Light-chain (AL) amyloidosis

Section editor		Page editor
	Andrew J. Cowan, MD Seattle, WA LinkedIn		Samuel Rubinstein, MD Nashville, TN

25 regimens on this page 48 variants on this page

Guidelines

BSH

• 2014: Guidelines on the management of AL amyloidosis PubMed

NCCN

• NCCN Guidelines - Systemic Light Chain Amyloidosis

First-line therapy (including transplant ineligible)

Bortezomib & Dexamethasone

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Variant #1, lower-dose dex

Study	Evidence	Efficacy
Sanchorawala et al. 2015	Phase II	HRR: 77%

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 4, 8, 11

Supportive medications

• Proton pump inhibitor
• Antiviral medication

21-day cycle for 2 cycles

Treatment followed by bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant.

Variant #2, higher-dose dex

Study	Evidence	Comparator	Efficacy
Huang et al. 2014	Randomized Phase II	High-dose melphalan, then auto HSCT	Seems to have superior OS

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 4, 8, 11

21-day cycle for 2 cycles

Treatment followed by high-dose melphalan with autologous hematopoietic stem cell transplant.

References

1. Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. link to original article contains verified protocol link to PMC article PubMed
2. Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. link to original article contains verified protocol PubMed

CRd

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CRd: Cyclophosphamide, Revlimid (Lenalidomide), low-dose dexamethasone
LDC: Lenalidomide, Dexamethasone, Cyclophosphamide
RdC: Revlimid (Lenalidomide), low-dose dexamethasone, Cyclophosphamide

Variant #1, "LDC"

Study	Evidence
Cibeira et al. 2015	Phase II

Chemotherapy

• Lenalidomide (Revlimid) as follows:
  • Normal eGFR: 15 mg PO once per day on days 1 to 21
  • eGFR greater than 30 mL/min/1.73m² but less than 50 mL/min/1.73m²: 10 mg PO once per day on days 1 to 21
  • eGFR less than 30 mL/min/1.73m²: 5 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12
  • Cycles 7 to 12: 20 mg PO once per day on days 1 to 4
  • Cardiac stage III (this is not defined): upfront modification "allowed" but not defined
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 6: 300 mg/m² IV once per day on days 1 & 8
  • Cycles 7 to 12: 300 mg/m² IV once on day 1

Supportive medications

• Aspirin 100 mg PO once per day, or Low molecular weight heparin

28-day cycle for 12 cycles

Patients without progression who were tolerating therapy proceeded to lenalidomide & dexamethasone maintenance.

Variant #2, "CRd"

Study	Evidence
Kumar et al. 2012	Phase II

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22

Supportive medications

• Aspirin 81, 100, or 325 mg PO once per day for thromboprophylaxis
• Patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive low molecular weight heparin or Warfarin (Coumadin)
• "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."

28-day cycle for up to 2 years

Variant #3, "RdC"

Study	Evidence
Kastritis et al. 2012	Phase I/II

This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.

Chemotherapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
• Cyclophosphamide (Cytoxan) 100 mg PO once per day on days 1 to 10

Supportive medications

• Aspirin 100 mg PO once daily for thromboprophylaxis
• Proton pump inhibitor
• Trimethoprim-sulfamethoxazole (Bactrim), dose and schedule not listed
• Valacyclovir (Valtrex), dose and schedule not listed

28-day cycle for 12 cycles

References

1. Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. link to original article contains verified protocol link to PMC article PubMed
2. Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. link to original article contains verified protocol PubMed
3. Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA cooperative study group. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. link to original article contains verified protocol PubMed

CTD

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CTD: Cyclophosphamide, Thalidomide, Dexamethasone

Variant #1

Study	Evidence
Wechalekar et al. 2007	Phase II

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg PO once per week
• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12

Supportive medications

• "Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis

21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response

Variant #2, risk attenuated regimen

Study	Evidence
Wechalekar et al. 2007	Phase II

For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
• Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 28, increased by 50 mg every 4 weeks as tolerated to a maximum dose of 200 mg PO once per day
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 15 to 18

Supportive medications

• "Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis

28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response

References

1. Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. link to original article contains verified protocol PubMed

CyBorD

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CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone

Regimen

Study	Evidence
Mikhael et al. 2012	Phase II, <20 pts

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² PO once per week
• Bortezomib (Velcade) 1.5 mg/m² (route not specified) once per week OR 1.3 mg/m² on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg (route not specified) once per week

Supportive medications

• "Antiviral prophylaxis"

28-day cycle for 2 to 6 cycles

References

1. Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. link to original article contains verified protocol link to PMC article PubMed
2. Retrospective: Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. link to original article link to PMC article PubMed
3. Retrospective: Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. link to original article PubMed

Lenalidomide monotherapy

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Variant #1, 15 mg dosing

Study	Evidence
Sanchorwala et al. 2006	Phase II

The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.

Chemotherapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21

Supportive medications

• Aspirin 81 or 325 mg (physician discretion) PO once per day as prophylaxis

28-day cycles

If no response after 3 cycles of therapy, then patients were escalated to lenalidomide & dexamethasone. Otherwise, treatment continued until progression of disease or unacceptable toxicity.

Variant #2, 25 mg dosing

Study	Evidence
Dispenzieri et al. 2006	Phase II

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycles

If no response after 3 cycles of therapy, then patients were escalated to lenalidomide & dexamethasone. Otherwise, treatment continued with a target of 12 cycles, total.

References

1. Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. link to original article contains verified protocol PubMed
   1. Update: Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. link to original article PubMed
2. Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. link to original article contains verified protocol PubMed

Melphalan & Dexamethasone

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Variant #1

Study	Evidence	Comparator	Efficacy
Jaccard et al. 2007	Phase III	High-dose melphalan, then auto HSCT	Seems to have superior OS

Chemotherapy

• Melphalan (Alkeran) 10 mg/m² PO once per day on days 1 to 4
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive medications

• Proton pump inhibitor
• Trimethoprim/Sulfamethoxazole (Bactrim DS) three times per week

1-month cycle for up to 18 cycles

Patients achieving complete hematologic remission could stop treatment after 12 cycles.

Variant #2

Study	Evidence
Palladini et al. 2003	Phase II

Chemotherapy

• Melphalan (Alkeran) 0.22 mg/kg PO once per day on days 1 to 4
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive medications

• Omeprazole (Prilosec) 20 mg PO once per day on days 1 to 10
• Ciprofloxacin (Cipro) 250 mg PO BID on days 1 to 10
• Itraconazole (Sporanox) 100 mg PO once per day on days 1 to 10

28-day cycle for up to 9 cycles

References

1. Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. link to original article contains protocol PubMed
   1. Update: Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. link to original articlePubMed
   2. Update: Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. link to original article link to PMC article PubMed
2. Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; Myélome Autogreffe (MAG) and Intergroupe Francophone du Myélome (IFM) Intergroup. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. link to original article contains verified protocol PubMed

Melphalan & Prednisone

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Regimen

Study	Evidence	Comparator	Efficacy
Kyle et al. 1978	Randomized	Placebo	Seems not superior
Kyle et al. 1985	Randomized	Colchicine	Seems not superior
Kyle et al. 1997	Phase III	Colchicine	Superior OS
		Melphalan, Prednisone, Colchicine	Seems not superior

Of historic interest.

Chemotherapy

• Melphalan (Alkeran)
• Prednisone (Sterapred)

References

1. Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. link to original article PubMed
2. Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis. Comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. link to SD article PubMed
3. Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. link to original article PubMed

MRD

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MRD: Melphalan, Revlimid (Lenalidomide), Dexamethasone
L-M-Dex: Lenalidomide, Melphalan, Dexamethasone

Variant #1, "L-M-Dex"

Study	Evidence
Hegenbart et al. 2017	Phase II

Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.

Chemotherapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
• Melphalan (Alkeran) 0.15 mg/kg PO once per day on days 1 to 4
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4

28-day cycle for 6 cycles

Supportive medications

• Thromboprophylaxis with ONE of the following:
  • Standard patients: Aspirin 100 mg PO once per day
  • Patients with a history of VTE or thrombophilia: low-molecular weight heparin (dose/schedule not specified)

Variant #2

Study	Evidence
Sanchorwala et al. 2012	Phase II, <20 pts

Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.

Chemotherapy

• Melphalan (Alkeran) 5 mg/m² PO once per day on days 1 to 4
• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week

Supportive medications

• Aspirin 325 mg PO once per day to decrease risk of Lenalidomide (Revlimid)-associated venous thromboembolism (VTE)
• Proton pump inhibitor to decrease risk of gastritis from Dexamethasone (Decadron)

28-day cycle for 12 cycles, until progression of disease, or unacceptable toxicity

Variant #3

Study	Evidence
Moreau et al. 2010	Phase I/II

This is the MTD dosing.

Chemotherapy

• Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive medications

• LMWH for the first 4 cycles, then Aspirin as another option if no thrombosis

28-day cycle for up to 9 cycles

References

1. Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. link to original article contains verified protocol PubMed
2. Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. link to original article contains verified protocol link to PMC article PubMed
3. Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. link to original article contains verified protocolPubMed

VMD

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VMD: Velcade (Bortezomib), Melphalan, Dexamethasone

Regimen

Study	Evidence
Zonder et al. 2009	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22, given first
  • Patients with peripheral neuropathy at baseline received 1.0 mg/m² IV once per day on days 1, 8, 15, 22
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4, given last
  • Patients with serum creatinine greater than 2.5 mg/dL received 6 mg/m² PO once per day on days 1 to 4
• Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1, 8, 15, 22, given second
  • Patients older than 70 years of age, with peripheral edema or congestive heart failure (CHF) received 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23

4 to 6 week cycle for up to 20 cycles

References

1. Abstract: Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. link to abstract

Consolidation after first-line therapy

Bortezomib & Melphalan, then auto HSCT

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Variant #1, HDM 200 mg/m²

Study	Evidence	Efficacy
Sanchorawala et al. 2015	Phase II	HRR: 77%

Preceding treatment

• Bortezomib & Dexamethasone x 2

Chemotherapy

• Bortezomib (Velcade) 1 mg/m² IV once per day on days -6, -3, +1, +4
• Melphalan (Alkeran) 100 mg/m² IV once per day on days -2 & -1

Stem cells re-infused on day 0

Variant #2, HDM 140 mg/m²

Study	Evidence	Efficacy
Sanchorawala et al. 2015	Phase II	HRR: 77%

Preceding treatment

• Bortezomib & Dexamethasone x 2

Chemotherapy

• Bortezomib (Velcade) 1 mg/m² IV once per day on days -6, -3, +1, +4
• Melphalan (Alkeran) 70 mg/m² IV once per day on days -2 & -1

Stem cells re-infused on day 0

References

1. Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. link to original article contains verified protocol PubMed

Melphalan, then auto HSCT

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To be completed. See details about preparative regimens.

References

1. Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; Myélome Autogreffe (MAG) and Intergroupe Francophone du Myélome (IFM) Intergroup. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. link to original article PubMed
2. Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. link to original article contains protocol PubMed
3. Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. link to original article link to PMC article PubMed

Maintenance after first-line therapy

Bortezomib & Dexamethasone

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Regimen

Study	Evidence
Landau et al. 2012	Phase II

Details of dosing not available in the abstract.

Preceding treatment

• High-dose melphalan with autologous hematopoietic stem cell transplant

Chemotherapy

• Bortezomib (Velcade)
• Dexamethasone (Decadron)

References

1. Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. link to original article contains protocol PubMed

Rd

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Rd: Revlimid (Lenalidomide) & low-dose dexamethasone
RevDex: Revlimid (Lenalidomide) & Dexamethasone
Ld: Lenalidomide & low-dose dexamethasone
Len-Dex: Lenalidomide & Dexamethasone

Regimen

Study	Evidence
Cibeira et al. 2015	Phase II

Preceding treatment

• LDC x 12

Chemotherapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4

Supportive medications

• Aspirin 100 mg PO once per day or Low molecular weight heparin

28-day cycle for 3 years

References

1. Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA cooperative study group. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. link to original article contains verified protocol PubMed

Relapsed or refractory

Bortezomib monotherapy

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Variant #1, twice per week

Study	Evidence
Reece et al. 2011 (CAN2007)	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² (route not specified) once per day on days 1, 4, 8, 11

21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit

Variant #2, weekly schedule

Study	Evidence
Reece et al. 2011 (CAN2007)	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.6 mg/m² (route not specified) once per day on days 1, 8, 15, 22

35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit

References

1. Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. link to original article contains verified protocol PubMed
   1. Update: Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. link to original article contains verified protocol link to PMC article PubMed

CRd

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CRd: Cyclophosphamide, Revlimid (Lenalidomide), low-dose dexamethasone

Variant #1

Study	Evidence
Kumar et al. 2012	Phase II
Palladini et al. 2012	Phase II

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
  • In Palladini et al. 2013 only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per week

Supportive medications

(varies depending on reference)

• Aspirin 81, 100, or 325 mg PO once per day for thromboprophylaxis
• In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive low molecular weight heparin or Warfarin (Coumadin)
• Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."

