Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up

Ute Hegenbart, Tilmann Bochtler, Axel Benner, Natalia Becker, Christoph Kimmich, Arnt V Kristen, Jörg Beimler, Ernst Hund, Markus Zorn, Anja Freiberger, Marianne Gawlik, Hartmut Goldschmidt, Dirk Hose, Anna Jauch, Anthony D Ho, Stefan O Schönland, Ute Hegenbart, Tilmann Bochtler, Axel Benner, Natalia Becker, Christoph Kimmich, Arnt V Kristen, Jörg Beimler, Ernst Hund, Markus Zorn, Anja Freiberger, Marianne Gawlik, Hartmut Goldschmidt, Dirk Hose, Anna Jauch, Anthony D Ho, Stefan O Schönland

Abstract

Chemotherapy in light chain amyloidosis aims to normalize the involved free light chain in serum, which leads to an improvement, or at least stabilization of organ function in most responding patients. We performed a prospective single center phase 2 trial with 50 untreated patients not eligible for high-dose treatment. The treatment schedule comprised 6 cycles of oral lenalidomide, melphalan and dexamethasone every 4 weeks. After 6 months, complete remission was achieved in 9 patients (18%), very good partial remission in 16 (32%) and partial response in 9 (18%). Overall, organ response was observed in 24 patients (48%). Hematologic and cardiac toxicities were predominant adverse events. Mortality at 3 months was low at 4% (n=2) despite the inclusion of 36% of patients (n=18) with cardiac stage Mayo 3. After a median follow-up of 50 months, median overall and event-free survival were 67.5 months and 25.1 months, respectively. We conclude that the treatment of lenalidomide, melphalan and dexamethasone is very effective in achieving a hematologic remission, organ response and, consecutively, a long survival in transplant ineligible patients with light chain amyloidosis. However, as toxicity and tolerability are the major problems of a 3-drug regimen, a strict surveillance program is necessary and sufficient to avoid severe toxicities. clinicaltrials.gov Identifier: 00883623 (Eudract2008-001405-41).

Trial registration: ClinicalTrials.gov NCT00883623.

Copyright© 2017 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Hematologic remission. Distribution of hematologic remission after 3, 6, 9 and 12 months after start of L-M-Dex. pts: patients; SD/PROG: stable disease/progression; PR: partial remission; VGPR: very good partial remission; CR: complete remission.
Figure 2.
Figure 2.
Survival of patients with lenalidomide, melphalan and dexamethasone. Estimated event-free survival (EFS) and overall survival (OS) in the L-M-Dex study group.
Figure 3.
Figure 3.
Survival in relation to the cardiac Mayo Stage. Estimated (A) event-free survival (EFS) and (B) overall survival (OS) in the L-M-Dex study group depending on cardiac Mayo stage 1/2 compared to Mayo stage 3.

References

    1. Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol. 2011; 29(14):1924–1933.
    1. Cibeira MT, Sanchorawala V, Seldin DC, et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood. 2011;118(16):4346–4352.
    1. Palladini G, Milani P, Foli A, et al. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014;99(4):743–750.
    1. Dietrich S, Schonland SO, Benner A, et al. Treatment with intravenous melphalan and dexamethasone is not able to overcome the poor prognosis of patients with newly diagnosed systemic light chain amyloidosis and severe cardiac involvement. Blood; 116(4):522–528.
    1. Moreau P, Jaccard A, Benboubker L, et al. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multi-center phase 1/2 dose-escalation study. Blood. 2010;116(23):4777–4782.
    1. Sanchorawala V, Patel JM, Sloan JM. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013;98(5):789–792.
    1. Dinner S, Witteles W, Afghahi A, et al. Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement. Haematologica. 2013;98(10):1593–1599.
    1. Palladini G, Milani P, Foli A, et al. Melphalan and dexamethasone with or without bortezomib in newly diagnosed AL amyloidosis: a matched case-control study on 174 patients. Leukemia. 2014;28(12):2311–2316.
    1. Kastritis E, Leleu X, Arnulf B, et al. A randomized phase III trial of melphalan and dexamethasone (MDex) versus bortezomib, melphalan and dexamethasone (BMDex) for untreated patients with AL amyloidosis. Blood 2016. 128:646; abstr.
    1. Palladini G, Russo P, Milani P, et al. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013;98(3):433–436.
    1. Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, et al. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol 2015;170(6):804–813.
    1. Kumar SK, Hayman SR, Buadi FK, et al. A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012;119(21):4860–4867.
    1. Kastritis E, Terpos E, Roussou M, et al. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012;119(23):5384–5390.
    1. Schonland SO, Dreger P, de Witte T, Hegenbart U. Current status of hematopoietic cell transplantation in the treatment of systemic amyloid light-chain amyloidosis. Bone Marrow Transplant. 2012;47(7):895–905.
    1. Tapan U, Seldin DC, Finn KT, et al. Increases in B-type natriuretic peptide (BNP) during treatment with lenalidomide in AL amyloidosis. Blood. 2010;116(23):5071–5072.
    1. Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18–22 April 2004. Am J Hematol 2005;79(4):319–328.
    1. Palladini G, Dispenzieri A, Gertz MA, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012;30(36):4541–4549.
    1. Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 2004;22(18):3751–3757.
    1. Kristen AV, Giannitsis E, Lehrke S, et al. Assessment of disease severity and outcome in patients with systemic light-chain amyloidosis by the high-sensitivity troponin T assay. Blood. 2010;116(14):2455–2461.
    1. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996;17(4):343–346.
    1. Grambsch P, Therneau T. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81:515–526.
    1. R Core Team (2014). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria URL .
    1. Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood. 2014; 124(15):2325–2332.
    1. Palumbo A, Cavallo F. Lenalidomide in the treatment of plasma cell dyscrasia: state of the art and perspectives. Haematologica 2013;98(5):660–661.
    1. Wechalekar AD, Schonland SO, Kastritis E, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood. 2013;121(17):3420–3427.
    1. Jaccard A, Comenzo RL, Hari P, et al. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naive patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014;99(9):1479–1485.
    1. Bochtler T, Hegenbart U, Kunz C, et al. Gain of chromosome 1q21 is an independent adverse prognostic factor in light chain amyloidosis patients treated with melphalan/dexamethasone. Amyloid 2014;21(1):9–17.
    1. Bochtler T, Hegenbart U, Kunz C, et al. Translocation t(11;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens. J Clin Oncol 2015;33(12):1371–1378
    1. Muchtar E, Dispenzieri A, Kumar SK, et al. Interphase fluorescence in-situ hybridization (iFISH) in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category. Leukemia. 2016. [Epub ahead of print].

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever