Background and significance: Light chain (AL) amyloidosis is a plasma cell malignancy characterized by the production of amyloidgenic clonal light chains that deposit in various tissues. The addition of daratumumab to bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) has improved the depth of hematologic and organ responses and is an approved induction therapy in newly diagnosed AL amyloid patients (DOI: 10.1056/NEJMoa2028631). However, this approach has not yet demonstrated an overall survival (OS) benefit and follow up remains short. With strict adherence to eligibility criteria, in particular severity of cardiac involvement, autologous stem cell transplantation (ASCT) as consolidative therapy is safe with transplant related mortality on par with multiple myeloma. This approach generates deep and sustained responses, but it is unclear if it offers an additional survival benefit following Dara-VCD induction. The only randomized trial evaluating the role of ASCT in AL amyloid is outdated (DOI: 10.1056/NEJMoa070484) and no randomized data exist to inform the optimal use of ASCT in the era of Dara-VCD induction. Furthermore, multi-organ involvement in AL amyloid drives morbidity and mortality thus the impact of any consolidative therapy on cardiac and renal involvement in addition to overall survival but must be defined. Finally, the approval of Dara-VCD therapy was based on complete hematologic response rates but there is increasing data demonstrating that achieving minimal residual disease (MRD) negativity by either bone marrow next generation flow cytometry (DOI: 10.1002/ajh.26562) or peripheral blood mass spectrometry (DOI: 10.1038/s41408-020-0291-8) generates improved organ response, hematologic progression free survival, and possibly OS.

Methods: This randomized phase 3 SWOG led intergroup trial (S2213; NCT06022939) is being conducted within the United States and will accrue a total of 143 participants per arm. The primary endpoint will compare MOD-PFS (major organ deterioration progression free survival: defined as time from randomization to death, cardiac/renal progression, or hematologic progression) between participants receiving an ASCT with those receiving 3 cycles of Dara-VCD consolidation following 3 cycles of uniform Dara-VCD induction. Following the assigned consolidation, all patients will receive 18 months of daratumumab maintenance therapy. A median MOD-PFS of 31 months is anticipated in the non-ASCT arm. This study has 90% power and a two-sided significance level of 0.05 to detect a hazard ratio of 0.62 corresponding to a MOD-PFS of 50 months in the ASCT arm. Important additional endpoints include OS, hematologic PFS, cardiac and renal responses, MRD negativity both by peripheral blood mass spectrometry and bone marrow next generation flow cytometry, delayed utilization of ASCT, and quality of life. Key inclusion criteria include non-severe cardiac AL amyloid (NT-proBNP <5000; TnT < 0.06; NYHA I or II, EF ≥ 40%), CrCl ≥30 mL/min, serum dFLC > 2 mg/dL, and supine systolic BP ≥ 90 mmHg. Importantly, patients are permitted to have up to one full cycle or 28 days of any plasma cell directed therapy prior to enrollment. This trial was activated on 12/1/2023 with the first patient enrolled 07/01/2024.

Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819; and in part by Janssen Pharmaceuticals Inc. of Johnson & Johnson (now J&J Innovative Medicine).

Disclosures

Sidana:BiolineRx: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Regeneron: Consultancy; Takeda: Consultancy; Kite, A Gilead company: Consultancy; Oncopeptides: Consultancy; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Legend: Consultancy; Novartis: Research Funding. Sanchorawala:Pfizer, Janssen, Attralus, GateBio, Abbvie, BridgeBio: Consultancy; Celgene, Millennium-Takeda, Janssen, Prothena, Sorrento, Karyopharm, Oncopeptide, Caelum, Alexion: Research Funding; Proclara, Caelum, Abbvie, Janssen, Regeneron, Protego, Pharmatrace, Telix, Prothena, AstraZeneca, Nexcella: Membership on an entity's Board of Directors or advisory committees. Zonder:Regeneron: Consultancy; BMS (employment of spouse): Current Employment; BMS, Janssen, RLL: Research Funding. Kourelis:Novartis: Research Funding; Pfizer: Research Funding. D'Souza:Novartis: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Research Funding; Prothena: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Takeda: Research Funding. Landau:Abbvie, Immix Biopharma, Legend Biotech, Alexion, Prothena: Consultancy; Janssen, Alexion, Protego, Prothena: Research Funding. Ailawadhi:Bristol-Myers Squibb: Consultancy, Research Funding; Cellectar: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Ascentage: Research Funding; Sanofi: Consultancy; Xencor: Research Funding; Abbvie: Research Funding; Johnson and Johnson: Consultancy, Research Funding; Regeneron: Consultancy; Beigene: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacuclics: Consultancy, Research Funding. Orlowski:BioTheryX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; DEM BioPharma, Inc., Karyopharm Therapeutics, Lytica Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Myeloma 360, Nanjing IASO Biotherapeutics, Neoleukin Corporation, Oncopeptides AB, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sporos Bio: Membership on an entity's Board of Directors or advisory committees; Sanofi, Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asylia Therapeutics Inc.: Current equity holder in private company, Patents & Royalties; AbbVie Inc, Adaptive Biotechnologies Corporation, Asylia Therapeutics Inc, BioTheryX Inc, Bristol Myers Squibb, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Nanjing IASO Biotherapeutics, Neoleukin Therapeutics, Oncopeptides, Pf: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, CARsgen Therapeutics, Exelixis Inc, Heidelberg Pharma, Janssen Biotech Inc, Sanofi, Takeda Pharmaceuticals USA Inc; Laboratory Research Funding: Asylia Therapeutics Inc, BioTheryX Inc, Heidelberg Pharma: Research Funding.

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2024
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