Abstract
BACKGROUND Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P=0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression.
| Original language | American English |
|---|---|
| Pages (from-to) | 46-58 |
| Number of pages | 13 |
| Journal | New England Journal of Medicine |
| Volume | 385 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1 Jul 2021 |
Bibliographical note
Funding Information:Supported by Janssen Research and Development. Dr. Kastritis reports receiving grant support and advisory board fees from Amgen, advisory board fees and travel support from Genesis Pharma, grant support, advisory board fees, and travel support from Janssen Global Services, and advisory board fees from Pfizer and Takeda Oncology; Dr. Palladini, receiving advisory board fees and presentation honoraria from Janssen Global Services and honoraria from Pfizer and Siemens; Dr. Minnema, receiving advisory board fees, paid to her institution, from Alnylam Pharmaceuticals and Takeda Oncology, travel support from Celgene and F. Hoffmann-La Roche, and consulting fees, paid to her institution, from Gilead Sciences and Johnson & Johnson Health Care Systems; Dr. Wechalekar, receiving advisory board fees from Alexion Pharmaceuticals, Caelum Biosciences, GlaxoSmithKline, and Janssen Biotech and lecture fees from Celgene and Takeda Oncology; Dr. Jaccard, receiving lecture fees and advisory board fees from Janssen Biotech; Dr. Lee, receiving grant support and consulting fees from Amgen, Celgene, GlaxoSmithKline, Janssen Biotech, and Takeda Oncology, consulting fees from Genentech and Sanofi-Aventis, and grant support from Regeneron Pharmaceuticals; Dr. Sanchorawala, receiving advisory board fees from AbbVie, Janssen Biotech, and Regeneron Pharmaceuticals; Dr. Gibbs, receiving advisory board fees from AbbVie and Akcea Therapeutics, grant support, paid to the Australian Amyloidosis Network, and lecture fees from Amgen, grant support, paid to the Australian Amyloidosis Network, and advisory board fees from Bristol-Myers Squibb and Pfizer, steering committee fees from Eidos Therapeutics, and grant support, paid to Eastern Health, and advisory board fees from Janssen Biotech; Dr. Mollee, receiving advisory board fees, paid to his institution, from Bristol-Myers Squibb, Caelum Biosciences, Celgene, Pfizer, and Takeda Oncology and grant support and advisory board fees, paid to his institution, from Janssen Pharmaceuticals; Dr. Venner, receiving advisory board fees from Akcea Therapeutics, Amgen Canada, Celgene, GlaxoSmithKline, Janssen Biotech, and Sanofi Pasteur and advisory board fees and end-point review committee fees from Takeda Oncology; Dr. Schönland, receiving advisory board fees from Janssen Biotech and Janssen Global Services, grant support, paid to University Hospital Heidelberg, from Sanofi Pasteur, and advisory board fees and travel support from Takeda Oncology; Dr. K. Kim, receiving grant support from Celgene and Janssen Global Services; Dr. Cibeira, receiving advisory board fees from Amgen and Janssen Biotech; Dr. Beksac, receiving advisory board fees, paid to Ankara University, from Amgen and Bristol-Myers Squibb and fees for serving on a speakers bureau and advisory board fees, paid to Ankara University, from Janssen Global Services, Sanofi Pasteur Biologics, and Takeda Oncology; Dr. Libby, receiving grant support, paid to the University of Washington, from the Academic Myeloma Consortium, BeiGene USA, Celgene, Genentech USA, GlaxoSmithKline, Janssen Biotech, and Prothena Biosciences and consulting fees from Adaptive Biotechnologies; Dr. Valent, receiving lecture fees and teaching fees from Amgen, Celgene, and Takeda Oncology; Dr. Hungria, receiving consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen Biotech, Sanofi Genzyme, and Takeda Oncology; Dr. Wong, receiving consulting fees from Amgen, fees for serving as principal investigator from Bristol-Myers Squibb, Fortis, Genentech USA, GlaxoSmithKline, and Janssen Biotech, and advisory board fees from Sanofi US Services; Dr. Rosenzweig, receiving advisory board fees from AbbVie Biotherapeutics, fees for serving on a speakers bureau and an educational council from Akcea Therapeutics, fees for serving on a speakers bureau from Bristol-Myers Squibb, Celgene, and Takeda Pharmaceutical, and advisory board fees and fees for serving on a speakers bureau from Janssen Biotech; Dr. Bumma, receiving advisory board fees from Alnylam Pharmaceuticals and fees for serving on a speakers bureau from Amgen and Sanofi US Services; Dr. Dimopoulos, receiving consulting fees from Amgen, BeiGene, Bristol-Myers Squibb, Janssen Global Services, and Takeda Oncology; Dr. Bhutani, receiving grant support from Sanofi US Services; Dr. Zonder, receiving consulting fees from Alnylam Pharmaceuticals, Amgen, Caelum Biosciences, Intellia Therapeutics, Janssen Biotech, Oncopeptides, Regeneron Pharmaceuticals, and Takeda Oncology and research support from Bristol-Myers Squibb; Dr. Lam, receiving advisory board fees from AbbVie, Amgen, Bristol-Myers Squibb, and Sanofi Pasteur and advisory board fees, lecture fees, and fees for an education program from Janssen Biotech; Dr. Song, receiving advisory board fees and fees for serving as a trial investigator from Amgen Canada, Bristol-Myers Squibb Canada, and Janssen Biotech and fees for serving as a trial investigator from Takeda Oncology; Dr. Hansen, receiving advisory board fees from Bristol-Myers Squibb, GlaxoSmithKline, Janssen Biotech, Sanofi Genzyme, and Takeda Oncology; Dr. Manier, receiving grant support, paid to Institut pour la Recherche sur le Cancer de Lille, from AbbVie, grant support and advisory board fees, paid to Institut pour la Recherche sur le Cancer de Lille, from Amgen and Celgene, and grant support, advisory board fees, paid to Journées d'Hématologie Clinique Lilloise, and travel support from Janssen Biotech; Dr. Jamroziak, receiving grant support, paid to the Polish Myeloma Consortium, grant support, paid to the Polish Adult Leukemia Group, and advisory board fees and lecture fees from Janssen Global Services; Dr. Crusoe, receiving research support from Janssen Biotech; Dr. Ahmadi, being employed by and owning stock and stock options in Genmab; Dr. Tran, being employed by and owning stock and stock options in Janssen Pharmaceuticals; Ms. Vasey, being employed by and owning stock in Janssen Pharmaceuticals; Ms. Tromp, being employed by and owning stock and stock options in Janssen Biotech; Dr. Schecter, being employed by and owning stock in Johnson & Johnson; Dr. Weiss, being employed by Janssen Research and Development and owning stock in Johnson & Johnson; Dr. Zhuang, being employed by and owning stock in Janssen Research and Development; Dr. Vermeulen, being employed by and owning stock in Johnson & Johnson Health Care Systems; Dr. Merlini, receiving advisory board fees from Janssen Global Services; and Dr. Comenzo, receiving steering committee fees from Janssen Biotech, receiving advisory board fees from Karyopharm Therapeutics, receiving fees for serving on a data and safety monitoring committee from Sanofi-Aventis, and holding patent WO2016187546A1 on anti-CD38 antibodies for treatment of light-chain amyloidosis and other CD38-positive hematologic cancers. No other potential conflict of interest relevant to this article was reported.
Funding Information:
Supported by Janssen Research and Development.
Publisher Copyright:
Copyright © 2021 Massachusetts Medical Society.
