]] versus weekly oral cyclophosphamide maintenance
 
−
 
 
−
===References===
 
−
# Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):874-85. Epub 2014 Jun 16. Erratum in: Lancet Oncol. 2014 Aug;15(9):e365. Dosage error in article text. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70245-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24948586 PubMed]
 
−
## '''Update:''' Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30049-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27374467 PubMed]
 
−
 
 
−
==PCP {{#subobject:c3aaf2|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
PCP: '''<u>P</u>'''omalidomide, '''<u>C</u>'''yclophosphamide, '''<u>P</u>'''rednisone
 
−
 
 
−
===Regimen {{#subobject:4a5941|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/122/16/2799.full Larocca et al. 2013]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|-
 
−
|}
 
−
 
 
−
''Details are for the phase II portion of the published phase I/II trial.''
 
−
====Chemotherapy====
 
−
*[[Pomalidomide (Pomalyst)]] 2.5 mg PO once per day
 
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once every other day
 
−
*[[Prednisone (Sterapred)]] 50 mg PO once every other day
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|low-molecular-weight heparin]] "according to patient risk"
 
−
 
 
−
'''28-day cycle for 6 cycles'''
 
−
====Subsequent treatment====
 
−
*[[#Pomalidomide_.26_Prednisone|Pomalidomide & prednisone maintenance]]
 
−
 
 
−
===References===
 
−
# Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, Galli M, Marcatti M, La Verde G, Giuliani N, Magarotto V, Guglielmelli T, Rota-Scalabrini D, Omedé P, Santagostino A, Baldi I, Carella AM, Boccadoro M, Corradini P, Palumbo A. Pomalidomide, cyclophosphamide and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013 Oct 17;122(16):2799-806. Epub 2013 Aug 16. [http://www.bloodjournal.org/content/122/16/2799.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23954889 PubMed]
 
−
 
 
−
==Pomalidomide, Dexamethasone, Daratumumab {{#subobject:5538a8|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:d6f1ac|Variant=1}}===
 
−
{| class="wikitable" style="color:white; background-color:#404040"
 
−
|<small>'''FDA-recommended dose'''</small>
 
−
|-
 
−
|}
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/130/8/974.long Chari et al. 2017 (EQUULEUS)]
 
−
|style="background-color:#91cf61"|Phase Ib
 
−
| style="background-color:#9ebcda" |ORR: 59% (95% CI, 49-69)
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week
 
−
**Patients older than 75 years or BMI less than 18.5: 20 mg PO once per week
 
−
*[[Daratumumab (Darzalex)]] as follows:
 
−
**Cycles 1 & 2: 16 mg/kg IV once per week
 
−
**Cycles 3 to 6: 16 mg/kg IV once every 2 weeks
 
−
**Cycle 7 onwards: 16 mg/kg IV once every 4 weeks
 
−
 
 
−
====Supportive medications====
 
−
*[[Dexamethasone (Decadron)]] 20 mg prior to [[Daratumumab (Darzalex)]] infusions
 
−
**For patients receiving the 40 mg/wk dose, the remainder is given after the infusion on day of infusion
 
−
*[[Acetaminophen (Tylenol)]] prior to [[Daratumumab (Darzalex)]]
 
−
*An [[:Category:Antihistamines|antihistamine]] prior to [[Daratumumab (Darzalex)]]
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# '''EQUULEUS:''' Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, Weiss BM, Krishnan A, Lentzsch S, Comenzo R, Wang J, Nottage K, Chiu C, Khokhar NZ, Ahmadi T, Lonial S. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017 Aug 24;130(8):974-981. Epub 2017 Jun 21. [http://www.bloodjournal.org/content/130/8/974.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28637662 PubMed]
 
−
 
 
−
==PVD {{#subobject:bf019d|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
PVD: '''<u>P</u>'''omalidomide, '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:77f633|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606008/ Paludo et al. 2017 (MC1082)]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
| style="background-color:#e0ecf4" |ORR: 86%
 
−
|-
 
−
|}
 
−
''This is the MTD used in the phase II portion of the trial.''
 
−
====Chemotherapy====
 
−
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV/SC once per day on days 1, 8, 15, 22
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 325 mg PO once per day
 
−
**Full dose anticoagulation with [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] could be substituted at physician discretion
 
−
*[[Acyclovir (Zovirax)]] or equivalent for VZV prophylaxis
 
−
 
 
−
'''28-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*Optionally, [[#Pomalidomide_monotherapy_2|pomalidomide maintenance]]
 
−
 
 
−
===References===
 
−
# '''MC1082:''' Paludo J, Mikhael JR, LaPlant BR, Halvorson AE, Kumar S, Gertz MA, Hayman SR, Buadi FK, Dispenzieri A, Lust JA, Kapoor P, Leung N, Russell SJ, Dingli D, Go RS, Lin Y, Gonsalves WI, Fonseca R, Bergsagel PL, Roy V, Sher T, Chanan-Khan AA, Ailawadhi S, Stewart AK, Reeder CB, Richardson PG, Rajkumar SV, Lacy MQ. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma. Blood. 2017 Sep 7;130(10):1198-1204. Epub 2017 Jul 6. [http://www.bloodjournal.org/content/130/10/1198.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606008/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28684537 PubMed]
 
