Reduction in Absolute Involved Free Light Chain and Difference between Involved and Uninvolved Free Light Chain Is Associated with Prolonged Major Organ Deterioration Progression-Free Survival in Patients with Newly Diagnosed AL Amyloidosis Receiving Bortezomib, Cyclophosphamide, and Dexamethasone with or without Daratumumab: Results from Andromeda
Blood, vol. 136, pp. 48–50
Abstract
Background: Systemic AL amyloidosis is characterized by the deposition of insoluble amyloid fibrils produced by light chains synthesized by clonal CD38+ plasma cells. Combining daratumumab (DARA) with bortezomib, cyclophosphamide, and dexamethasone (VCd) has demonstrated significantly improved outcomes in patients with AL amyloidosis. The classification of hematologic complete response (CR) in this disease is evolving, and the absolute reduction of the involved free light chain (iFLC) and the difference between iFLC and uninvolved free light chain (dFLC) are being recognized as very meaningful endpoints. Here, we present results from the ANDROMEDA study (NCT03201965) to demonstrate the impact of achieving deep reductions of iFLC and dFLC on major organ deterioration progression-free survival (MOD-PFS), a novel, key secondary endpoint in this study. Methods: Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease (serum monoclonal protein ≥0.5 g/dL by protein electrophoresis or serum free light chain ≥5.0 mg/dL with an abnormal kappa:lambda ratio or dFLC ≥50 mg/L), ≥1 involved organ, cardiac stage I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to receive DARA-VCd or VCd alone. All patients received bortezomib (1.3 mg/m2 subcutaneous [SC] weekly), cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection weekly in Cycles 1-2, every other week in Cycles 3-6, and every 4 weeks thereafter for up to 24 cycles. Disease evaluations occurred every 4 weeks (Cycles 1-6) and every 8 weeks (after Cycle 7) until major organ deterioration, death, end of study, or withdrawal. The primary endpoint was overall (ie, at any time) hematologic CR rate, defined here as normalization of FLC levels and ratio (FLCr) and negative serum and urine immunofixation, confirmed at a subsequent visit; normalization of uninvolved FLC level and FLCr were not required if iFLC Results: A total of 388 patients were randomized to receive DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The median age was 64 years and 65% of patients had ≥2 organs involved. The proportions of patients with heart and kidney involvement were 71% and 59%, respectively, and the proportions of patients with cardiac stage I, II, and IIIA were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 months for DARA-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+). The rates of deep hematological responses by all criteria strongly favored the DARA-VCd treatment arm (Table). MOD-PFS was longer in patients achieving deep hematological responses by all criteria (Figure). In addition, the corresponding MOD-PFS was similar regardless of the hematological response criteria used. Conclusions: Regardless of the criteria used, the addition of DARA to VCd increased the rates of deep hematologic responses in patients with newly diagnosed AL amyloidosis, which, in turn, was associated with prolonged MOD-PFS. These results support the benefit of DARA in this patient population. References 1. Comenzo RL, et al. Leukemia. 2012;26(11):2317-25 2. Sidana S, et al. Leukemia. 2019;34(5):1472-75 3. Muchtar E, et al. Leukemia. 2019;33(3):790-94 4. Manwani R, et al. Blood. 2019;134(25):2271-2280 Disclosures Comenzo: Amgen: Consultancy; Sanofi: Consultancy; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Unum: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Caleum: Consultancy. Kastritis:Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Palladini:Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Minnema:Celgene: Other: travel support, Research Funding; Kite, a Gilead Company: Speakers Bureau; Amgen: Consultancy; Servier: Consultancy. Wechalekar:Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel; Celgene: Honoraria. Jaccard:Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding; Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding. Sanchorawala:Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Regeneron: Other: advisory board; Caleum: Other: advisory board; Janssen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Prothena: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding. Lee:Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Gibbs:Janssen, BMS/Celgene, Amgen, Takeda, Pfizer, Caelum, Abbvie and Eidos: Membership on an entity's Board of Directors or advisory committees. Mollee:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Suzuki:Takeda, Amgen, Janssen and Celgene: Consultancy; Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Kim:Amgen, BMS, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Cibeira:Janssen, Akcea Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene, Amgen: Honoraria, Other: Educational lectures. Beksac:Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Valent:Amgen Inc.: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau. Wong:Fortis: Research Funding; GSK: Research Funding; Amgen: Consultancy; Janssen: Research Funding; Roche: Research Funding; Bristol Myers Squibb: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenzweig:Janssen: Speakers Bureau. Bumma:Sanofi: Speakers Bureau; Amgen: Speakers Bureau. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:J
