Daratumumab for patients with myeloma with early or late relapse after initial therapy: subgroup analysis of CASTOR and POLLUX.

"Conflict-of-interest disclosure: A.S. served on an advisory board for AbbVie, Amgen, Antegene, Bristol Myers Squibb, HaemaLogiX, Janssen, Pfizer, Roche, and Secura Bio; served on a speakers bureau for Bristol Myers Squibb and Janssen; received research support from AbbVie, Amgen, Bristol Myers Squibb, HaemaLogiX, Janssen, and PharmaMar; and received honoraria from AbbVie, Amgen, Antegene, Bristol Myers Squibb, HaemaLogiX, Janssen, Pfizer, Roche, and Secura Bio. P.M. served in a consulting or advisory role for Celgene, Janssen, Amgen, GlaxoSmithKline, Sanofi, AbbVie, Oncopeptides, and Roche; and received honoraria from Celgene, Janssen-Cilag, Amgen, GlaxoSmithKline, AbbVie, Sanofi, Oncopeptides, and Roche. M.-V.M. served in a consulting or advisory role for Takeda, Janssen-Cilag, Celgene, Amgen, AbbVie, GlaxoSmithKline, Pfizer, Regeneron, and Roche/Genentech, and received honoraria from Janssen-Cilag, Celgene, Amgen, Takeda, GlaxoSmithKline, AbbVie/Genentech, and Sanofi. H.G. received grants and/or provision of an investigational medicinal product from Amgen, Bristol Myers Squibb, Celgene, Chugai, Dietmar Hopp Foundation, Janssen, Johns Hopkins University, and Sanofi; received research support from Amgen, Bristol Myers Squibb, Celgene, Chugai, Janssen, Incyte, Molecular Partners, Merck Sharp & Dohme, Sanofi, Mundipharma GmbH, Takeda, and Novartis; served on advisory boards for Adaptive Biotechnology, Amgen, Bristol Myers Squibb, Celgene, Janssen, Sanofi, and Takeda; and received honoraria from Amgen, Bristol Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Janssen, Novartis, and Sanofi. K.S. received honoraria from Celgene, Takeda, Ono Pharmaceutical, Amgen, Novartis, Sanofi, Bristol Myers Squibb, AbbVie, and Janssen; served in a consulting or advisory role for Amgen, Janssen, Takeda, and Celgene; and received research funding from Bristol Myers Squibb and Celgene. M.-D.L. received travel support from Takeda and Janssen, and received honoraria from AbbVie, Celgene, Janssen, and Takeda. P.S. received research support from Amgen, Celgene, Janssen, