Light-chain (AL) amyloidosis

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Untreated (including transplant ineligible)

CRD

CRD: Cyclophosphamide, Revlimid, Dexamethasone

Regimen, Kumar et al. 2012

Phase II

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

Supportive medications:

• Aspirin 81, 100, or 325 mg PO once daily 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 cycles x up to 2 years

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 PubMed

CTD

CTD: Cyclophosphamide, Thalidomide, Dexamethasone

Regimen #1, Wechalekar et al. 2007

Phase II

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

Regimen #2, Wechalekar et al. 2007 - risk attenuated regimen

Phase II

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

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

CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone

Regimen

Phase II, <20 patients reported

• 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 cycles x 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 PubMed

Lenalidomide +/- Dexamethasone

Regimen #1, Sanchorwala et al. 2007

Phase II

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

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

28-day cycles; if no response after 3 cycles of therapy, then patients would also receive:

• Dexamethasone (Decadron) 10 to 20 mg PO once daily 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 daily as prophylaxis
• Proton pump inhibitor used for patients receiving dexamethasone

28-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2, Dispenzieri et al. 2007

Phase II

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

28-day cycles; if no response after 3 cycles of therapy, then patients would also receive:

• Dexamethasone (Decadron) 40 mg PO once daily on days 1 to 4, 15 to 18

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

Supportive medications: not specified

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. 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

Regimen

Phase II

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

Supportive medications:

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

28-day cycles x 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
2. Retrospective: Wechalekar AD, Schonland SO, Kastritis E, Gillmore JD, Dimopoulos MA, Lane T, Foli A, Foard D, Milani P, Rannigan L, Hegenbart U, Hawkins PN, Merlini G, Palladini G. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood. 2013 Apr 25;121(17):3420-7. Epub 2013 Mar 11. link to original article PubMed Melphalan & dexamethasone (MDex) only regimen explicitly mentioned in cohort. Others included thalidomide combination, bortezomib combination, and lenalidomide combination.
3. 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 PubMed

MRD

MRD: Melphalan, Revlimid, Dexamethasone

Regimen #1, Sanchorwala et al. 2012

Phase II, <20 patients reported

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.

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

Supportive medications:

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

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

Regimen #2, Moreau et al. 2010

Phase II

To be completed

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 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 PubMed

RdC

RdC: Revlimid, dexamethasone, Cyclophosphamide

Regimen

Phase II

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

• Lenalidomide (Revlimid) 15 mg PO once daily on days 1 to 21
• Dexamethasone (Decadron) 20 mg PO once daily on days 1 to 4
• Cyclophosphamide (Cytoxan) 100 mg PO once daily 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 cycles x 12 cycles

References

1. 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

VMD

VMD: Velcade, Melphalan, Dexamethasone

Regimen

Phase II

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

4 to 6 week cycles x up to 20 cycles

References

1. 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

Relapsed/refractory

Bortezomib (Velcade)

Regimen #1, Reece et al. 2011 - twice per week (CAN2007)

Phase II

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

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

Regimen #2, Reece et al. 2011 - weekly schedule (CAN2007)

Phase II

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

35-day cycle x 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
2. 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 PubMed

CRD

CRD: Cyclophosphamide, Revlimid, Dexamethasone

Regimen

Phase II

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

Supportive medications (varies depending on reference):

• Aspirin 81, 100, or 325 mg PO once daily 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 cycles x up to 9 cycles or 2 years, depending on reference

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 PubMed
2. 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 PubMed

CTD

CTD: Cyclophosphamide, Thalidomide, Dexamethasone

Regimen #1, Wechalekar et al. 2007

Phase II

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

Regimen #2, Wechalekar et al. 2007 - risk attenuated regimen

Phase II

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

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

Lenalidomide & Dexamethasone

Regimen #1, Sanchorwala et al. 2007

Phase II

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

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

28-day cycles; if no response after 3 cycles of therapy, then patients would also receive:

• Dexamethasone (Decadron) 10 to 20 mg PO once daily 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 daily as prophylaxis
• Proton pump inhibitor used for patients receiving Dexamethasone (Decadron)

28-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2, Dispenzieri et al. 2007

Phase II

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

28-day cycles; if no response after 3 cycles of therapy, then patients would also receive:

• Dexamethasone (Decadron) 40 mg PO once daily on days 1 to 4, 15 to 18

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

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. 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

Pomalidomide (Pomalyst)

Regimen

Phase II

• Pomalidomide (Pomalyst) 2 mg PO once daily on days 1 to 28
  • 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 daily for thromboprophylaxis

28-day cycles, given until progression of disease

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 PubMed

RdC

RdC: Revlimid, dexamethasone, Cyclophosphamide

Regimen

Phase II

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

• Lenalidomide (Revlimid) 15 mg PO once daily on days 1 to 21
• Dexamethasone (Decadron) 20 mg PO once daily on days 1 to 4
• Cyclophosphamide (Cytoxan) 100 mg PO once daily 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 cycles x 12 cycles

References

1. 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