Authors 33
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Affiliation as printed
Division of Hematology/Oncology, John C. Davis Myeloma and Amyloid Program, Tufts Medical Center, Boston, MA
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National and Kapodistrian University of Athens
Affiliation as printed
Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, ATHENS, Greece
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University of Pavia · Policlinico San Matteo Fondazione
Affiliation as printed
Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, Pavia, Italy
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University Medical Center Utrecht
Affiliation as printed
Department of Hematology, UMC Utrecht, Utrecht, Netherlands
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Affiliation as printed
University College London, London, United Kingdom
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Centre Hospitalier Universitaire de Limoges
Affiliation as printed
Centre Hospitalier Universitaire and Reference Center for AL Amyloidosis, Limoges, France
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Affiliation as printed
Amyloidosis Center, Boston University School of Medicine, Boston, MA
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The University of Texas MD Anderson Cancer Center
Affiliation as printed
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
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Affiliation as printed
The Victorian and Tasmanian Amyloidosis Service, Department of Haematology, Monash University Easter Health Clinical School, Melbourne, Australia
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Affiliation as printed
Department of Haematology, Princess Alexandra Hospital, Brisbane, Australia
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University of Alberta · Cross Cancer Institute
Affiliation as printed
Cross Cancer Institute, University of Alberta, Edmonton, Canada
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Peking University People's Hospital
Affiliation as printed
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Collaborative Innovation Center of Hematology, Beijing, China
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Heidelberg University · University Hospital Heidelberg
Affiliation as printed
Medical Department V, Amyloidosis Center, Heidelberg University Hospital, Heidelberg, Germany
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Affiliation as printed
Department of Hematology, Hadassah-Hebrew University Medical Center-, Jerusalem, Israel
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Japanese Red Cross Medical Center
Affiliation as printed
Japanese Red Cross Medical Center, Department of Hematology, Tokyo, Japan
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Samsung Medical Center · Sungkyunkwan University
Affiliation as printed
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of (South)
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Affiliation as printed
Hospital Clinic of Barcelona, Barcelona, Spain
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Affiliation as printed
Cebeci Yerleskesi Dikimevi, Ankara, Turkey
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Affiliation as printed
Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA
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Affiliation as printed
Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
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Affiliation as printed
São Germano Clinic, São Paulo, Brazil
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Affiliation as printed
Tufts Medical Center, San Francisco, CA
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City Of Hope National Medical Center · City of Hope
Affiliation as printed
Department of Hematology and Hematopoietic Cell Transplantation, Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute · The Ohio State University
Affiliation as printed
Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
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Centre Hospitalier Universitaire de Toulouse · Hôpital Rangueil
Affiliation as printed
CHU de Toulouse-Hôpital Rangueil, Toulouse, France
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National and Kapodistrian University of Athens
Affiliation as printed
University of Athens School of Medicine, KIFISIA, Greece
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Janssen Research & Development (United States)
Affiliation as printed
Janssen Research & Development, LLC, Los Angeles, CA
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Affiliation as printed
Janssen Research & Development, LLC, Spring House, PA
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Affiliation as printed
Janssen Research & Development, LLC, Spring House, PA
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Affiliation as printed
Janssen Research & Development, LLC, Leiden, Netherlands
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Affiliation as printed
Janssen Research & Development, LLC, Spring House, PA
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Affiliation as printed
Janssen Research & Development, LLC, Leiden, Netherlands
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University of Pavia · Policlinico San Matteo Fondazione
Affiliation as printed
Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, Pavia, Italy
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