−
 
 
−
==RVD {{#subobject:3f1c8e|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
RVD: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone
 
−
<br>VDR: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>R</u>'''evlimid (Lenalidomide)
 
−
<br>VRD: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone
 
−
<br>VRd: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
===Regimen {{#subobject:bf4291|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!Study
 
−
![[Levels_of_Evidence#Evidence|Evidence]]
 
−
|'''ORR'''
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123434/ Richardson et al. 2014]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|64%
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
**Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 81 mg or 325 mg PO once per day
 
−
*[[:Category:Antivirals|Antiviral]] therapy for VZV prophylaxis
 
−
 
 
−
'''21-day cycle for 8 cycles'''
 
−
====Subsequent treatment====
 
−
*Patients with SD or better: [[#RVD_5|RVD maintenance]] at previously tolerated dose
 
−
 
 
−
===References===
 
−
# Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, Alsina M, Ghobrial IM, Schlossman RL, Munshi NC, Mazumder A, Vesole DH, Kaufman JL, Colson K, McKenney M, Lunde LE, Feather J, Maglio ME, Warren D, Francis D, Hideshima T, Knight R, Esseltine DL, Mitsiades CS, Weller E, Anderson KC. A phase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014 Mar 6;123(10):1461-9. Epub 2014 Jan 15. [http://www.bloodjournal.org/content/123/10/1461.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123434/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24429336 PubMed]
 
−
 
 
−
==Thalidomide monotherapy {{#subobject:ff02e1|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:43a4e3|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJM199911183412102 Singhal et al. 1999]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day, increased by 200 mg every two weeks for six weeks, to final dose of 800 mg per day
 
−
 
 
−
'''Continued until progression'''
 
−
 
 
−
===References===
 
−
# Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565-71. Erratum in: N Engl J Med 2000 Feb 3;342(5):364. [http://www.nejm.org/doi/full/10.1056/NEJM199911183412102 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10564685 PubMed]
 
−
 
 
−
==Vemurafenib monotherapy {{#subobject:c957e9|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:5b6425|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971773/ Hyman et al. 2015]
 
−
|style="background-color:#ffffbe"|Basket trial, <20 pts in subgroup
 
−
|-
 
−
|}
 
−
''Note that Andrulis et al. 2013 is a single patient case report with a good response. Sharman et al. reports two patients with good response. In the Hyman et al. 2015 trial, there were 5 patients with multiple myeloma; "No patients with multiple myeloma have had a response to date."''
 
−
====Chemotherapy====
 
−
*[[Vemurafenib (Zelboraf)]] 960 mg PO BID
 
−
 
 
−
'''Continued indefinitely'''
 
−
 
 
−
===References===
 
−
# '''Case report:''' Andrulis M, Lehners N, Capper D, Penzel R, Heining C, Huellein J, Zenz T, von Deimling A, Schirmacher P, Ho AD, Goldschmidt H, Neben K, Raab MS. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov. 2013 Aug;3(8):862-9. Epub 2013 Apr 23. [http://cancerdiscovery.aacrjournals.org/content/3/8/862.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23612012 PubMed]
 
−
# '''Case series:''' Sharman JP, Chmielecki J, Morosini D, Palmer GA, Ross JS, Stephens PJ, Stafl J, Miller VA, Ali SM. Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma. Clin Lymphoma Myeloma Leuk. 2014 Oct;14(5):e161-3. Epub 2014 Jun 11. [http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(14)00138-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24997557 PubMed]
 
−
# Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015 Aug 20;373(8):726-36. [http://www.nejm.org/doi/full/10.1056/NEJMoa1502309 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971773/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26287849 PubMed]
 
−
 
 
−
==VMPT {{#subobject:c7cda5|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
VMPT: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>T</u>'''halidomide
 
−
 
 
−
===Regimen {{#subobject:d55f41|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/109/7/2767.full Palumbo et al. 2007]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1 to 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 15, 22
 
−
*[[Melphalan (Alkeran)]] 6 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
−
*[[Thalidomide (Thalomid)]] 50 mg PO once per day on days 1 to 35
 
−
 
 
−
'''35-day cycle for 6 cycles'''
 
−
 
 
−
===References===
 
−
# Palumbo A, Ambrosini MT, Benevolo G, Pregno P, Pescosta N, Callea V, Cangialosi C, Caravita T, Morabito F, Musto P, Bringhen S, Falco P, Avonto I, Cavallo F, Boccadoro M; Italian Multiple Myeloma Network; Gruppo Italiano Malattie Ematologicche dell'Adulto. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood. 2007 Apr 1;109(7):2767-72. [http://www.bloodjournal.org/content/109/7/2767.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17148584 PubMed]
 
