Light-chain (AL) amyloidosis

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Andrew J. Cowan, MD
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Samuel Rubinstein, MD
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23 regimens on this page
41 variants on this page

Contents


Guidelines

BSH

EMN

NCCN

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

Supportive medications

21-day cycle for 2 cycles

Subsequent treatment

Variant #2, higher-dose dex

Study Evidence Comparator Efficacy
Huang et al. 2014 Randomized Phase II (E) No induction Seems to have superior OS

Chemotherapy

21-day cycle for 2 cycles

Subsequent treatment

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

Colchicine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Kyle et al. 1985 Randomized (E) MP Seems not superior
Cohen et al. 1987 Non-randomized
Kyle et al. 1997 Phase III (C) 1. MP Inferior OS
2. Melphalan, Prednisone, Colchicine Inferior OS

Of historic interest.

Therapy

References

  1. 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
  2. Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. link to original 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

CRd (Cyclophosphamide)

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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

  • 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
  • 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

Supportive medications

28-day cycle for 12 cycles

Subsequent treatment

  • Patients without progression who were tolerating therapy: Rd maintenance

Variant #2, "CRd"

Study Evidence
Kumar et al. 2012 Phase II

Chemotherapy

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

Supportive medications

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

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

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 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

Supportive medications

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

28-day cycles

Subsequent treatment

  • If no response after 3 cycles of therapy, then patients were escalated to lenalidomide & dexamethasone. Otherwise, treatment continued indefinitely

Variant #2, 25 mg dosing

Study Evidence
Dispenzieri et al. 2006 Phase II

Chemotherapy

28-day cycles

Subsequent treatment

  • If no response after 3 cycles of therapy, then patients were escalated to lenalidomide & dexamethasone. Otherwise, treatment continued up to 12 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
    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

M-DEX

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M-DEX: Melphalan & DEXamethasone

Variant #1

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

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

Chemotherapy

Supportive medications

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

Supportive medications

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

MP

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MP: Melphalan & Prednisone

Regimen

Study Evidence Comparator Efficacy
Kyle et al. 1978 Randomized (E) Placebo Longer time on treatment
Kyle et al. 1985 Randomized (E) Colchicine Seems not superior
Kyle et al. 1997 Phase III (C) 1. Colchicine Superior OS
2. Melphalan, Prednisone, Colchicine Seems not superior

Of historic interest.

Chemotherapy

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

28-day cycle for 6 cycles

Supportive medications

  • Thromboprophylaxis with ONE of the following:

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

Supportive medications

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

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

No induction

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Regimen

Study Evidence Comparator Efficacy
Huang et al. 2014 Randomized Phase II (C) BD Seems to have inferior OS

No induction prior to transplant.

Subsequent treatment

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

VDC

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VDC: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone

Variant #1, 300/1.3/40

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

Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.

Chemotherapy

Supportive medications

28-day cycle for 2 to 6 cycles

Variant #2, 300/1.5/40

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

Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.

Chemotherapy

Supportive medications

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

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 third
    • 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 IV or PO 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 IV or PO 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 & Dexamethasone

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BD: Bortezomib & Dexamethasone

Regimen

Study Evidence
Landau et al. 2012 Phase II

Preceding treatment

Chemotherapy

  • Bortezomib (Velcade) as follows:
    • Cycles 1 & 2: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
    • Cycles 2 to 6: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
    • Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)

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 verified protocol PubMed

Bortezomib & Melphalan, then auto HSCT

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Variant #1, HDM 140 mg/m2

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

Preceding treatment

Chemotherapy

Stem cells re-infused on day 0

Variant #2, HDM 200 mg/m2

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

Preceding treatment

Chemotherapy

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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Variant #1, 100 mg/m2

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

Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.

Chemotherapy

Stem cell re-infused on day not specified

Subsequent treatment

Variant #2, 140 mg/m2

Study Evidence Comparator Efficacy
Skinner et al. 2004 Phase II
Jaccard et al. 2007 Phase III (E) M-DEX Seems to have inferior OS
Landau et al. 2012 Phase II, <20 pts
Huang et al. 2014 Non-randomized portion of RCT

Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In Landau et al. 2012, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In Huang et al. 2014, this dose was intended for patients up to age 65 with cardiac or renal compromise.

Preceding treatment

Chemotherapy

Stem cell re-infused on day 2

Subsequent treatment

Variant #3, 200 mg/m2

Study Evidence Comparator Efficacy
Skinner et al. 2004 Phase II
Jaccard et al. 2007 Phase III (E) M-DEX Seems to have inferior OS
Landau et al. 2012 Phase II, <20 pts
Huang et al. 2014 Non-randomized portion of RCT

Note: in Landau et al. 2012, this dose was intended for patients up to age 60 without cardiac or renal compromise. In Huang et al. 2014, this dose was intended for patients up to age 65 without cardiac or renal compromise.

Preceding treatment

Chemotherapy

Stem cell re-infused on day 2

Subsequent treatment

References

  1. Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. link to original article contains verified protocol 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
  3. 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
  4. 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 contains protocol PubMed

Maintenance after first-line therapy

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

Chemotherapy

Supportive medications

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

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

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

References

  1. CAN2007: 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 (Cyclophosphamide)

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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

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

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

Chemotherapy

Supportive medications

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

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

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

Daratumumab monotherapy

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Regimen

Study Evidence
Kaufman et al. 2017 Retrospective

Chemotherapy

  • Daratumumab (Darzalex) 16 mg/kg IV once per week for 8 weeks, then every other week for 8 doses, then every 4 weeks

Supportive medications

Continued indefinitely

References

  1. Retrospective: Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. link to original article 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

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

Subsequent treatment

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

Preceding treatment

Chemotherapy

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

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

28-day cycles

Variant #3

Study Evidence
Dispenzieri et al. 2012 Phase II

Chemotherapy

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

Variant #1, weekly dexamethasone

Study Evidence
Palladini et al. 2012 Phase II

Chemotherapy

Supportive medications

28-day cycles

Variant #2, pulsed dexamethasone

Study Evidence
Sanchorwala et al. 2006 Phase II

Preceding treatment

Chemotherapy

Supportive medications

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 contains verified protocol PubMed

RD

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RD: Revlimid (Lenalidomide) & high-dose Dexamethasone

Regimen

Study Evidence
Dispenzieri et al. 2006 Phase II

Preceding treatment

Chemotherapy

'28-day cycle for 12 or more cycles

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