Multiple myeloma, consolidation and maintenance

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 Samuel M. Rubinstein, MD
University of North Carolina
Chapel Hill, NC, USA
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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 historical regimens page. If you still can't find it, please let us know so we can add it!.
Note: due to its size/complexity, multiple myeloma has been split into sub-pages:

30 regimens on this page
68 variants on this 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

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

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mellqvist et al. 2013 (NMSG 15/05) 2005-2009 Phase 3 (E-esc) Observation Might have superior PFS (primary endpoint)

This trial only included bortezomib-naive patients; induction regimen was not specified but the majority received Cy-Dex.

Preceding treatment

Targeted therapy

  • Bortezomib (Velcade) as follows:
    • Cycles 1 & 2: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
    • Cycles 3 to 6: 1.3 mg/m2 IV once per day on days 1, 8, 15

Supportive therapy

21-day cycle for 2 cycles, then 28-day cycle for 4 cycles


Regimen variant #2, 4 out of 5 weeks for 20 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Einsele et al. 2017 (MMY-3012) 2006-2013 Phase 3 (E-esc) Observation Seems to have superior PFS1
Median PFS: 33.6 vs 27.8 mo
(HR 0.75, 95% CI 0.59-0.97)
Einsele et al. 2017 (MMY-3013) 2006-2013 Phase 3 (E-esc) Observation Seems to have superior PFS1
Median PFS: 33.6 vs 27.8 mo
(HR 0.75, 95% CI 0.59-0.97)

1Reported efficacy is based on the combined analysis.

Targeted therapy

35-day cycle for 4 cycles


Regimen variant #3, 4 out of 5 weeks for 25 weeks

Study Dates of enrollment Evidence
Niesvizky et al. 2015 (UPFRONT) 2007-2010 Non-randomized part of phase 3b RCT

Preceding treatment

  • Induction Vd x 8 versus VMP x 8 versus VTD x 8

Targeted therapy

35-day cycle for 5 cycles


Regimen variant #4, 4 out of 6 weeks for 24 weeks

Study Dates of enrollment Evidence
Kumar et al. 2012 (EVOLUTION) 2008-2009 Non-randomized part of phase 2 RCT

Preceding treatment

Targeted therapy

Supportive therapy

42-day cycle for 4 cycles

References

  1. 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. link to original article contains dosing details in manuscript PubMed NCT00507442
  2. 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00417911
  3. 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. link to original article contains dosing details in manuscript PubMed NCT00507416
  4. MMY-3012: Einsele H, Knop S, Vogel M, Müller J, Kropff M, Metzner B, Langer C, Sayer H, Jung W, Dürk HA, Salwender H, Wandt H, Bassermann F, Gramatzki M, Rösler W, Wolf HH, Brugger W, Engelhardt M, Fischer T, Liebisch P, Straka C. Response-adapted consolidation with bortezomib after ASCT improves progression-free survival in newly diagnosed multiple myeloma. Leukemia. 2017 Jun;31(6):1463-1466. Epub 2017 Mar 15. link to original article contains dosing details in manuscript PubMed NCT00416273
  5. MMY-3013: Einsele H, Knop S, Vogel M, Müller J, Kropff M, Metzner B, Langer C, Sayer H, Jung W, Dürk HA, Salwender H, Wandt H, Bassermann F, Gramatzki M, Rösler W, Wolf HH, Brugger W, Engelhardt M, Fischer T, Liebisch P, Straka C. Response-adapted consolidation with bortezomib after ASCT improves progression-free survival in newly diagnosed multiple myeloma. Leukemia. 2017 Jun;31(6):1463-1466. Epub 2017 Mar 15. link to original article contains dosing details in manuscript PubMed NCT00416208

Bortezomib & Melphalan, then auto HSCT

Bor-HDM: Bortezomib, High Dose Melphalan

Regimen

Study Evidence
Roussel et al. 2009 Phase 2

Targeted therapy

Chemotherapy

  • Melphalan (Alkeran) 100 mg/m2 IV once per day on days -2 & -1
    • Roussel et al. 2009 gave as a single 200 mg/m2 dose on day -2

Supportive therapy

One course

References

  1. 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. 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. link to original article contains dosing details in manuscript PubMed NCT00642395

DCEP

DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol (Cisplatin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Harousseau et al. 2010 (IFM 2005-01) 2005-2008 Phase 3 (E-esc) Observation Did not meet composite primary endpoint of CR/nCR rate

Preceding treatment

  • Induction Vd x 4 versus VAD x 4

Glucocorticoid therapy

Chemotherapy

  • Cyclophosphamide (Cytoxan) 400 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1600 mg/m2)
  • Etoposide (Vepesid) 40 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 160 mg/m2)
  • Cisplatin (Platinol) 15 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 60 mg/m2)

28-day cycle for 2 cycles

Subsequent treatment

References

  1. 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. link to original article contains dosing details in manuscript PubMed NCT00200681

KTD

KTD: Kyprolis (Carfilzomib), Thalidomide, Dexamethasone

Regimen variant #1, 27/50/20

Study Dates of enrollment Evidence
Sonneveld et al. 2014 (CARTHADEX) 2010-2013 Phase 2

Note: this was the dosing for Cohort 1.

Preceding treatment

Targeted therapy

Glucocorticoid therapy

28-day cycle for 4 cycles


Regimen variant #2, 36/50/20

Study Dates of enrollment Evidence
Sonneveld et al. 2014 (CARTHADEX) 2010-2013 Phase 2

Note: this was the dosing for Cohort 2.

Preceding treatment

Targeted therapy

Glucocorticoid therapy

28-day cycle for 4 cycles

References

  1. CARTHADEX: 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. link to original article contains dosing details in manuscript link to PMC article PubMed NTR2422

Melphalan monotherapy, then auto HSCT

HDM: High-Dose Melphalan

Synopsis

Development

The concept of high-dose chemotherapy followed by ASCT emerged as a treatment modality for hematological malignancies in the 1980s. The rationale was to provide high doses of chemotherapy to eradicate malignant cells that were resistant to conventional doses. However, these high doses also destroyed the patient's bone marrow, necessitating a rescue with previously harvested and stored stem cells. Autologous transplantation uses the patient's own stem cells, harvested prior to the high-dose chemotherapy.

Clinical Trials & Evidence

[1] Attal et al., 1996 (Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. New England Journal of Medicine. 1996;335:91-7): In this landmark trial, patients with multiple myeloma were randomized to receive either standard chemotherapy or high-dose chemotherapy followed by ASCT. The results showed a higher response rate and prolonged event-free survival in the ASCT group.

[2] Barlogie et al., 1999 (Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1999;93:1172-9): This study demonstrated the benefit of two consecutive ASCTs (tandem transplants) over a single transplant in patients with newly diagnosed multiple myeloma.

2000s-2010s Trials: Further studies over these years demonstrated the sustained benefit of ASCT in multiple myeloma, especially when combined with novel agents like proteasome inhibitors, immunomodulatory agents, CD38 monoclonal antibodies, and corticosteroids.

Application in the Modern Era

1. Induction Therapy: Before ASCT, patients receive induction therapy with a combination of drugs for cytoreduction. Modern regimens often include monoclonal antibodies (e.g., daratumumab), proteasome inhibitors (e.g., bortezomib or carfilzomib), immunomodulatory drugs (e.g., lenalidomide), and steroids (typically dexamethasone).

2. Stem Cell Harvesting: Stem cells are collected from the patient’s peripheral blood after mobilization with growth factors, usually granulocyte colony-stimulating factor (G-CSF) often in combination with plerixafor.

3. High-Dose Chemotherapy: Melphalan remains the standard conditioning agent for multiple myeloma. Patients receive high doses of melphalan, which kill myeloma cells but also suppress the bone marrow.

4. Stem Cell Infusion: After chemotherapy, the previously harvested stem cells are infused back into the patient to "rescue" the bone marrow.

5. Maintenance Therapy: Following recovery from ASCT, patients often receive maintenance therapy with agents like lenalidomide to prolong remission.

Conclusion

High-dose chemotherapy followed by ASCT has significantly improved outcomes for patients with multiple myeloma over the past few decades. While newer therapies continue to emerge, ASCT remains an integral part of the treatment paradigm for eligible patients.
The draft for this synopsis was generated by a large language model and then manually edited by the page editor for accuracy and style. See this page for more information about this pilot project.


Regimen variant #1, 140 mg/m2

Study Evidence
Barlogie et al. 1986 Non-randomized, fewer than 20 pts

Chemotherapy

Supportive therapy

One course


Regimen variant #2, 200 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bladé et al. 2005 1994-1999 Phase 3 (E-esc) VBMCP/VBAD Did not meet efficacy endpoint
Moreau et al. 2002 (IFM 9502) 1995-1999 Phase 3 (E-de-esc) Melphalan & TBI, then auto HSCT Did not meet primary endpoint of CR rate
Cavo et al. 2007 (Bologna 96) 1996-2001 Phase 3 (C) Melphalan, then auto HSCT, then Melphalan & Busulfan, then auto HSCT Inferior EFS
Mai et al. 2016 (GMMG-HD2) 1998-2002 Phase 3 (C) Tandem melphalan, then auto HSCT Non-inferior EFS
Lokhorst et al. 2009 (HOVON-50) 2001-2005 Non-randomized part of phase 3 RCT
Björkstrand et al. 2011 (EBMT-NMAM2000) 2001-2005 Phase 3 (C) MEL200, then auto HSCT, then RIC allo HSCT Seems to have inferior OS
Morgan et al. 2010 (MRC Myeloma IX) 2003-2007 Non-randomized part of phase 3 RCT
Sonneveld et al. 2012 (HOVON-65) 2005-2008 Non-randomized part of phase 3 RCT
Rosiñol et al. 2012 (GEM05/MENOS65) 2006-2009 Non-randomized part of phase 3 RCT
Moreau et al. 2011 (IFM 2007-02) 2008-03 to 2009-01 Non-randomized part of phase 3 RCT
Roussel et al. 2014 (IFM 2008) 2009 Phase 2
Mai et al. 2015 (GMMG-MM5) 2010-2012 Non-randomized part of phase 3 RCT
Attal et al. 2017 (IFM 2009) 2010-2012 Phase 3 (C) RVD consolidation Superior PFS
Median PFS: 50 vs 36 mo
(HR 0.65, 95% CI 0.53-0.80)
Sonneveld et al. 2014 (CARTHADEX) 2010-2013 Phase 2
Stadtmauer et al. 2019 (STAMINA) 2010-2013 Phase 3 (C) 1. Tandem melphalan, then auto HSCT
2. MEL200, then auto HSCT, then RVD consolidation 		Did not meet primary endpoint of PFS38
Richardson et al. 2022 (DETERMINATION) 2010-10-01 to 2018-01-30 Phase 3 (C) RVD consolidation Superior PFS (primary endpoint)
Median PFS: 67.5 vs 46.2 mo
(HR 0.65, 95% CI 0.52-0.81)
Lok et al. 2014 2011-2013 Non-randomized
Bashir et al. 2019 (MDACC 2010-0071) 2011-2017 Phase 3 (C) Bu/Mel, then auto HSCT Seems to have inferior PFS
Roussel et al. 2022 (IFM 2014-02) 2015-01-21 to 2016-09-21 Phase 3 (C) Bor-HDM, then auto HSCT Did not meet composite primary endpoint of sCR/CR rate at day +60

Preceding treatment

  • IFM 9502: Induction VAD x 3
  • Bladé et al. 2005: Induction VBMCP/VBAD x 4
  • Bologna 96: Induction VAD x 4
  • HOVON-50: Induction TAD x 3 versus VAD x 3
  • IFM 2007-02: Induction vtD x 4 versus Vd x 4
  • MRC Myeloma IX: Induction CTD x 4 to 6 versus CVAD x 4 to 6
  • GEM05/MENOS65: Induction TD x 6 versus VBMCP/VBAD/B x 6 versus VTD x 6
  • HOVON-65: Induction PAD x 3 versus VAD x 3
  • Lok et al. 2014: Induction vtD x 4
  • IFM 2008: Induction RVD x 3
  • CARTHADEX: Induction KTD x 4
  • GMMG-MM5: Induction VCD x 3 versus PAd x 3
  • IFM 2009 & DETERMINATION: Induction RVD x 3
  • IFM 2014-02: Induction VTd or CyBorD or RVd

Chemotherapy

Supportive therapy

One course

Subsequent treatment

References

  1. 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. link to original article contains dosing details in abstract PubMed
  2. 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 800 cGy 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. link to original article PubMed
  3. 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; 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. link to original article contains dosing details in manuscript PubMed
  4. 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. link to original article contains dosing details in manuscript PubMed NCT00378222
  5. HOVON-50: 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; 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. link to original article contains dosing details in manuscript PubMed NCT00028886
    1. Update: van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. link to original article PubMed
  6. 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. link to original article link to PMC article PubMed ISRCTN68454111
    1. Update: Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article contains dosing details in manuscript link to PMC article PubMed
    2. Update: 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. link to original article contains dosing details in manuscript PubMed
    3. 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. link to original article contains dosing details in manuscript link to PMC article PubMed
    4. 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. link to original article PubMed
  7. 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. link to original article contains dosing details in manuscript PubMed
    1. 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. link to original article PubMed
  8. 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. link to original article contains dosing details in manuscript PubMed NCT00910897
  9. GEM05/MENOS65: 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; PETHEMA; GEM. 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. link to original article contains dosing details in manuscript PubMed NCT00461747
    1. Update: 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. link to original article contains dosing details in manuscript PubMed
  10. HOVON-65: 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. link to original article contains dosing details in manuscript PubMed ISRCTN64455289
    1. 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. link to original article PubMed
    2. 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. link to original article PubMed
  11. 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. link to original article contains dosing details in manuscript link to PMC article PubMed
  12. IFM 2008: 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. link to original article contains dosing details in manuscript PubMed NCT01206205
  13. CARTHADEX: 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. link to original article contains dosing details in manuscript link to PMC article PubMed NTR2422
  14. 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. link to original article contains dosing details in manuscript PubMed EudraCT 2010-019173-16
    1. Subgroup analysis: Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C, Hielscher T, Blau IW, Scheid C, Hose D, Seckinger A, Jauch A, Hillengass J, Raab MS, Schurich B, Munder M, Schmidt-Wolf IG, Gerecke C, Lindemann HW, Zeis M, Weisel K, Duerig J, Goldschmidt H. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica. 2015 Jul;100(7):964-9. Epub 2015 Apr 3. link to original article link to PMC article PubMed
    2. Update: Goldschmidt H, Mai EK, Dürig J, Scheid C, Weisel KC, Kunz C, Bertsch U, Hielscher T, Merz M, Munder M, Lindemann HW, Hügle-Dörr B, Tichy D, Giesen N, Hose D, Seckinger A, Huhn S, Luntz S, Jauch A, Elmaagacli A, Rabold B, Fuhrmann S, Brossart P, Goerner M, Bernhard H, Hoffmann M, Hillengass J, Raab MS, Blau IW, Hänel M, Salwender HJ; German-speaking Myeloma Multicenter Group (GMMG). Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia. 2020 Jul;34(7):1853-1865. Epub 2020 Feb 7. link to original article PubMed
  15. 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. link to original article PubMed DRKS00008864
  16. 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01191060
  17. STAMINA: Stadtmauer EA, Pasquini MC, Blackwell B, Hari P, Bashey A, Devine S, Efebera Y, Ganguly S, Gasparetto C, Geller N, Horowitz MM, Koreth J, Knust K, Landau H, Brunstein C, McCarthy P, Nelson C, Qazilbash MH, Shah N, Vesole DH, Vij R, Vogl DT, Giralt S, Somlo G, Krishnan A. Autologous Transplantation, Consolidation, and Maintenance Therapy in Multiple Myeloma: Results of the BMT CTN 0702 Trial. J Clin Oncol. 2019 Mar 1;37(7):589-597. Epub 2019 Jan 17. link to original article link to PMC article contains dosing details in abstract PubMed NCT01109004
  18. MDACC 2010-0071: Bashir Q, Thall PF, Milton DR, Fox PS, Kawedia JD, Kebriaei P, Shah N, Patel K, Andersson BS, Nieto YL, Valdez BC, Parmar S, Rondon G, Delgado R, Hosing C, Popat UR, Oran B, Ciurea SO, Lin P, Weber DM, Thomas SK, Lee HC, Manasanch EE, Orlowski RZ, Williams LA, Champlin RE, Qazilbash MH. Conditioning with busulfan plus melphalan versus melphalan alone before autologous haemopoietic cell transplantation for multiple myeloma: an open-label, randomised, phase 3 trial. Lancet Haematol. 2019 May;6(5):e266-e275. Epub 2019 Mar 22. link to original article contains dosing details in abstract link to PMC article PubMed NCT01413178
  19. EMN02/HOVON-95: Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA, Dozza L, van der Holt B, Zweegman S, Oliva S, van der Velden VHJ, Zamagni E, Palumbo GA, Patriarca F, Montefusco V, Galli M, Maisnar V, Gamberi B, Hansson M, Belotti A, Pour L, Ypma P, Grasso M, Croockewit A, Ballanti S, Offidani M, Vincelli ID, Zambello R, Liberati AM, Andersen NF, Broijl A, Troia R, Pascarella A, Benevolo G, Levin MD, Bos G, Ludwig H, Aquino S, Morelli AM, Wu KL, Boersma R, Hajek R, Durian M, von dem Borne PA, Caravita di Toritto T, Zander T, Driessen C, Specchia G, Waage A, Gimsing P, Mellqvist UH, van Marwijk Kooy M, Minnema M, Mandigers C, Cafro AM, Palmas A, Carvalho S, Spencer A, Boccadoro M, Sonneveld P. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020 Jun;7(6):e456-e468. Epub 2020 Apr 30. Erratum in: Lancet Haematol. 2020 Jun;7(6):e443. Erratum in: Lancet Haematol. 2020 Nov;7(11):e785. link to original article PubMed NCT01208766
    1. Update: Sonneveld P, Dimopoulos MA, Beksac M, van der Holt B, Aquino S, Ludwig H, Zweegman S, Zander T, Zamagni E, Wester R, Hajek R, Pantani L, Dozza L, Gay F, Cafro A, De Rosa L, Morelli A, Gregersen H, Gulbrandsen N, Cornelisse P, Troia R, Oliva S, van de Velden V, Wu K, Ypma PF, Bos G, Levin MD, Pour L, Driessen C, Broijl A, Croockewit A, Minnema MC, Waage A, Hveding C, van de Donk NWCJ, Offidani M, Palumbo GA, Spencer A, Boccadoro M, Cavo M. Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2021 Nov 10;39(32):3613-3622. Epub 2021 Sep 14. link to original article PubMed
  20. IFM 2014-02: Roussel M, Lauwers-Cances V, Macro M, Leleu X, Royer B, Hulin C, Karlin L, Perrot A, Touzeau C, Chrétien ML, Rigaudeau S, Dib M, Nicolas-Virelizier E, Escoffre-Barbe M, Belhadj K, Mariette C, Stoppa AM, Araujo C, Doyen C, Fontan J, Kolb B, Garderet L, Brechignac S, Malfuson JV, Jaccard A, Lenain P, Borel C, Hebraud B, Benbrahim O, Dorvaux V, Manier S, Augeul-Meunier K, Vekemans MC, Randriamalala E, Chaoui D, Caers J, Chaleteix C, Benboubker L, Vincent L, Glaisner S, Zunic P, Slama B, Eveillard JR, Humbrecht-Kraut C, Morel V, Mineur P, Eisenmann JC, Demarquette H, Richez V, Vignon M, Caillot D, Facon T, Moreau P, Colin AL, Olivier P, Wuilleme S, Avet-Loiseau H, Corre J, Attal M. Bortezomib and high-dose melphalan conditioning regimen in frontline multiple myeloma: an IFM randomized phase 3 study. Blood. 2022 May 5;139(18):2747-2757. link to original article contains dosing details in abstract PubMed NCT02197221
  21. DETERMINATION: Richardson PG, Jacobus SJ, Weller EA, Hassoun H, Lonial S, Raje NS, Medvedova E, McCarthy PL, Libby EN, Voorhees PM, Orlowski RZ, Anderson LD Jr, Zonder JA, Milner CP, Gasparetto C, Agha ME, Khan AM, Hurd DD, Gowin K, Kamble RT, Jagannath S, Nathwani N, Alsina M, Cornell RF, Hashmi H, Campagnaro EL, Andreescu AC, Gentile T, Liedtke M, Godby KN, Cohen AD, Openshaw TH, Pasquini MC, Giralt SA, Kaufman JL, Yee AJ, Scott E, Torka P, Foley A, Fulciniti M, Hebert K, Samur MK, Masone K, Maglio ME, Zeytoonjian AA, Nadeem O, Schlossman RL, Laubach JP, Paba-Prada C, Ghobrial IM, Perrot A, Moreau P, Avet-Loiseau H, Attal M, Anderson KC, Munshi NC; DETERMINATION Investigators. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. N Engl J Med. 2022 Jul 14;387(2):132-147. Epub 2022 Jun 5. link to original article link to PMC article PubMed NCT01208662

MPR

MPR: Melphalan, Prednisone, Revlimid (Lenalidomide)

Regimen variant #1, 0.18/2/10

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Palumbo et al. 2014 (MPRvsMEL200) 2007-2009 Phase 3 (C) Tandem Melphalan, then auto HSCT 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. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Preceding treatment

  • Rd induction x 4

Chemotherapy

Glucocorticoid therapy

Targeted therapy

28-day cycle for 6 cycles

Subsequent treatment


Regimen variant #2, 2/50/10

Study Dates of enrollment Evidence
Falco et al. 2012 2008-2009 Phase 2

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

  • RP induction x 4

Chemotherapy

Glucocorticoid therapy

Targeted therapy

Supportive therapy

  • Thromboprophylaxis: Aspirin 100 mg PO once per day, taken during lenalidomide treatment (unclear from protocol if this also means off weeks)
  • Antiviral prophylaxis if history of VZV.

28-day cycle for 6 cycles

Subsequent treatment

  • RP maintenance


Regimen variant #3, 2/50/15

Study Dates of enrollment Evidence
Falco et al. 2012 2008-2009 Phase 2

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

  • RP induction x 4

Chemotherapy

Glucocorticoid therapy

Targeted therapy

Supportive therapy

  • Thromboprophylaxis: Aspirin 100 mg PO once per day, taken during lenalidomide treatment (unclear from protocol if this also means off weeks)
  • Antiviral prophylaxis if history of VZV.

28-day cycle for 6 cycles

Subsequent treatment

  • RP maintenance

References

  1. 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. link to original article contains dosing details in manuscript PubMed
  2. MPRvsMEL200: 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. link to original article contains dosing details in manuscript PubMed NCT00551928

Lenalidomide & Prednisone (RP)

RP: Revlimid (Lenalidomide) & Prednisone

Regimen

Study Evidence
Palumbo et al. 2010 Phase 2

Preceding treatment

Targeted therapy

Glucocorticoid therapy

Supportive therapy

  • Aspirin 100 mg PO once per day during lenalidomide treatment

28-day cycle for 4 cycles

Subsequent treatment

References

  1. 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. link to original article contains dosing details in manuscript PubMed EudraCT 2005-004714-32
    1. 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. link to original article contains dosing details in abstract PubMed

RVD

RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone
VRd: Velcade (Bortezomib), Revlimid (Lenalidomide), low-dose dexamethasone

Regimen variant #1, 2 cycles post-transplant with lower-dose dex

Study Dates of enrollment Evidence
Attal et al. 2017 (IFM 2009) 2010-2012 Non-randomized part of phase 3 RCT

Preceding treatment

Targeted therapy

Glucocorticoid therapy

21-day cycle for 2 cycles

Subsequent treatment


Regimen variant #2, 2 cycles with intermediate-dose dex

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cavo et al. 2020 (EMN02/HOVON-95) 2011-2014 Phase 3 (E-esc) No further consolidation Seems to have superior PFS1 (primary endpoint)
Median PFS: 59.3 vs 42.9 mo
(HR 0.81, 95% CI 0.68-0.96)

1Reported efficacy is based on the 2021 update.

Preceding treatment

Targeted therapy

Glucocorticoid therapy

28-day cycle for 2 cycles

Subsequent treatment


Regimen variant #3, 2 cycles post-transplant with higher-dose dex

Study Dates of enrollment Evidence
Roussel et al. 2014 (IFM 2008) 2009 Phase 2

Two months after hematologic recovery, patients without progressive disease began treatment.

Preceding treatment

Targeted therapy

Glucocorticoid therapy

Supportive therapy

21-day cycle for 2 cycles

Subsequent treatment


Regimen variant #4, 5 cycles, no transplant

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Attal et al. 2017 (IFM 2009) 2010-2012 Phase 3 (E-de-esc) Melphalan, then auto HSCT Inferior PFS (primary endpoint)
Richardson et al. 2022 (DETERMINATION) 2010-10-01 to 2018-01-30 Phase 3 (E-de-esc) Melphalan, then auto HSCT Inferior PFS (primary endpoint)

Preceding treatment

  • RVD induction x 3

Targeted therapy

Glucocorticoid therapy

21-day cycle for 5 cycles

Subsequent treatment


Regimen variant #4, 5 cycles, no transplant, SC bortezomib

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Richardson et al. 2022 (DETERMINATION) 2010-10-01 to 2018-01-30 Phase 3 (E-de-esc) Melphalan, then auto HSCT Inferior PFS (primary endpoint)

Preceding treatment

  • RVD induction x 3

Targeted therapy

Glucocorticoid therapy

21-day cycle for 5 cycles

Subsequent treatment


Regimen variant #6, 8 cycles, no transplant

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jacobus et al. 2016 (ECOG E1A05) 2008-2010 Phase 3 (E-esc) Rd Not reported

Note: this trial closed early due to poor accrual so only descriptive results are available.

Preceding treatment

Targeted therapy

Glucocorticoid therapy

21-day cycle for 8 cycles

References

  1. 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. link to original article PubMed
  2. IFM 2008: 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. link to original article contains dosing details in manuscript PubMed NCT01206205
  3. ECOG 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. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00522392
  4. 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01191060
  5. EMN02/HOVON-95: Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA, Dozza L, van der Holt B, Zweegman S, Oliva S, van der Velden VHJ, Zamagni E, Palumbo GA, Patriarca F, Montefusco V, Galli M, Maisnar V, Gamberi B, Hansson M, Belotti A, Pour L, Ypma P, Grasso M, Croockewit A, Ballanti S, Offidani M, Vincelli ID, Zambello R, Liberati AM, Andersen NF, Broijl A, Troia R, Pascarella A, Benevolo G, Levin MD, Bos G, Ludwig H, Aquino S, Morelli AM, Wu KL, Boersma R, Hajek R, Durian M, von dem Borne PA, Caravita di Toritto T, Zander T, Driessen C, Specchia G, Waage A, Gimsing P, Mellqvist UH, van Marwijk Kooy M, Minnema M, Mandigers C, Cafro AM, Palmas A, Carvalho S, Spencer A, Boccadoro M, Sonneveld P. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020 Jun;7(6):e456-e468. Epub 2020 Apr 30. Erratum in: Lancet Haematol. 2020 Jun;7(6):e443. Erratum in: Lancet Haematol. 2020 Nov;7(11):e785. link to original article PubMed NCT01208766
    1. Update: Sonneveld P, Dimopoulos MA, Beksac M, van der Holt B, Aquino S, Ludwig H, Zweegman S, Zander T, Zamagni E, Wester R, Hajek R, Pantani L, Dozza L, Gay F, Cafro A, De Rosa L, Morelli A, Gregersen H, Gulbrandsen N, Cornelisse P, Troia R, Oliva S, van de Velden V, Wu K, Ypma PF, Bos G, Levin MD, Pour L, Driessen C, Broijl A, Croockewit A, Minnema MC, Waage A, Hveding C, van de Donk NWCJ, Offidani M, Palumbo GA, Spencer A, Boccadoro M, Cavo M. Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2021 Nov 10;39(32):3613-3622. Epub 2021 Sep 14. link to original article contains dosing details in manuscript PubMed
  6. DETERMINATION: Richardson PG, Jacobus SJ, Weller EA, Hassoun H, Lonial S, Raje NS, Medvedova E, McCarthy PL, Libby EN, Voorhees PM, Orlowski RZ, Anderson LD Jr, Zonder JA, Milner CP, Gasparetto C, Agha ME, Khan AM, Hurd DD, Gowin K, Kamble RT, Jagannath S, Nathwani N, Alsina M, Cornell RF, Hashmi H, Campagnaro EL, Andreescu AC, Gentile T, Liedtke M, Godby KN, Cohen AD, Openshaw TH, Pasquini MC, Giralt SA, Kaufman JL, Yee AJ, Scott E, Torka P, Foley A, Fulciniti M, Hebert K, Samur MK, Masone K, Maglio ME, Zeytoonjian AA, Nadeem O, Schlossman RL, Laubach JP, Paba-Prada C, Ghobrial IM, Perrot A, Moreau P, Avet-Loiseau H, Attal M, Anderson KC, Munshi NC; DETERMINATION Investigators. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. N Engl J Med. 2022 Jul 14;387(2):132-147. Epub 2022 Jun 5. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01208662

Tandem melphalan, then auto HSCT

Protocol variant #1, MEL100 x 2

Study Evidence Efficacy
Palumbo et al. 2010 Phase 2 VGPR or better: 82%

Preceding treatment

Chemotherapy

Supportive therapy

Two courses

Subsequent treatment

  • RP maintenance


Protocol variant #2, MEL140, then MEL200

Study Dates of enrollment Evidence
Attal et al. 2006 (IFM 99-02) 2000-2003 Non-randomized part of phase 3 RCT

Preceding treatment

  • VAD induction x 3 to 4

Chemotherapy

  • Melphalan (Alkeran) as follows:
    • First transplant: 140 mg/m2 IV once (day not specified)
    • Second transplant: 200 mg/m2 IV once (day not specified)

Supportive therapy

One course

Subsequent treatment


Protocol variant #3, MEL200 x 2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mai et al. 2016 (GMMG-HD2) 1998-2002 Phase 3 (E-esc) Melphalan, then auto HSCT Non-inferior EFS24 (primary endpoint)
Lokhorst et al. 2009 (HOVON-50) 2001-2005 Non-randomized part of phase 3 RCT
Palumbo et al. 2009 (GIS MM2001) 2001-2006 Phase 3 (C) MEL100, then auto HSCT x 2 Superior PFS
Krishnan et al. 2011 (BMT CTN 0102) 2003-2007 Phase 3 (C) MEL200, then auto HSCT, then RIC allo HSCT Did not meet primary endpoint of PFS36
Sonneveld et al. 2012 (GMMG-HD4) 2005-2008 Non-randomized part of phase 3 RCT
Palumbo et al. 2014 (MPRvsMEL200) 2007-2009 Phase 3 (E-esc) MPR consolidation Superior PFS (primary endpoint)
Median PFS: 43 vs 22.4 mo
(HR 0.44, 95% CI 0.32-0.61)

Superior OS (secondary endpoint)
OS48: 81.6% vs 65.3%
(HR 0.55, 95% CI 0.32-0.93)
Gay et al. 2015 (EMN-441) 2009-2011 Phase 3 (C) CRd consolidation Superior PFS (primary endpoint)
Median PFS: 43.3 vs 28.6 mo
(HR 0.40, 95% CI 0.25-0.625)

Preceding treatment

  • HOVON-50: Induction TAD x 3 versus VAD x 3
  • GMMG-HD4: Induction PAD x 3 versus VAD x 3
  • MPRvsMEL200 & EMN-441: Induction Rd x 4

Chemotherapy

Supportive therapy

Two courses

Subsequent treatment


Protocol variant #4, MEL200 x 2 (split doses)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Barlogie et al. 1997 (Total Therapy 1) 1990-1994 Non-randomized CR rate: 40%
Bruno et al. 2007 1998-2004 Pseudo-Mendelian randomization1 MEL-auto HSCT x 1, then TBI, then allo HSCT Inferior OS

1Randomization was based on the availability of an HLA-identical sibling.
Note: reported efficacy for Total Therapy 1 is based on the 1999 update. Bruno et al. 2007 does not contain treatment details.

Preceding treatment

Chemotherapy

Supportive therapy

Two courses

Subsequent treatment

References

  1. Total Therapy 1: 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. link to original article PubMed
    1. Update: 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. link to original article contains dosing details in manuscript PubMed
    2. Pooled 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. link to original article link to PMC article PubMed
  2. 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; IFM. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. link to original article contains dosing details in manuscript PubMed NCT00222053
    1. Pooled 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. link to original article PubMed
  3. 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. link to original article does not contain dosing details PubMed NCT00415987
  4. HOVON-50: 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. 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. link to original article contains dosing details in manuscript PubMed NCT00028886
    1. Update: van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. link to original article PubMed
  5. GIS MM2001: Palumbo A, Bringhen S, Bruno B, Falcone AP, Liberati AM, Grasso M, Ria R, Pisani F, Cangialosi C, Caravita T, Levi A, Meloni G, Nozza A, Pregno P, Gabbas A, Callea V, Rizzo M, Annino L, De Stefano V, Musto P, Baldi I, Cavallo F, Petrucci MT, Massaia M, Boccadoro M. Melphalan 200 mg/m(2) versus melphalan 100 mg/m(2) in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study. Blood. 2010 Mar 11;115(10):1873-9. Epub 2009 Dec 1. Erratum in: Blood. 2010 Sep 23;116(12):2195. link to original article contains dosing details in abstract PubMed NCT00950768
  6. 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. link to original article contains dosing details in manuscript PubMed EudraCT 2005-004714-32
    1. 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. link to original article contains dosing details in abstract PubMed
  7. 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. 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. link to original article PubMed NCT01134484
    1. 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. 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. link to original article contains dosing details in manuscript PubMed
  8. BMT CTN 0102: 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; 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. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00075829
  9. 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. link to original article contains dosing details in manuscript PubMed ISRCTN64455289
    1. 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. link to original article PubMed
    2. 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. link to original article PubMed
  10. 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. link to original article PubMed
  11. MPRvsMEL200: 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. link to original article contains dosing details in manuscript PubMed NCT00551928
  12. 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. link to original article contains dosing details in abstract PubMed NCT01091831
  13. 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. link to original article PubMed DRKS00008864
  14. EMN02/HOVON-95: Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA, Dozza L, van der Holt B, Zweegman S, Oliva S, van der Velden VHJ, Zamagni E, Palumbo GA, Patriarca F, Montefusco V, Galli M, Maisnar V, Gamberi B, Hansson M, Belotti A, Pour L, Ypma P, Grasso M, Croockewit A, Ballanti S, Offidani M, Vincelli ID, Zambello R, Liberati AM, Andersen NF, Broijl A, Troia R, Pascarella A, Benevolo G, Levin MD, Bos G, Ludwig H, Aquino S, Morelli AM, Wu KL, Boersma R, Hajek R, Durian M, von dem Borne PA, Caravita di Toritto T, Zander T, Driessen C, Specchia G, Waage A, Gimsing P, Mellqvist UH, van Marwijk Kooy M, Minnema M, Mandigers C, Cafro AM, Palmas A, Carvalho S, Spencer A, Boccadoro M, Sonneveld P. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020 Jun;7(6):e456-e468. Epub 2020 Apr 30. Erratum in: Lancet Haematol. 2020 Jun;7(6):e443. Erratum in: Lancet Haematol. 2020 Nov;7(11):e785. link to original article PubMed NCT01208766
    1. Update: Sonneveld P, Dimopoulos MA, Beksac M, van der Holt B, Aquino S, Ludwig H, Zweegman S, Zander T, Zamagni E, Wester R, Hajek R, Pantani L, Dozza L, Gay F, Cafro A, De Rosa L, Morelli A, Gregersen H, Gulbrandsen N, Cornelisse P, Troia R, Oliva S, van de Velden V, Wu K, Ypma PF, Bos G, Levin MD, Pour L, Driessen C, Broijl A, Croockewit A, Minnema MC, Waage A, Hveding C, van de Donk NWCJ, Offidani M, Palumbo GA, Spencer A, Boccadoro M, Cavo M. Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2021 Nov 10;39(32):3613-3622. Epub 2021 Sep 14. link to original article PubMed
  15. DSMM V: NCT00546988

Thalidomide & Dexamethasone (TD)

TD: Thalidomide & Dexamethasone
Thal-Dex: Thalidomide & Dexamethasone

Regimen

Study Dates of enrollment Evidence
Cavo et al. 2010 (GIMEMA MM-BO2005) 2006-2008 Non-randomized part of phase 3 RCT

Preceding treatment

Targeted therapy

Glucocorticoid therapy

Supportive therapy

35-day cycle for 2 cycles

Subsequent treatment

References

  1. 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. 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. link to original article PubMed NCT01134484
    1. 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. 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. link to original article contains dosing details in manuscript PubMed

Thalidomide & Prednisolone (TP)

TP: Thalidomide & Prednisolone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Horvath et al. 2019 (VCAT) 2012-2016 Randomized (C) VTP Did not meet primary endpoint of CR + VGPR rate

Note: duration of thalidomide is unclear from the abstract.

Preceding treatment

Targeted therapy

Glucocorticoid therapy

References

  1. VCAT: Horvath N, Spencer A, Kenealy M, Joshua D, Campbell PJ, Lee JJ, Hou J, Qiu L, Kalff A, Khong T, Londhe A, Siggins S, van Kooten Losio M, Eisbacher M, Prince HM. Phase 3 study of subcutaneous bortezomib, thalidomide, and prednisolone consolidation after subcutaneous bortezomib-based induction and autologous stem cell transplantation in patients with previously untreated multiple myeloma: the VCAT study. Leuk Lymphoma. 2019 Sep;60(9):2122-2133. Epub 2019 Feb 19. link to original article PubMed NCT01539083

VMP

VMP: Velcade (Bortezomib), Melphalan, Prednisone

Regimen

Study Dates of enrollment Evidence
Mateos et al. 2006 2004-2005 Phase 1/2

Note: this was the phase II portion of this phase I/II study.

Preceding treatment

Targeted therapy

Chemotherapy

Glucocorticoid therapy

35-day cycle for 5 cycles

References

  1. 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. link to original article contains dosing details in manuscript PubMed
  2. EMN02/HOVON-95: Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA, Dozza L, van der Holt B, Zweegman S, Oliva S, van der Velden VHJ, Zamagni E, Palumbo GA, Patriarca F, Montefusco V, Galli M, Maisnar V, Gamberi B, Hansson M, Belotti A, Pour L, Ypma P, Grasso M, Croockewit A, Ballanti S, Offidani M, Vincelli ID, Zambello R, Liberati AM, Andersen NF, Broijl A, Troia R, Pascarella A, Benevolo G, Levin MD, Bos G, Ludwig H, Aquino S, Morelli AM, Wu KL, Boersma R, Hajek R, Durian M, von dem Borne PA, Caravita di Toritto T, Zander T, Driessen C, Specchia G, Waage A, Gimsing P, Mellqvist UH, van Marwijk Kooy M, Minnema M, Mandigers C, Cafro AM, Palmas A, Carvalho S, Spencer A, Boccadoro M, Sonneveld P. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020 Jun;7(6):e456-e468. Epub 2020 Apr 30. Erratum in: Lancet Haematol. 2020 Jun;7(6):e443. Erratum in: Lancet Haematol. 2020 Nov;7(11):e785. link to original article PubMed NCT01208766
    1. Update: Sonneveld P, Dimopoulos MA, Beksac M, van der Holt B, Aquino S, Ludwig H, Zweegman S, Zander T, Zamagni E, Wester R, Hajek R, Pantani L, Dozza L, Gay F, Cafro A, De Rosa L, Morelli A, Gregersen H, Gulbrandsen N, Cornelisse P, Troia R, Oliva S, van de Velden V, Wu K, Ypma PF, Bos G, Levin MD, Pour L, Driessen C, Broijl A, Croockewit A, Minnema MC, Waage A, Hveding C, van de Donk NWCJ, Offidani M, Palumbo GA, Spencer A, Boccadoro M, Cavo M. Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2021 Nov 10;39(32):3613-3622. Epub 2021 Sep 14. link to original article PubMed

VTD

VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone

Regimen variant #1, "vTD"

Study Dates of enrollment Evidence
Lok et al. 2014 2011-2013 Non-randomized

Preceding treatment

Targeted therapy

Glucocorticoid therapy

21-day cycle for 2 cycles


Regimen variant #2

Study Dates of enrollment Evidence
Cavo et al. 2010 (GIMEMA MM-BO2005) 2006-2008 Non-randomized part of phase 3 RCT

VTD consolidation is to begin 3 months after the second transplant.

Preceding treatment

Targeted therapy

Glucocorticoid therapy

Supportive therapy

35-day cycle for 2 cycles

Subsequent treatment


Regimen variant #3

Study Evidence
Ladetto et al. 2010 (GIMEMA VEL-03-096) Phase 2

Preceding treatment

Targeted therapy

Glucocorticoid therapy

35-day cycle for 4 cycles

References

  1. 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. link to original article contains dosing details in manuscript PubMed EudraCT 2004-000531-28
    1. 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, Caravita 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. link to original article PubMed
  2. 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. 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. link to original article contains dosing details in abstract PubMed NCT01134484
    1. 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. 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. link to original article contains dosing details in manuscript PubMed
  3. 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. link to original article contains dosing details in manuscript link to PMC article 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

Regimen variant #1, IV x 2 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sonneveld et al. 2012 (HOVON-65) 2005-2008 Phase 3 (E-switch-ooc) Thalidomide Superior PFS1 (primary endpoint)
Sonneveld et al. 2012 (GMMG-HD4) 2005-2008 Phase 3 (E-switch-ooc) Thalidomide Superior PFS1 (primary endpoint)

1In the initial publication, this arm seemed to have an overall survival advantage; this was no longer present in the updated report of 2017. HOVON-65/GMMG-HD4 was a single phase 3 RCT but the consolidation was different by group, so is reported here as 2 distinct trials.

Preceding treatment

Targeted therapy

14-day cycle for 52 cycles (2 years)


Regimen variant #2, SC, indefinite

Study Evidence
Larocca et al. 2016 (MMY2069) Phase 2

Preceding treatment

  • Induction VP x 9

Targeted therapy

14-day cycles

References

  1. HOVON-65: 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. link to original article contains dosing details in manuscript PubMed ISRCTN64455289
    1. 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. link to original article PubMed
    2. 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. link to original article PubMed
  2. 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. link to original article contains dosing details in manuscript PubMed ISRCTN64455289
    1. 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. link to original article PubMed
    2. 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. link to original article PubMed
  3. MMY2069: 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. Epub 2016 Feb 22. link to original article contains dosing details in manuscript PubMed NCT01190787

Bortezomib & Dexamethasone (Vd)

VD: Velcade (Bortezomib) & low-dose dexamethasone

Regimen

Study Evidence Efficacy
Berdeja et al. 2017 (SCRI MM 23) Phase 2 ORR: 91%

Note: this is the modified treatment schema.

Preceding treatment

  • Induction BBD x 8

Targeted therapy

Glucocorticoid therapy

14-day cycle for 52 cycles (2 years)

References

  1. SCRI MM 23: 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. link to original article contains dosing details in manuscript PubMed NCT01056276

Carfilzomib monotherapy

Regimen variant #1, bi-weekly

Study Evidence
Bringhen et al. 2014 (IST-CAR-506) Phase 2

Preceding treatment

Targeted therapy

28-day cycles


Regimen variant #2, weekly

Study Evidence
Bringhen et al. 2017 (IST-CAR-561) Phase 1/2

Note: this is the MTD established for the phase II portion of the trial.

Preceding treatment

Targeted therapy

28-day cycles

References

  1. 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. link to original article contains dosing details in manuscript PubMed NCT01346787
  2. 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. link to original article contains dosing details in manuscript PubMed NCT01857115

Carfilzomib & Lenalidomide (KR)

KR: Kyprolis (Carfilzomib) & Revlimid (Lenalidomide)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gay et al. 2021 (FORTE) 2015-2017 Randomized Phase 2 (E-esc) Lenalidomide Superior PFS (co-primary endpoint)
PFS36: 75% vs 65%
(HR 0.64, 95% CI 0.44-0.94)

Note: treatment details are as provided in a 2020 ASH abstract.

Targeted therapy

28-day cycles

References

  1. FORTE: Gay F, Musto P, Rota-Scalabrini D, Bertamini L, Belotti A, Galli M, Offidani M, Zamagni E, Ledda A, Grasso M, Ballanti S, Spadano A, Cea M, Patriarca F, D'Agostino M, Capra A, Giuliani N, de Fabritiis P, Aquino S, Palmas A, Gamberi B, Zambello R, Petrucci MT, Corradini P, Cavo M, Boccadoro M. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. Lancet Oncol. 2021 Dec;22(12):1705-1720. Epub 2021 Nov 11. link to original article PubMed NCT02203643

Daratumumab monotherapy

Regimen variant #1, q4wk indefinite

Study Dates of enrollment Evidence
Mateos et al. 2017 (ALCYONE) 2015-02-09 to 2016-07-14 Non-randomized part of phase 3 RCT

Preceding treatment

Targeted therapy

Supportive therapy

28-day cycles


Regimen variant #2, q8wk x 2y

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moreau et al. 2019 (CASSIOPEIA part 2) 2016-2018 Phase 3 (E-esc) Observation Superior PFS (co-primary endpoint)
Median PFS: NYR vs 46.7 mo
(HR 0.53, 95% CI 0.42-0.68)

Note: the protocol is somewhat confusing about what dose of steroids to use as premedication. See the original paper.

Preceding treatment

Targeted therapy

56-day cycle for 13 cycles (2 years)

References

  1. 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. link to original article contains dosing details in manuscript PubMed NCT02195479
  2. CASSIOPEIA part 2: Moreau P, Hulin C, Perrot A, Arnulf B, Belhadj K, Benboubker L, Béné MC, Zweegman S, Caillon H, Caillot D, Corre J, Delforge M, Dejoie T, Doyen C, Facon T, Sonntag C, Fontan J, Mohty M, Jie KS, Karlin L, Kuhnowski F, Lambert J, Leleu X, Macro M, Orsini-Piocelle F, Roussel M, Stoppa AM, van de Donk NWCJ, Wuillème S, Broijl A, Touzeau C, Tiab M, Marolleau JP, Meuleman N, Vekemans MC, Westerman M, Klein SK, Levin MD, Offner F, Escoffre-Barbe M, Eveillard JR, Garidi R, Ahmadi T, Krevvata M, Zhang K, de Boer C, Vara S, Kampfenkel T, Vanquickelberghe V, Vermeulen J, Avet-Loiseau H, Sonneveld P. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Oct;22(10):1378-1390. Epub 2021 Sep 13. link to original article contains dosing details in manuscript PubMed NCT02541383

Ixazomib monotherapy

Regimen variant #1, indefinite

Study Dates of enrollment Evidence
Kumar et al. 2014 (C16005) 2010-2012 Phase 1/2

Preceding treatment

  • Induction IRd x 12

Targeted therapy

28-day cycles


Regimen variant #2, 2-year course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Dimopoulos et al. 2018 (TOURMALINE-MM3) 2014-2016 Phase 3 (E-esc) Placebo Superior PFS (primary endpoint)
Median PFS: 26.5 vs 21.3 mo
(HR 0.72, 95% CI 0.58-0.89)
Dimopoulos et al. 2020 (TOURMALINE-MM4) 2015-2018 Phase 3 (E-esc) Placebo Superior PFS (primary endpoint)
Median PFS: 17.4 vs 9.4 mo
(HR 0.66, 95% CI 0.54-0.80)

Note: dose was escalated in cycle 5 if the prior dose was tolerated.

Preceding treatment

  • TOURMALINE-MM3: Melphalan with auto HSCT consolidation
  • TOURMALINE-MM4: Standard-of-care induction therapy x 6 to 12 months

Targeted therapy

  • Ixazomib (Ninlaro) as follows:
    • Cycles 1 to 4: 3 mg PO once per day on days 1, 8, 15
    • Cycles 5 to 26: 4 mg PO once per day on days 1, 8, 15

28-day cycle for up to 26 cycles (2 years)

References

  1. C16005: 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. Epub 2014 Nov 14. link to original article contains dosing details in abstract PubMed NCT01217957
    1. Update: 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, Rajkumar SV, Richardson PG. Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance. Leukemia. 2019 Jul;33(7):1736-1746. Epub 2019 Jan 29. link to original article link to PMC article PubMed
  2. TOURMALINE-MM3: Dimopoulos MA, Gay F, Schjesvold F, Beksac M, Hajek R, Weisel KC, Goldschmidt H, Maisnar V, Moreau P, Min CK, Pluta A, Chng WJ, Kaiser M, Zweegman S, Mateos MV, Spencer A, Iida S, Morgan G, Suryanarayan K, Teng Z, Skacel T, Palumbo A, Dash AB, Gupta N, Labotka R, Rajkumar SV; TOURMALINE-MM3 study group. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2019 Jan 19;393(10168):253-264. Epub 2018 Dec 10. link to original article contains dosing details in abstract PubMed NCT02181413
  3. TOURMALINE-MM4: Dimopoulos MA, Špička I, Quach H, Oriol A, Hájek R, Garg M, Beksac M, Bringhen S, Katodritou E, Chng WJ, Leleu X, Iida S, Mateos MV, Morgan G, Vorog A, Labotka R, Wang B, Palumbo A, Lonial S; TOURMALINE-MM4 study group. Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial. J Clin Oncol. 2020 Dec 1;38(34):4030-4041. Epub 2020 Oct 6. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02312258

KRd

KRd: Kyprolis (Carfilzomib), Revlimid (Lenalidomide), low-dose dexamethasone
CRd: Carfilzomib, Revlimid (Lenalidomide), low-dose dexamethasone

Regimen variant #1, biweekly carfilzomib

Study Dates of enrollment Evidence
Jakubowiak et al. 2012 (UMCC 2009.056) 2009-2011 Phase 1/2

This is the MTD dosing in this phase 1/2 trial.

Preceding treatment

  • Induction KRd x 8

Targeted therapy

Glucocorticoid therapy

28-day cycle for 16 cycles

Subsequent treatment

  • UMCC 2009.056: It was recommended that patients proceed to lenalidomide maintenance


Regimen variant #2, carfilzomib 3 weeks on/1 week off

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Dytfeld et al. 2023 (ATLAS-MM) 2016-2020 Phase 3 (E-esc) Lenalidomide Superior PFS (primary endpoint)
Median PFS: 59.1 vs 41.4 mo
(HR 0.51, 95% CI 0.31-0.86)

Note: This trial is named ATLAS-MM here, to distinguish from trials named ATLAS in multiple other cancer subtypes.

Preceding treatment

Targeted therapy

Glucocorticoid therapy

28-day cycle for 36 cycles

Subsequent treatment

References

  1. UMCC 2009.056: 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01029054
  2. ATLAS-MM: Dytfeld D, Wróbel T, Jamroziak K, Kubicki T, Robak P, Walter-Croneck A, Czyż J, Tyczyńska A, Druzd-Sitek A, Giannopoulos K, Nowicki A, Szczepaniak T, Łojko-Dankowska A, Matuszak M, Gil L, Puła B, Rybka J, Majcherek M, Usnarska-Zubkiewicz L, Szukalski Ł, Końska A, Zaucha JM, Walewski J, Mikulski D, Czabak O, Robak T, Lahoud OB, Zonder JA, Griffith K, Stefka A, Major A, Derman BA, Jakubowiak AJ. Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023 Feb;24(2):139-150. Epub 2023 Jan 12. link to original articlecontains dosing details in manuscript PubMed NCT02659293

Lenalidomide monotherapy

Regimen variant #1, indefinite 10 mg 21/28

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Palumbo et al. 2007a 2005 Phase 2
Palumbo et al. 2010 2005-2007 Phase 2
Palumbo et al. 2012 (MM-015) 2007-02 to 2008-09 Phase 3 (E-esc) Placebo Superior PFS (primary endpoint)
Palumbo et al. 2014 (MPRvsMEL200) 2007-2009 Phase 3 (E-esc) Observation Superior PFS (primary endpoint)
Median PFS: 41.9 vs 21.6 mo
(HR 0.47, 95% CI 0.33-0.65)
Stewart et al. 2015 (ECOG E1A06) 2008-2011 Non-randomized part of phase 3 RCT
Gay et al. 2015 (EMN-441) 2009-2011 Phase 3 (C) RP Did not meet primary endpoint of PFS
Magarotto et al. 2016 (EMN01) 2009-2012 Phase 3 (C) RP Not reported
Zweegman et al. 2016 (HOVON87/NMSG18) 2009-2012 Phase 3 (E-switch-ic) Thalidomide Did not meet primary endpoint of PFS
Jackson et al. 2018 (UK NCRI Myeloma XI) 2011-01-13 to 2017-08-11 Phase 3 (E-esc) 1. Observation Superior PFS (co-primary endpoint)
Median PFS: 39 vs 20 mo
(HR 0.46, 95% CI 0.41-0.53)
2. Lenalidomide & Vorinostat Did not meet co-primary endpoint of PFS
Larocca et al. 2021 (RV-MM-PI-0752) 2014-2017 Phase 3 (E-de-esc) Rd; continuous Seems to have superior EFS (primary endpoint)
Median EFS: 10.4 vs 6.9 mo
(HR 0.70, 95% CI 0.51-0.95)

Preceding treatment

Targeted therapy

Supportive therapy

  • Varies depending on reference:
  • MM-015: Aspirin 75 to 100 mg PO once per day
  • Palumbo et al. 2007a 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 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. 2007a: Ciprofloxacin (Cipro) 500 mg PO twice per day

28-day cycles


Protocol variant #2, indefinite 10 -> 15 mg per day with higher dose lead-in

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Attal et al. 2012 (IFM 2005-02) 2006-2008 Phase 3 (E-RT-esc) Placebo Superior PFS (primary endpoint)
Median PFS: 41 vs 23 mo
(HR 0.50)

Note: this is "Maintenance Study 2" listed in the package insert.

Targeted therapy

  • Lenalidomide (Revlimid) as follows:
    • Cycles 1 & 2: 25 mg PO once per day on days 1 to 21
    • Cycle 3: 10 mg PO once per day on days 1 to 90
    • Cycle 4 onwards: 15 mg PO once per day on days 1 to 90

Supportive therapy

  • "Thromboprophylaxis was not used"

28-day cycle for 2 cycles, then 90-day cycles


Regimen variant #3, indefinite 10 -> 15 mg per day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
McCarthy et al. 2012 (CALGB 100104) 2005-2009 Phase 3 (E-RT-esc) Placebo Superior OS1 (secondary endpoint)
Median OS: 113.8 vs 84.1 mo
(HR 0.61, 95% CI 0.46-0.81)

Superior TTP (primary endpoint)

1Reported efficacy is based on the 2017 update.
Note: this is "Maintenance Study 1" listed in the package insert. There may be some dosing discrepancies between papers; this dose is the one described in the 2017 update.

Preceding treatment

Targeted therapy

  • Lenalidomide (Revlimid) as follows:
    • Cycle 1: 10 mg PO once per day on days 1 to 90
    • Cycle 2 onwards: 15 mg PO once per day on days 1 to 90

Supportive therapy

  • Patients at high risk of deep venous thrombosis (DVT) or pulmonary embolism (PE) received Aspirin, 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 of at least 2, smoking history, use of oral contraceptives, and[/or] concurrent use of epoetin."

90-day cycles


Regimen variant #4, 2 years of 25 mg 21/28

Study Dates of enrollment Evidence
Korde et al. 2016 (NCI 12-C-0107) 2011-2013 Phase 2
Korde et al. 2016 (NCI 11-C-0221) 2011-2013 Phase 2

Preceding treatment

  • Induction KRd x 8

Targeted therapy

28-day cycle for up to 24 cycles


Regimen variant #5, 1 year of 10 to 15 mg per day

Study Dates of enrollment Evidence
Roussel et al. 2014 (IFM 2008) 2009 Phase 2
Attal et al. 2017 (IFM 2009) 2010-2012 Non-randomized part of phase 3 RCT

Note: Thalidomide dose was increased only if the starting dose was tolerated.

Preceding treatment

  • RVD consolidation

Targeted therapy

12-month course


Regimen variant #6, indefinite 25 mg 21/28

Study Dates of enrollment Evidence
Jakubowiak et al. 2012 (UMCC 2009.056) 2009-2011 Phase 1/2

Preceding treatment

  • Induction KRd x 24

Targeted therapy

28-day cycles

References

  1. 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. 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. link to original article contains dosing details in manuscript PubMed
  2. 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. link to original article contains dosing details in manuscript PubMed EudraCT 2005-004714-32
    1. 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. link to original article contains dosing details in abstract PubMed
  3. CALGB 100104: 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. link to original article link to supplementary appendix contains dosing details in manuscript link to PMC article PubMed NCT00114101
    1. 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. link to original article link to PMC article PubMed
  4. IFM2005-02: 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. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1782-91. link to original article contains dosing details in manuscript PubMed NCT00430365
    1. Update: Abstract: 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. link to abstract
  5. UMCC 2009.056: 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01029054
  6. 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. link to original article contains dosing details in manuscript PubMed NCT00405756
  7. IFM 2008: 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. link to original article contains dosing details in manuscript PubMed NCT01206205
  8. MPRvsMEL200: 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. link to original article contains dosing details in manuscript PubMed NCT00551928
  9. 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. link to original article contains dosing details in manuscript PubMed EudraCT 2010-019173-16
    1. Subgroup analysis: Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C, Hielscher T, Blau IW, Scheid C, Hose D, Seckinger A, Jauch A, Hillengass J, Raab MS, Schurich B, Munder M, Schmidt-Wolf IG, Gerecke C, Lindemann HW, Zeis M, Weisel K, Duerig J, Goldschmidt H. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica. 2015 Jul;100(7):964-9. Epub 2015 Apr 3. link to original article link to PMC article PubMed
    2. Update: Goldschmidt H, Mai EK, Dürig J, Scheid C, Weisel KC, Kunz C, Bertsch U, Hielscher T, Merz M, Munder M, Lindemann HW, Hügle-Dörr B, Tichy D, Giesen N, Hose D, Seckinger A, Huhn S, Luntz S, Jauch A, Elmaagacli A, Rabold B, Fuhrmann S, Brossart P, Goerner M, Bernhard H, Hoffmann M, Hillengass J, Raab MS, Blau IW, Hänel M, Salwender HJ; German-speaking Myeloma Multicenter Group (GMMG). Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia. 2020 Jul;34(7):1853-1865. Epub 2020 Feb 7. link to original article PubMed
  10. 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00602641
  11. 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. link to original article contains dosing details in abstract PubMed NCT01091831
  12. 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. link to original article contains dosing details in manuscript PubMed NCT01093196
  13. 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. link to original article contains dosing details in manuscript PubMed EudraCT 2007-004007-34
  14. 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) link to abstract
  15. NCI 11-C-0221: 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01402284
  16. NCI 12-C-0107: 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01572480
  17. 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01191060
  18. UK NCRI Myeloma XI: Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Hockaday A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Jenner MW, Cook G, Russell NH, Kaiser MF, Drayson MT, Owen RG, Gregory WM, Morgan GJ; UK NCRI Haemato-oncology Clinical Studies Group. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):57-73. Epub 2018 Dec 14. link to original article link to PMC article PubMed NCT01554852
    1. Update: Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Waterhouse A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Allotey D, Shafeek S, Jenner MW, Cook G, Russell NH, Kaiser MF, Drayson MT, Owen RG, Gregory WM, Morgan GJ, Clinical Studies Group UNHO. Lenalidomide before and after autologous stem cell transplantation for transplant-eligible patients of all ages in the randomized, phase III, Myeloma XI trial. Haematologica. 2021 Jul 1;106(7):1957-1967. link to original article link to PMC article PubMed
    2. Update: Jenner MW, Pawlyn C, Davies FE, Menzies T, Hockaday A, Olivier C, Jones JR, Karunanithi K, Lindsay J, Kishore B, Cook G, Drayson MT, Kaiser MF, Owen RG, Gregory W, Cairns DA, Morgan GJ, Jackson GH; UK National Cancer Research Institute (NCRI) Haemato-oncology Clinical Studies Group. The addition of vorinostat to lenalidomide maintenance for patients with newly diagnosed multiple myeloma of all ages: results from 'Myeloma XI', a multicentre, open-label, randomised, phase III trial. Br J Haematol. 2023 Apr;201(2):267-279. Epub 2022 Dec 21. link to original article PubMed
  19. RV-MM-PI-0752: Larocca A, Bonello F, Gaidano G, D'Agostino M, Offidani M, Cascavilla N, Capra A, Benevolo G, Tosi P, Galli M, Marasca R, Giuliani N, Bernardini A, Antonioli E, Rota-Scalabrini D, Cellini C, Pompa A, Monaco F, Patriarca F, Caravita di Toritto T, Corradini P, Tacchetti P, Boccadoro M, Bringhen S. Dose/schedule-adjusted Rd-R vs continuous Rd for elderly, intermediate-fit patients with newly diagnosed multiple myeloma. Blood. 2021 Jun 3;137(22):3027-3036. link to original article contains dosing details in manuscript PubMed NCT02215980
  20. AURIGA: NCT03901963
  21. DRAMMATIC: NCT04071457
  22. LenaMain-Trial: NCT00891384
  23. MagnetisMM-7: NCT05317416
  24. MajesTEC-4: NCT05243797

Lenalidomide & Dexamethasone (Rd)

Rd: Revlimid (Lenalidomide) & low-dose dexamethasone

Regimen variant #1, 15/20

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rosiñol et al. 2023 (GEM2014MAIN) 2014-11 to 2017-05 Phase 3 (C) IRd Did not meet primary endpoint of PFS12

Preceding treatment

  • VRd consolidation x 2

Targeted therapy

Glucocorticoid therapy

28-day cycle for 24 cycles

Subsequent treatment

  • GEM2014MAIN, negative MRD at 2 years: No further treatment
  • GEM2014MAIN, positive MRD at 2 years: Rd continuation x 36 cycles (60 cycles total)


Regimen variant #2, 25/40

Study Dates of enrollment Evidence
Durie et al. 2016 (SWOG S0777) 2008-2012 Non-randomized part of phase 3 RCT

Preceding treatment

  • Induction Rd x 6 versus VRd x 8

Targeted therapy

Glucocorticoid therapy

28-day cycles

References

  1. 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00644228
  2. GEM2014MAIN: Rosiñol L, Oriol A, Ríos R, Blanchard MJ, Jarque I, Bargay J, Hernández MT, Cabañas V, Carrillo-Cruz E, Sureda A, Martínez-López J, Krsnik I, González ME, Casado LF, Martí JM, Encinas C, de Arriba F, Palomera L, Sampol A, González-Montes Y, Cabezudo E, Paiva B, Puig N, Cedena MT, de la Cruz J, Mateos MV, San Miguel J, Lahuerta JJ, Bladé J. Lenalidomide and dexamethasone maintenance with or without ixazomib, tailored by residual disease status in myeloma. Blood. 2023 Nov 2;142(18):1518-1528. Epub 2023 Jul 28. link to original article contains dosing details in manuscript PubMed NCT02406144

Lenalidomide & Prednisone (RP)

RP: Revlimid (Lenalidomide) & Prednisone

Regimen variant #1, prednisone 25 mg every other day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Magarotto et al. 2016 (EMN01) 2009-2012 Phase 3 (E-esc) Lenalidomide Not reported

Preceding treatment

  • Induction CPR x 9 versus MPR x 9 versus Rd x 9

Targeted therapy

Glucocorticoid therapy

  • Prednisone (Sterapred) 25 mg PO once every other day on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27

Supportive therapy

28-day cycles


Regimen variant #2, prednisone 25 mg TIW

Study Dates of enrollment Evidence
Falco et al. 2012 2008-2009 Phase 2

Preceding treatment

  • MPR consolidation x 6

Targeted therapy

Glucocorticoid therapy

Supportive therapy

  • Thromboprophylaxis: Aspirin 100 mg PO once per day, taken during lenalidomide treatment (unclear from protocol if this also means off weeks)
  • Antiviral prophylaxis if history of VZV.

28-day cycles


Regimen variant #3, prednisone 50 mg every other day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gay et al. 2015 (EMN-441) 2009-2011 Phase 3 (E-esc) Lenalidomide Did not meet primary endpoint of PFS
Median PFS: 37.5 vs 28.5 mo
(HR 0.84, 95% CI 0.59-1.20)

Preceding treatment

Targeted therapy

Glucocorticoid therapy

  • Prednisone (Sterapred) 50 mg PO once every other day on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27

28-day cycles

References

  1. 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. link to original article contains dosing details in manuscript PubMed
  2. 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. link to original article contains dosing details in abstract PubMed NCT01091831
  3. 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. link to original article contains dosing details in manuscript PubMed NCT01093196

RVD

RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone
VRd: Velcade (Bortezomib), Revlimid (Lenalidomide), low-dose dexamethasone

Regimen variant #1, 3-year course

Study Dates of enrollment Evidence
Nair et al. 2010 (2006-66) 2006-11 to 2008-09 Non-randomized

Preceding treatment

  • VTD-PACE consolidation (per Total Therapy 3 protocol)

Targeted therapy

  • 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:
    • Cycles 1 to 13: 1 mg/m2 IV once per day on days 1, 4, 8, 11
    • Cycles 14 to 39: 1 mg/m2 IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 13: 20 mg (route not specified) once per day on days 1 to 4, 8 to 11
    • Cycles 14 to 39: 20 mg (route not specified) once per day on days 1, 8, 15, 22

28-day cycle for 39 cycles (3 years)


Regimen variant #2, Indefinite

Study Dates of enrollment Evidence
Richardson et al. 2010 (DFCI 06-150) 2006-2008 Phase 1/2

Preceding treatment

  • Induction RVD x 4 to 8

Targeted therapy

Glucocorticoid therapy

Supportive therapy

21-day cycles

References

  1. 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. link to original article link to PMC article PubMed
  2. DFCI 06-150: 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. link to original article contains dosing details in abstract link to PMC article PubMed NCT00378105
  3. 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. link to original article PubMed

Thalidomide monotherapy

Regimen variant #1, 50 mg/day x 2 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sonneveld et al. 2012 (HOVON-65) 2005-2008 Phase 3 (C) Bortezomib Inferior PFS1
Sonneveld et al. 2012 (GMMG-HD4) 2005-2008 Phase 3 (C) Bortezomib Inferior PFS1

1In 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.
Note: 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. HOVON-65/GMMG-HD4 was a single phase 3 RCT but the consolidation was different by group, so is reported here as 2 distinct trials.

Preceding treatment

Targeted therapy

2-year course


Regimen variant #2, 50 mg/d, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lokhorst et al. 2009 (HOVON-50) 2001-2005 Phase 3 (E-esc) See link See link
Wijermans et al. 2010 (HOVON 49) 2002-2007 Non-randomized part of phase 3 RCT

Preceding treatment

  • HOVON 49: Induction MPT x 8
  • HOVON-50: single or tandem melphalan auto HSCT consolidation

Targeted therapy

Supportive therapy

Continued indefinitely


Regimen variant #3, 50 -> 100 mg/d, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX) 2003-2007 Phase 3 (E-esc) Observation Superior PFS1 (co-primary endpoint)
Median PFS: 23 vs 15 mo
(HR 0.69, 95% CI 0.58-0.82)

1Reported efficacy is based on the update e-published on 2011 Oct 20.

Preceding treatment

Targeted therapy

  • Thalidomide (Thalomid) as follows:
    • Cycle 1: 50 mg PO once per day on days 1 to 28
    • Cycle 2 onwards: 100 mg PO once per day on days 1 to 28

28-day cycles


Regimen variant #4, 100 mg/day x 3 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rosiñol et al. 2012 (GEM05/MENOS65) 2006-2009 Phase 3 (E-switch-ooc) 1. Interferon alfa-2b Not reported
2. TV Seems to have inferior PFS1 (secondary endpoint)

1Reported efficacy for GEM05/MENOS65 is based on the 2017 update.

Preceding treatment

Targeted therapy

3-year course


Regimen variant #5, 100 mg/d, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Palumbo et al. 2006 (GISMM2001-A) 2002-2005 Non-randomized part of phase 3 RCT
Stewart et al. 2015 (ECOG E1A06) 2008-2011 Non-randomized part of phase 3 RCT
Zweegman et al. 2016 (HOVON87/NMSG18) 2009-2012 Phase 3 (C) Lenalidomide Did not meet primary endpoint of PFS

Preceding treatment

  • GISMM2001-A: Induction MPT x 6
  • ECOG E1A06: Induction MPT x 12
  • HOVON87/NMSG18: Induction MPT x 9

Targeted therapy

Supportive therapy

  • 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 indefinitely


Regimen variant #6, 400 mg/day x 18 months

Study Evidence
Sahebi et al. 2006 Phase 2

Preceding treatment

Targeted therapy

  • Thalidomide (Thalomid) 50 mg PO once per day, escalated by 50 mg every week to a target dose of 400 mg PO once per day

Supportive therapy

18 months of treatment or 6 months past CR, whichever comes first


Regimen variant #7, 400 mg/d, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Attal et al. 2006 (IFM 99-02) 2000-2003 Phase 3 (E-esc) 1. Observation
2. Pamidronate 		Superior OS

Preceding treatment

Targeted therapy

Supportive therapy

28-day cycles

Dose and schedule modifications

  • Thalidomide dose reductions to a minimum of 50 mg PO once per day were allowed

References

  1. GISMM2001-A: 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. 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. link to original article contains dosing details in abstract PubMed NCT00232934
    1. 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. link to original article contains dosing details in abstract PubMed
  2. 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. link to original article contains dosing details in manuscript PubMed
  3. 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; IFM. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. link to original article contains dosing details in manuscript PubMed NCT00222053
    1. Pooled 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. link to original article link to PMC article PubMed
  4. **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. link to original article contains dosing details in manuscript PubMed **RETRACTED** NCT00207805
  5. HOVON-50: 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. 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. link to original article contains dosing details in manuscript PubMed NCT00028886
    1. Update: van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. link to original article PubMed
  6. 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; 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. link to original article contains dosing details in manuscript PubMed
  7. 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. link to original article link to PMC article PubMed ISRCTN68454111
    1. Update: Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article contains dosing details in manuscript link to PMC article PubMed
    2. Update: 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. link to original article contains dosing details in manuscript PubMed
    3. 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. link to original article contains dosing details in manuscript link to PMC article PubMed
    4. 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. link to original article PubMed
  8. GEM05/MENOS65: 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; PETHEMA; GEM. 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. link to original article contains dosing details in manuscript PubMed NCT00461747
    1. Update: 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. link to original article contains dosing details in manuscript PubMed
  9. HOVON-65: 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. link to original article contains dosing details in manuscript PubMed ISRCTN64455289
    1. 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. link to original article PubMed
    2. 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. link to original article PubMed
  10. 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. link to original article contains dosing details in manuscript PubMed ISRCTN64455289
    1. 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. link to original article PubMed
    2. 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. link to original article PubMed
  11. 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00602641
  12. 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. link to original article contains dosing details in manuscript PubMed EudraCT 2007-004007-34

Thalidomide & Dexamethasone (TD)

TD: Thalidomide, Dexamethasone
Thal-Dex: Thalidomide, Dexamethasone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Maiolino et al. 2012 (GBRAM0001) 2003-2008 Phase 3 (E-esc) Dexamethasone Superior PFS (primary endpoint)
Median PFS: 36 vs 19 mo

Preceding treatment

Targeted therapy

Glucocorticoid therapy

28-day cycle for 12 months or until disease progression

References

  1. BMT CTN 0102: 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; 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. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00075829
  2. GBRAM0001: 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. 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. link to original article contains dosing details in manuscript PubMed NCT01296503

Thalidomide & Prednisolone (TP)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Spencer et al. 2009 (ALLG MM6) 2002-2005 Phase 3 (E-esc) Prednisolone Superior OS1 (co-primary endpoint)
OS60: 66% vs 47%
(HR 0.12, 95% CI 0.03-0.56)

1Reported efficacy is based on the 2014 update.
Note: Thalidomide dose was increased only if the starting dose was tolerated.

Preceding treatment

Targeted therapy

  • 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 28
    • Cycles 2 to 13: 200 mg PO once per day on days 1 to 28

Glucocorticoid therapy

28-day cycles

References

  1. ALLG MM6: 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. link to original article contains dosing details in manuscript PubMed ACTRN12607000382471
    1. Subgroup analysis: Ho PJ, Brown RD, Spencer A, Jeffels M, Daniher D, Gibson J, Joshua DE. Thalidomide consolidation improves progression-free survival in myeloma with normal but not up-regulated expression of fibroblast growth factor receptor 3: analysis from the Australasian Leukaemia and Lymphoma Group MM6 clinical trial. Leuk Lymphoma. 2012 Sep;53(9):1728-34. Epub 2012 Mar 13. link to original article PubMed
    2. Update: Kalff A, Kennedy N, Smiley A, Prince HM, Roberts AW, Bradstock K, De Abreu Lourenço R, Frampton C, Spencer A. Thalidomide and prednisolone versus prednisolone alone as consolidation therapy after autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the ALLG MM6 multicentre, open-label, randomised phase 3 study. Lancet Haematol. 2014 Dec;1(3):e112-9. Epub 2014 Dec 1. link to original article PubMed

Thalidomide & Prednisone (TP)

TP: Thalidomide & Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Stewart et al. 2013 (NCIC-CTG MY.10) 2002-2009 Phase 3 (E-esc) Observation Did not meet primary endpoint of OS
OS48: 68% vs 60%
(HR 0.77) 		Decreased QOL

Preceding treatment

Targeted therapy

Glucocorticoid therapy

Supportive therapy

  • "Bisphosphonates, histamine-2 blockers, and laxatives were recommended"
  • "Anticoagulant and antiplatelet medications were not mandated"

Four years or until disease progression

References

  1. NCIC-CTG MY.10: 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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00049673

Bortezomib & Prednisone (VP)

VP: Velcade (Bortezomib) & Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mateos et al. 2010 (GEM2005) 2006-2008 Phase 3 (C) VT Did not meet primary endpoint of ORR

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

  • Induction VMP x 6 versus VTP x 6

Targeted therapy

Glucocorticoid therapy

Supportive therapy

3-month cycle for up to 12 cycles (3 years)

References

  1. 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. link to original article contains dosing details in manuscript PubMed NCT00443235
    1. Subgroup analysis: Mateos MV, Gutiérrez NC, Martín-Ramos ML, Paiva B, Montalbán MA, Oriol A, Martínez-López J, Teruel AI, Bengoechea E, Martín A, Díaz-Mediavilla J, de Arriba F, Palomera L, Hernández JM, Sureda A, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, Fernández M, García-Sanz R, Vidriales MB, Bladé J, Lahuerta JJ, San Miguel JF. Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood. 2011 Oct 27;118(17):4547-53. Epub 2011 Sep 6. link to original article PubMed
    2. 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. link to original article PubMed
    3. 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. link to original article contains dosing details in manuscript PubMed

VT

VT: Velcade (Bortezomib) & Thalidomide
TV: Thalidomide & Velcade (Bortezomib)

Regimen variant #1, 1.3/50 x 2 y

Study Dates of enrollment Evidence
Palumbo et al. 2010 (GIMEMA MM-03-05) 2006-2009 Non-randomized part of phase 3 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

Targeted therapy

14-day cycle for up to 2 years or until disease progression or relapse


Regimen variant #2, 1.3/50 x 3 y

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mateos et al. 2010 (GEM2005) 2006-2008 Phase 3 (E-esc) VP Did not meet primary endpoint of ORR

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

  • Induction VMP x 6 versus VTP x 6

Targeted therapy

Supportive therapy

3-month cycle for up to 12 cycles (3 years)


Regimen variant #3, 1.3/100

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rosiñol et al. 2012 (GEM05/MENOS65) 2006-2009 Phase 3 (E-esc) 1. Interferon alfa-2b
2. Thalidomide 		Seems to have superior PFS1 (secondary endpoint)

1Reported efficacy is based on the 2017 update.
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

Targeted therapy

3-month cycle for up to 12 cycles (3 years)

References

  1. 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. link to original article contains dosing details in manuscript PubMed NCT00443235
    1. Subgroup analysis: Mateos MV, Gutiérrez NC, Martín-Ramos ML, Paiva B, Montalbán MA, Oriol A, Martínez-López J, Teruel AI, Bengoechea E, Martín A, Díaz-Mediavilla J, de Arriba F, Palomera L, Hernández JM, Sureda A, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, Fernández M, García-Sanz R, Vidriales MB, Bladé J, Lahuerta JJ, San Miguel JF. Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood. 2011 Oct 27;118(17):4547-53. Epub 2011 Sep 6. link to original article PubMed
    2. 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. link to original article PubMed
    3. 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. link to original article contains dosing details in manuscript PubMed
  2. GIMEMA MM-03-05: 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. link to original article contains dosing details in manuscript PubMed NCT01063179
    1. 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. link to original article contains dosing details in manuscript PubMed
    2. Subgroup analysis: Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. link to original article PubMed
    3. Subgroup 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. link to original article PubMed
    4. 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. link to original article contains dosing details in manuscript PubMed
  3. GEM05/MENOS65: 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; PETHEMA; GEM. 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. link to original article contains dosing details in manuscript PubMed NCT00461747
    1. Update: 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. link to original article contains dosing details in manuscript PubMed


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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