−
 
 
−
==ZRd {{#subobject:4e6061|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
ZRd: '''<u>Z</u>'''olinza (Vorinostat), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
===Regimen {{#subobject:0c164a|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.14429/abstract Sanchez et al. 2016]
 
−
|style="background-color:#91cf61"|Phase IIb
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Vorinostat (Zolinza)]] 400 mg PO once per day on days 1 to 7, 15 to 21
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 40 mg PO once per week on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Sanchez L, Vesole DH, Richter JR, Biran N, Bilotti E, McBride L, Anand P, Ivanovski K, Siegel DS. A phase IIb trial of vorinostat in combination with lenalidomide and dexamethasone in patients with multiple myeloma refractory to previous lenalidomide-containing regimens. Br J Haematol. 2017 Feb;176(3):440-447. Epub 2016 Nov 18. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14429/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27859001 PubMed]
 
−
<section end=rrmm />
 
−
<section begin=rrmm-consol />
 
−
=Consolidation after second-line therapy=
 
−
 
 
−
==Bortezomib monotherapy {{#subobject:bb5567|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:ba71b2|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa043445 Richardson et al. 2005 (APEX)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_3|High-dose dexamethasone]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS (*)
 
−
|-
 
−
|}
 
−
''Note: efficacy is reported based on the 2007 update.''
 
−
====Preceding treatment====
 
−
*[[#Bortezomib_monotherapy_3|Bortezomib induction]]
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*[[:Category:Bisphosphonates|Bisphosphonate]] IV therapy once every 3 to 4 weeks unless contraindicated
 
−
 
 
−
'''35-day cycle for 3 cycles'''
 
−
 
 
−
===References===
 
−
# '''APEX:''' Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005 Jun 16;352(24):2487-98. [http://www.nejm.org/doi/full/10.1056/NEJMoa043445 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15958804 PubMed]
 
−
## '''Update:''' Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Miguel JS, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007 Nov 15;110(10):3557-60. Epub 2007 Aug 9. [http://www.bloodjournal.org/content/110/10/3557.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17690257 PubMed]
 
−
 
 
−
==Melphalan, then auto HSCT {{#subobject:149d91|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:83243a|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70245-1/fulltext Cook et al. 2014 (NCRI Myeloma X Relapse)]
 
−
|style="background-color:#1a9851"|Phase III (E)
 
−
|Cyclophosphamide
 
−
|style="background-color:#91cf60"|Seems to have superior OS (*)
 
−
|-
 
−
|}
 
−
''Efficacy reported is based on the 2016 update.''
 
−
====Preceding treatment====
 
−
*[[#PAD_2|PAD]] x 4
 
−
====Preparative regimen====
 
−
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV on day -2
 
−
 
 
−
'''Stem cells re-infused on day 0'''
 
−
 
 
−
===References===
 
−
# '''NCRI Myeloma X Relapse:''' Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):874-85. Epub 2014 Jun 16. Erratum in: Lancet Oncol. 2014 Aug;15(9):e365. Dosage error in article text. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70245-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24948586 PubMed]
 
−
## '''Update:''' Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30049-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27374467 PubMed]
 
−
 
 
−
=Maintenance after second-line therapy=
 
−
 
 
−
==Bortezomib monotherapy {{#subobject:2c45eb|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:366c79|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|Comparator
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737504/ Orlowski et al. 2015]
 
−
|style="background-color:#1a9851"|Randomized Phase II (C)
 
−
|Bortezomib & Siltuximab
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#Bortezomib_monotherapy_3|Bortezomib induction]]
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
 
 
−
'''35-day cycles'''
 
−
===References===
 
−
# Orlowski RZ, Gercheva L, Williams C, Sutherland H, Robak T, Masszi T, Goranova-Marinova V, Dimopoulos MA, Cavenagh JD, Špička I, Maiolino A, Suvorov A, Bladé J, Samoylova O, Puchalski TA, Reddy M, Bandekar R, van de Velde H, Xie H, Rossi JF. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol. 2015 Jan;90(1):42-9. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737504/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25294016 PubMed]
 
−
 
 
−
==Bortezomib & Cyclophosphamide {{#subobject:eaadfe|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:5e9a21|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13653/full de Waal et al. 2015]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#VDC_2|VDC]] x 6
 
−
 
 
−
====Chemotherapy====
 
−
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV/SC every 2 weeks
 
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day (continuous)
 
−
 
 
−
====Supportive medications====
 
−
*Pneumococccal and anti-fungal prophylaxis "according to local protocols"
 
−
*[[Valacyclovir (Valtrex)]] (dose not specified) for herpes prophylaxis
 
−
 
 
−
'''1-year course'''
 
−
 
 
−
===References===
 
−
# de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13653/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26358087 PubMed]
 
−
 
 
−
==CPD {{#subobject:bfa533|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CPD: '''<u>C</u>'''arfilzomib, '''<u>P</u>'''omalidomide, '''<u>D</u>'''examethasone
 
−
<br>KPD: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>P</u>'''omalidomide, '''<u>D</u>'''examethasone
 
−
 
 
−
===Regimen {{#subobject:edd05b|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643003/ Shah et al. 2015]
 
−
|style="background-color:#91cf61"|Phase I (*)
 
−
|-
 
−
|}
 
−
''Note, although this is described as a Phase I trial, an additional 20 patients were enrolled at the MTD, which is the dose reported here.''
 
