Light-chain (AL) amyloidosis

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First-Line Therapy (including transplant ineligible)

Bortezomib (Velcade)

Regimen #1, Reece, et al. 2009 & 2011 - twice per week

• 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. 2009 & 2011 - weekly schedule

• 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, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. doi: 10.1182/blood-2009-02-203398. Epub 2009 Jun 4. link to original article contains verified protocol PubMed
2. 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. doi: 10.1182/blood-2011-02-334227. Epub 2011 May 11. link to original article contains verified protocol PubMed

CRD

CRD: Cyclophosphamide, Revlimid, Dexamethasone

Regimen

• Cyclophosphamide (Cytoxan) 500 mg PO once daily on days 1, 8, 15
• Lenalidomide (Revlimid) 15 mg PO once daily on days 1-21
• 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

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

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."

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. doi: 10.1182/blood-2012-01-407791. 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. doi: 10.3324/haematol.2012.073593. Epub 2012 Sep 14. link to original article contains verified protocol PubMed

CTD

CTD: Cyclophosphamide, Thalidomide, Dexamethasone

Regimen #1, Wechalekar, et al. 2007

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

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

Supportive medications:

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

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

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 1-28, increased by 50 mg every 4 weeks as tolerated to a maximum dose of 200 mg PO once daily daily
• Dexamethasone (Decadron) 20 mg PO once daily on days 1-4, 15-18

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

Supportive medications:

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

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

• 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

28-day cycles x 2-6 cycles

Supportive medications:

• "Antiviral prophylaxis"

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. doi: 10.1182/blood-2011-11-390930. Epub 2012 Feb 13. link to original article contains verified protocol PubMed

Lenalidomide (Revlimid) +/- Dexamethasone (Decadron)

Regimen

• Lenalidomide (Revlimid) 15 mg PO once daily on days 1-21
  • The trial used an initial dose of 25 mg PO once daily, but it was reduced to 15 mg because 25 mg was poorly tolerated.

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

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

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

Supportive medications:

• Aspirin 81 or 325 mg (physician discretion) PO once daily as prophylaxis
• Proton pump inhibitor used for patients receiving dexamethasone

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

Melphalan (Alkeran) & Dexamethasone (Decadron)

Regimen

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

28-day cycles x up to 9 cycles

Supportive medications:

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

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

MRD

MRD: Melphalan, Revlimid, Dexamethasone

Regimen

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 1-4
• Lenalidomide (Revlimid) 10 mg PO once daily on days 1-21
• Dexamethasone (Decadron) 40 mg PO once per week

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

Supportive medications:

• Aspirin 325 mg PO once daily to decrease risk of lenalidomide-associated venous thromboembolism (VTE)
• Proton pump inhibitor to decrease risk of gastritis from dexamethasone

References

1. Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of AL amyloidosis: results of a phase II trial. Haematologica. 2012 Nov 9. [Epub ahead of print] link to original article contains verified protocol PubMed

RdC

RdC: Revlimid, dexamethasone, Cyclophosphamide

Regimen

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 1-21
• Cyclophosphamide (Cytoxan) 100 mg PO once daily on days 1-10
• Dexamethasone (Decadron) 20 mg PO once daily on days 1-4

28-day cycles x 12 cycles

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

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. doi: 10.1182/blood-2011-12-396903. Epub 2012 Apr 18. link to original article contains verified protocol PubMed

VMD

VMD: Velcade, Melphalan, Dexamethasone

Regimen

• Melphalan (Alkeran) 9 mg/m2 PO once daily on days 1-4
  • Patients with serum creatinine >2.5 mg/dL received Melphalan (Alkeran) 6 mg/m2 PO once daily on days 1-4
• Bortezomib (Velcade) 1.3 mg/m2 IV once daily on days 1, 8, 15, 22, given first before dexamethasone
  • 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
• 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

4-6 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 Disease

Pomalidomide (Pomalyst)

Regimen

• Pomalidomide (Pomalyst) 2 mg PO once daily on days 1-28
  • See Dispenzieri, et al. 2012 for dose escalations and reductions
• Dexamethasone (Decadron) 40 mg PO once per week

28-day cycles, given until progression of disease

Supportive medications:

• Aspirin 325 mg PO once daily for thromboprophylaxis

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. doi: 10.1182/blood-2012-02-413161. Epub 2012 Apr 4. link to original article contains verified protocol PubMed