28-day cycle for up to 9 cycles or 2 years, depending on reference

Variant #2

Study	Evidence	ORR
Kastritis et al. 2012	Phase I/II	55% (hematologic response) 22% (organ response)

This was the highest dose level tested, which had no dose-limiting toxicities.

Chemotherapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
• Cyclophosphamide (Cytoxan) 100 mg PO once per day on days 1 to 10

Supportive medications

• Aspirin 100 mg PO once per day for thromboprophylaxis
• Proton pump inhibitor
• Trimethoprim-sulfamethoxazole (Bactrim), dose and schedule not listed
• Valacyclovir (Valtrex), dose and schedule not listed

28-day cycle for 12 cycles

References

1. Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. link to original article contains verified protocol link to PMC article PubMed
2. Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. link to original article contains verified protocol PubMed
3. Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. link to original article contains verified protocol link to PMC article PubMed

CTD

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CTD: Cyclophosphamide, Thalidomide, Dexamethasone

Variant #1

Study	Evidence
Wechalekar et al. 2007	Phase II

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg PO once per week
• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12

Supportive medications

• "Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis

21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response

Variant #2, risk attenuated regimen

Study	Evidence
Wechalekar et al. 2007	Phase II

For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
• Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 28, increased by 50 mg every 4 weeks as tolerated to a maximum dose of 200 mg PO once per day
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 15 to 18

Supportive medications

• "Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis

28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response

References

1. Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. link to original article contains verified protocol PubMed

Ixazomib monotherapy

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Regimen

Study	Evidence
Sanchorawala et al. 2017	Phase I/II

This is the MTD dosing determined in this phase I/II trial.

Chemotherapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15

28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"

Patients with less than PR after four cycles proceeded to received ixazomib & dexamethasone.

References

1. Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. link to original article contains verified protocol PubMed

Ixazomib & Dexamethasone

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Regimen

Study	Evidence
Sanchorawala et al. 2017	Phase I/II

This was a pre-planned protocol for patients with less than PR on ixazomib monotherapy.

Chemotherapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

28-day cycles

References

1. Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. link to original article contains verified protocol PubMed

Pomalidomide & Dexamethasone

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Variant #1

Study	Evidence
Palladini et al. 2017	Phase II

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day
• Dexamethasone (Decadron) 20 mg PO once per week

28-day cycles

Variant #2

Study	Evidence
Sanchorawala et al. 2016	Phase I/II, <20 pts

Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 20 mg PO once per week

28-day cycles

Variant #3

Study	Evidence
Dispenzieri et al. 2012	Phase II

Chemotherapy

• Pomalidomide (Pomalyst) 2 mg PO once per day
  • See Dispenzieri et al. 2012 for dose escalations and reductions
• Dexamethasone (Decadron) 40 mg PO once per week

Supportive medications

• Aspirin 325 mg PO once per day for thromboprophylaxis

28-day cycles

References

1. Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. link to original article contains verified protocol link to PMC article PubMed
2. Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. link to original article contains verified protocol PubMed
3. Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. link to original article contains verified protocol PubMed

Rd

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Rd: Revlimid (Lenalidomide) & low-dose dexamethasone
RevDex: Revlimid (Lenalidomide) & Dexamethasone
Ld: Lenalidomide & low-dose dexamethasone
Len-Dex: Lenalidomide & Dexamethasone

Regimen

Study	Evidence
Sanchorwala et al. 2006	Phase II

Preceding treatment

• Treatment failure after lenalidomide x 3 cycles

Chemotherapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20, given every other cycle

Supportive medications

• Aspirin 81 or 325 mg (physician discretion) PO once per day as thromboprophylaxis
• Proton pump inhibitor

28-day cycles

References

1. Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. link to original article contains verified protocol PubMed
2. Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. link to original article PubMed

RD

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RD: Revlimid (Lenalidomide) & high-dose Dexamethasone

Regimen

Study	Evidence
Dispenzieri et al. 2006	Phase II

Preceding treatment

• Treatment failure after lenalidomide x 3 cycles

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 15 to 18

28-day cycle with target 12 total cycles, could continue if response observed

References

1. Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. link to original article contains verified protocol PubMed