−
====Preceding treatment====
 
−
*[[#CPD|CPD]] x 6
 
−
====Chemotherapy====
 
−
*[[Carfilzomib (Kyprolis)]] 27 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 2, 15, 16
 
−
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21
 
−
*[[Dexamethasone (Decadron)]] 20 mg PO/IV once per week on days 1, 8, 15, 22
 
−
 
 
−
====Supportive medications====
 
−
*"[[:Category:Antivirals|Anti-viral therapy]]"
 
−
*[[Aspirin]] 81 mg PO once per day
 
−
**[[:Category:Low molecular weight heparins|Low molecular weight heparin]] was used in patients intolerant of aspirin
 
−
 
 
−
'''28-day cycles, given until disease progression, or unacceptable toxicity'''
 
−
 
 
−
===References===
 
−
<!-- # '''Abstract:''' Jatin J. Shah, MD, Edward A. Stadtmauer, MD, Rafat Abonour, MD, Adam D. Cohen, MD, William I. Bensinger, MD, Cristina Gasparetto, MD, Jonathan L. Kaufman, MD, Suzanne Lentzsch, MD, Dan T. Vogl, MD, Robert Z. Orlowski, MD, PhD, Erica L. Kim, MPH, Marti McKinley, BSN, MBA, Brian G.M. Durie, MD. A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma. 2013 ASH Annual Meeting abstract 690. [http://www.myelomabeacon.com/resources/mtgs/ash2013/abs/690/ link to abstract] [http://myeloma.org/pdfs/Shah-74-3909.pdf link to presentation] '''contains verified protocol''' -->
 
−
# '''Phase I:''' Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015 Nov 12;126(20):2284-90. Epub 2015 Sep 17. [http://www.bloodjournal.org/content/126/20/2284.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643003/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26384354 PubMed]
 
−
 
 
−
==Daratumumab monotherapy {{#subobject:05dc39|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:05fb0a|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1606038 Palumbo et al. 2016 (CASTOR)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#DVd_2|DVd]] x 8
 
−
====Chemotherapy====
 
−
*[[Daratumumab (Darzalex)]] 16 mg/kg IV once on day 1
 
−
 
 
−
'''28-day cycles until progression'''
 
−
 
 
−
===References===
 
−
<!-- # ASCO 2016 Abstract LBA4 -->
 
−
# '''CASTOR:''' Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. [http://www.nejm.org/doi/full/10.1056/NEJMoa1606038 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1606038/suppl_file/nejmoa1606038_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27557302 PubMed]
 
−
 
 
−
==Pomalidomide monotherapy {{#subobject:5d4f4d|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
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===Regimen {{#subobject:a3138c|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!Study
 
−
![[Levels_of_Evidence#Evidence|Evidence]]
 
−
|'''ORR'''
 
−
|-
 
−
|[http://www.bloodjournal.org/content/130/10/1198.long Paludo et al. 2017]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|86%
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#PVD|PVD]] x 8
 
−
====Chemotherapy====
 
−
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 325 mg PO once per day
 
−
**Full dose anticoagulation with [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] could be substituted at physician discretion
 
−
*[[Acyclovir (Zovirax)]] or equivalent for VZV prophylaxis
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===References===
 
−
# Paludo J, Mikhael JR, LaPlant BR, Halvorson AE, Kumar S, Gertz MA, Hayman SR, Buadi FK, Dispenzieri A, Lust JA, Kapoor P, Leung N, Russell SJ, Dingli D, Go RS, Lin Y, Gonsalves WI, Fonseca R, Bergsagel PL, Roy V, Sher T, Chanan-Khan AA, Ailawadhi S, Stewart AK, Reeder CB, Richardson PG, Rajkumar SV, Lacy MQ. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma. Blood. 2017 Sep 7;130(10):1198-1204. Epub 2017 Jul 6. [http://www.bloodjournal.org/content/130/10/1198.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28684537 PubMed]
 
−
 
 
−
==Pomalidomide & Prednisone {{#subobject:519843|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
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|[[#top|back to top]]
 
−
|}
 
−
 
 
−
===Regimen {{#subobject:171099|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!Study
 
−
![[Levels_of_Evidence#Evidence|Evidence]]
 
−
|'''ORR'''
 
−
|-
 
−
|[http://www.bloodjournal.org/content/122/16/2799.full Larocca et al. 2013]
 
−
|style="background-color:#91cf61"|Phase I/II
 
−
|51%
 
−
|-
 
−
|}
 
−
''Details are for the phase II portion of the published phase I/II trial.''
 
−
====Preceding treatment====
 
−
*[[#PCP|PCP]] x 6
 
−
====Chemotherapy====
 
−
*[[Pomalidomide (Pomalyst)]] 1 mg PO once per day
 
−
*[[Prednisone (Sterapred)]] 25 mg PO once every other day
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|low-molecular-weight heparin]] "according to patient risk"
 
−
 
 
−
'''Continuously until any signs of relapse or progression'''
 
−
 
 
−
===References===
 
−
# Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, Galli M, Marcatti M, La Verde G, Giuliani N, Magarotto V, Guglielmelli T, Rota-Scalabrini D, Omedé P, Santagostino A, Baldi I, Carella AM, Boccadoro M, Corradini P, Palumbo A. Pomalidomide, cyclophosphamide and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013 Oct 17;122(16):2799-806. Epub 2013 Aug 16. [http://www.bloodjournal.org/content/122/16/2799.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23954889 PubMed]
 
−
 
 
−
==RVD {{#subobject:fe8a85|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|-
 
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−
|}
 
−
RVD: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone
 
−
<br>VDR: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>R</u>'''evlimid (Lenalidomide)
 
−
<br>VRD: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone
 
−
<br>VRd: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone
 
−
===Regimen {{#subobject:0c163e|Variant=1}}===
 
−
{| class="wikitable" style="width: 100%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123434/ Richardson et al. 2014]
 
−
|style="background-color:#91cf61"|Phase II
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#RVD_4|Salvage RVD]]
 
−
====Chemotherapy====
 
−
*[[Lenalidomide (Revlimid)]] (at previously tolerated dose) PO once per day on days 1 to 14
 
−
*[[Bortezomib (Velcade)]] (at previously tolerated dose) IV once per day on days 1 & 8
 
−
*[[Dexamethasone (Decadron)]] 10 mg PO once per day on days 1, 2, 8, 9
 
−
 
 
−
====Supportive medications====
 
−
*[[Aspirin]] 81 mg or 325 mg PO once per day
 
−
*[[:Category:Antivirals|Antiviral]] therapy for VZV prophylaxis
 
−
 
 
−
'''21-day cycles until progression or intolerance'''
 
−
 
 
−
===References===
 
−
# Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, Alsina M, Ghobrial IM, Schlossman RL, Munshi NC, Mazumder A, Vesole DH, Kaufman JL, Colson K, McKenney M, Lunde LE, Feather J, Maglio ME, Warren D, Francis D, Hideshima T, Knight R, Esseltine DL, Mitsiades CS, Weller E, Anderson KC. A phase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014 Mar 6;123(10):1461-9. Epub 2014 Jan 15. [http://www.bloodjournal.org/content/123/10/1461.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123434/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24429336 PubMed]
 
−
<section end=rrmm-consol />
 
 
<section begin=bottom />
 
<section begin=bottom />
−
=Investigational agents=
 
−
''These are drugs under study with at least some promising results for this disease.''
 
−
 
−
*[[Afuresertib (GSK2110183)]]
 
−
*[[Dinaciclib (SCH 727965)]]
 
−
*[[Isatuximab (SAR-650984)]]
 
−
*[[MOR202]]
 
−
*[[Perifosine (KRX-0401)]]
 
−
*[[Ricolinostat (ACY-1215, Rocilinostat)]]
 
−
*[[Selinexor (KPT-330)]]
 
  
 
=Response criteria=
 
=Response criteria=
−
*[https://www.nature.com/leu/journal/v20/n9/full/2404284a.html IMWG international uniform response criteria for multiple myeloma. (Durie et al. Leukemia 2006)] [https://www.ncbi.nlm.nih.gov/pubmed/16855634 PubMed]
+
*[https://www.nature.com/leu/journal/v20/n9/full/2404284a.html IMWG international uniform response criteria for multiple myeloma. (Durie et al. Leukemia 2006)] [https://pubmed.ncbi.nlm.nih.gov/16855634/ PubMed]
 
**[https://www.nature.com/leu/journal/v21/n5/full/2404582a.html Make note of these errors] which remain in the online version of the IMWG criteria as of 7/7/2013.
 
**[https://www.nature.com/leu/journal/v21/n5/full/2404582a.html Make note of these errors] which remain in the online version of the IMWG criteria as of 7/7/2013.
−
**[https://www.nature.com/leu/journal/v29/n12/full/leu2015290a.html Clarification of the definition of complete response in multiple myeloma (Leukemia 2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26487274 PubMed]
+
**[https://www.nature.com/leu/journal/v29/n12/full/leu2015290a.html Clarification of the definition of complete response in multiple myeloma (Leukemia 2015)] [https://pubmed.ncbi.nlm.nih.gov/26487274/ PubMed]
 
*[https://www.nature.com/leu/journal/v20/n9/fig_tab/2404284t6.html#figure-title Disease progression criteria (Durie et al. Leukemia 2006)].
 
*[https://www.nature.com/leu/journal/v20/n9/fig_tab/2404284t6.html#figure-title Disease progression criteria (Durie et al. Leukemia 2006)].
−
*[https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.1998.00930.x/full European Blood and Marrow Transplant (EBMT) criteria. (Bladé et al. Br J Hematol 1998)] [https://www.ncbi.nlm.nih.gov/pubmed/9753033 PubMed]
+
*[https://doi.org/10.1046/j.1365-2141.1998.00930.x European Blood and Marrow Transplant (EBMT) criteria. (Bladé et al. Br J Hematol 1998)] [https://pubmed.ncbi.nlm.nih.gov/9753033/ PubMed]
  
 
=Prognosis=
 
=Prognosis=
  
 
==[http://myeloma.org/pdfs/Durie-SalmonSS.pdf Durie-Salmon Staging System] - 1975==
 
==[http://myeloma.org/pdfs/Durie-SalmonSS.pdf Durie-Salmon Staging System] - 1975==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Composed of four factors with a modifier based on renal function===
 
===Composed of four factors with a modifier based on renal function===
 
*Serum levels of monoclonal protein (only defined for IgM, IgA, and Bence-Jones)
 
*Serum levels of monoclonal protein (only defined for IgM, IgA, and Bence-Jones)
Line 8,079: Line 105:
  
 
===References===
 
===References===
−
#Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975 Sep;36(3):842-54. [https://onlinelibrary.wiley.com/doi/10.1002/1097-0142(197509)36:3%3C842::AID-CNCR2820360303%3E3.0.CO;2-U/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1182674 PubMed]
+
#Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975 Sep;36(3):842-54. [https://doi.org/10.1002/1097-0142(197509)36:3%3C842::AID-CNCR2820360303%3E3.0.CO;2-U link to original article] [https://pubmed.ncbi.nlm.nih.gov/1182674/ PubMed]
  
 
==[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2627786/table/T3/ International Staging System (ISS)] - 2005==
 
==[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2627786/table/T3/ International Staging System (ISS)] - 2005==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Composed of two factors===
 
===Composed of two factors===
 
*Serum albumin level
 
*Serum albumin level
Line 8,100: Line 123:
  
 
===References===
 
===References===
−
# Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J. International staging system for multiple myeloma. J Clin Oncol. 2005 May 20;23(15):3412-20. Epub 2005 Apr 4. [http://jco.ascopubs.org/content/23/15/3412.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15809451 PubMed]
+
# Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J. International staging system for multiple myeloma. J Clin Oncol. 2005 May 20;23(15):3412-20. Epub 2005 Apr 4. [https://doi.org/10.1200/jco.2005.04.242 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15809451/ PubMed]
−
# Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009 Jan;23(1):3-9. Epub 2008 Oct 30. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2627786/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18971951 PubMed]
+
# Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009 Jan;23(1):3-9. Epub 2008 Oct 30. [https://doi.org/10.1038/leu.2008.291 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2627786/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18971951/ PubMed]
  
 
==IMWG consensus on risk stratification - 2013==
 
==IMWG consensus on risk stratification - 2013==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Composed of four factors===
 
===Composed of four factors===
 
*Serum albumin level
 
*Serum albumin level
Line 8,126: Line 146:
  
 
===References===
 
===References===
−
# Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentzsch S, Munshi N, Palumbo A, Miguel JS, Sonneveld P, Cavo M, Usmani S, Durie BG, Avet-Loiseau H; International Myeloma Working Group. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014 Feb;28(2):269-77. Epub 2013 Aug 26. Review. [https://www.nature.com/leu/journal/v28/n2/full/leu2013247a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23974982 PubMed]
+
# Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentzsch S, Munshi N, Palumbo A, San Miguel J, Sonneveld P, Cavo M, Usmani S, Durie BG, Avet-Loiseau H; International Myeloma Working Group. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014 Feb;28(2):269-77. Epub 2013 Aug 26. [https://www.nature.com/leu/journal/v28/n2/full/leu2013247a.html link to original article] [https://pubmed.ncbi.nlm.nih.gov/23974982/ PubMed]
  
 
==[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846284/ Revised International Staging System (R-ISS)] - 2015==
 
==[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846284/ Revised International Staging System (R-ISS)] - 2015==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Composed of four factors===
 
===Composed of four factors===
 
*Serum albumin level
 
*Serum albumin level
Line 8,153: Line 170:
  
 
===References===
 
===References===
−
# Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P. Revised International Staging System for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015 Sep 10;33(26):2863-9. Epub 2015 Aug 3. [http://jco.ascopubs.org/content/33/26/2863.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846284/ link to PMC article]
+
# Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P. Revised International Staging System for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015 Sep 10;33(26):2863-9. Epub 2015 Aug 3. [https://doi.org/10.1200/jco.2015.61.2267 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846284/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26240224/ PubMed]
  
 
==Miscellaneous==
 
==Miscellaneous==
−
# Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, Leyvraz S, Michallet M, Yakoub-Agha I, Garderet L, Marit G, Michaux L, Voillat L, Renaud M, Grosbois B, Guillerm G, Benboubker L, Monconduit M, Thieblemont C, Casassus P, Caillot D, Stoppa AM, Sotto JJ, Wetterwald M, Dumontet C, Fuzibet JG, Azais I, Dorvaux V, Zandecki M, Bataille R, Minvielle S, Harousseau JL, Facon T, Mathiot C. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007 Apr 15;109(8):3489-95. Epub 2007 Jan 5. [http://www.bloodjournal.org/content/109/8/3489.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17209057 PubMed]
+
# Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, Leyvraz S, Michallet M, Yakoub-Agha I, Garderet L, Marit G, Michaux L, Voillat L, Renaud M, Grosbois B, Guillerm G, Benboubker L, Monconduit M, Thieblemont C, Casassus P, Caillot D, Stoppa AM, Sotto JJ, Wetterwald M, Dumontet C, Fuzibet JG, Azais I, Dorvaux V, Zandecki M, Bataille R, Minvielle S, Harousseau JL, Facon T, Mathiot C. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007 Apr 15;109(8):3489-95. Epub 2007 Jan 5. [https://doi.org/10.1182/blood-2006-08-040410 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17209057/ PubMed]
−
# Avet-Loiseau H, Hulin C, Campion L, Rodon P, Marit G, Attal M, Royer B, Dib M, Voillat L, Bouscary D, Caillot D, Wetterwald M, Pegourie B, Lepeu G, Corront B, Karlin L, Stoppa AM, Fuzibet JG, Delbrel X, Guilhot F, Kolb B, Decaux O, Lamy T, Garderet L, Allangba O, Lifermann F, Anglaret B, Moreau P, Harousseau JL, Facon T. Chromosomal abnormalities are major prognostic factors in elderly patients with multiple myeloma: the Intergroupe Francophone du Myélome experience. J Clin Oncol. 2013 Aug 1;31(22):2806-9. Epub 2013 Jun 24. [http://jco.ascopubs.org/content/31/22/2806.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718879/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23796999 PubMed]
+
# Avet-Loiseau H, Hulin C, Campion L, Rodon P, Marit G, Attal M, Royer B, Dib M, Voillat L, Bouscary D, Caillot D, Wetterwald M, Pegourie B, Lepeu G, Corront B, Karlin L, Stoppa AM, Fuzibet JG, Delbrel X, Guilhot F, Kolb B, Decaux O, Lamy T, Garderet L, Allangba O, Lifermann F, Anglaret B, Moreau P, Harousseau JL, Facon T. Chromosomal abnormalities are major prognostic factors in elderly patients with multiple myeloma: the Intergroupe Francophone du Myélome experience. J Clin Oncol. 2013 Aug 1;31(22):2806-9. Epub 2013 Jun 24. [https://doi.org/10.1200/jco.2012.46.2598 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718879/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23796999/ PubMed]
  
 
=External links=
 
=External links=
 
*[https://www.msmart.org/ Mayo Clinic mSMART (Stratification for Myeloma And Risk-adapted Therapy)]
 
*[https://www.msmart.org/ Mayo Clinic mSMART (Stratification for Myeloma And Risk-adapted Therapy)]
 +
*[https://twitter.com/VincentRK/status/1231334776197480450 Myeloma Patient FAQs by Dr. Vincent Rajkumar (Twitter - no longer works unless you are a Twitter user)]
  
 
=References=
 
=References=
 
<references/>
 
<references/>
 +
<section end=bottom />
  
−
[[Category:Multiple myeloma regimens]]
+
[[Category:Null pages]]
−
[[Category:Disease-specific pages]]
 
−
[[Category:Plasma cell dyscrasias]]
 
−
<section end=bottom />
 

Revision as of 01:41, 27 June 2024

Back to Top

Section editor
Samuelrubinstein.jpg
 Samuel M. Rubinstein, MD
University of North Carolina
Chapel Hill, NC, USA
LinkedIn

Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!

Note: due to its size/complexity, the multiple myeloma page has been split into sub-pages:

This page will remain as a consolidated location for guidelines and prognostic information.

  • We have moved How I Treat articles to a dedicated page.


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO/CCO

BSH/UKMF

European Myeloma Network (EMN)

EHA/ESMO

IMWG

NCCN

SITC

Response criteria

Prognosis

Durie-Salmon Staging System - 1975

Composed of four factors with a modifier based on renal function

  • Serum levels of monoclonal protein (only defined for IgM, IgA, and Bence-Jones)
  • Number of lytic bone lesions
  • Hemoglobin
  • Serum calcium level

Risk stratification

  • Stage I: (must meet ALL criteria)
    • Hemoglobin greater than 10 g/dL
    • Calcium normal or less than or equal to 12 mg/dL
    • Skeletal survey with normal bone structure (scale 0) or solitary bone plasmacytoma only
    • Monoclonal protein relatively small (IgG M-spike value less than 5 g/dL OR IgA M-spike value less than 3 g/dL OR urine light chain protein less than 4 g/24 hr)
  • Stage II: not stage I or stage III
  • Stage III: (if meets ANY of the criteria)
    • Hemoglobin less than 8.5 g/dL
    • Calcium greater than 12 mg/dL
    • Skeletal survey with extensive skeletal destruction and major fractures
    • Monoclonal protein relatively large (IgG M-spike value greater than 7 g/dL OR IgA M-spike value greater than 5 g/dL OR urine light chain protein greater than 12 g/24 hr)

Modifier

  • A: relatively normal creatinine (less than 2 mg/dL)
  • B: creatinine greater than or equal to 2 mg/dL

References

  1. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975 Sep;36(3):842-54. link to original article PubMed

International Staging System (ISS) - 2005

Composed of two factors

  • Serum albumin level
  • Serum beta-2 microglobulin level

Risk stratification

  • Stage I: Median survival of 62 months
    • Beta-2 microglobulin less than 3.5 mg/l
    • Albumin greater than or equal to 3.5 g/dl
  • Stage II: Median survival of 44 months
    • Not meeting stage I or stage III criteria
  • Stage III: Median survival of 29 months
    • Beta-2 microglobulin greater than or equal to 5.5 mg/l

References

  1. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J. International staging system for multiple myeloma. J Clin Oncol. 2005 May 20;23(15):3412-20. Epub 2005 Apr 4. link to original article PubMed
  2. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009 Jan;23(1):3-9. Epub 2008 Oct 30. link to original article link to PMC article PubMed

IMWG consensus on risk stratification - 2013

Composed of four factors

  • Serum albumin level
  • Serum beta-2 microglobulin level
  • Age
  • Chromosomal abnormalities detected by interphase fluorescent in situ hybridization (FISH)

Risk stratification

  • Low risk: (must meet all criteria) Median survival of greater than 10 years
    • ISS Stage I or II
    • Age less than 55 years
    • Absence of the following: del(17p13), t(4;14), +1q21
  • Standard risk: Median survival of 7 years
    • Not meeting low risk or high risk criteria
  • High risk: (if meets both criteria) Median survival of 2 years
    • ISS Stage II or III
    • Either of the following: del(17p13) or t(4;14)

References

  1. Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentzsch S, Munshi N, Palumbo A, San Miguel J, Sonneveld P, Cavo M, Usmani S, Durie BG, Avet-Loiseau H; International Myeloma Working Group. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014 Feb;28(2):269-77. Epub 2013 Aug 26. link to original article PubMed

Revised International Staging System (R-ISS) - 2015

Composed of four factors

  • Serum albumin level
  • Serum beta-2 microglobulin level
  • Serum LDH
  • Chromosomal abnormalities detected by interphase fluorescent in situ hybridization (FISH)

Risk stratification

  • Low risk: 5-year overall survival = 82%
    • Beta-2 microglobulin less than 3.5 mg/l
    • Albumin less than or equal to 3.5 g/dl
    • LDH less than the upper limit of normal range
    • Absence of the following: del(17p), t(4;14), t(14;16)
  • Intermediate risk: 5-year overall survival = 62%
    • Not meeting low risk or high risk criteria
  • High risk: (if meets ANY of the criteria) 5-year overall survival = 40%
    • Beta-2 microglobulin greater than or equal to 5.5 mg/l
    • LDH greater than the upper limit of normal range
    • Any of the following: del(17p), t(4;14), t(14;16)

References

  1. Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P. Revised International Staging System for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015 Sep 10;33(26):2863-9. Epub 2015 Aug 3. link to original article link to PMC article PubMed

Miscellaneous

  1. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, Leyvraz S, Michallet M, Yakoub-Agha I, Garderet L, Marit G, Michaux L, Voillat L, Renaud M, Grosbois B, Guillerm G, Benboubker L, Monconduit M, Thieblemont C, Casassus P, Caillot D, Stoppa AM, Sotto JJ, Wetterwald M, Dumontet C, Fuzibet JG, Azais I, Dorvaux V, Zandecki M, Bataille R, Minvielle S, Harousseau JL, Facon T, Mathiot C. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007 Apr 15;109(8):3489-95. Epub 2007 Jan 5. link to original article PubMed
  2. Avet-Loiseau H, Hulin C, Campion L, Rodon P, Marit G, Attal M, Royer B, Dib M, Voillat L, Bouscary D, Caillot D, Wetterwald M, Pegourie B, Lepeu G, Corront B, Karlin L, Stoppa AM, Fuzibet JG, Delbrel X, Guilhot F, Kolb B, Decaux O, Lamy T, Garderet L, Allangba O, Lifermann F, Anglaret B, Moreau P, Harousseau JL, Facon T. Chromosomal abnormalities are major prognostic factors in elderly patients with multiple myeloma: the Intergroupe Francophone du Myélome experience. J Clin Oncol. 2013 Aug 1;31(22):2806-9. Epub 2013 Jun 24. link to original article link to PMC article PubMed

External links

References

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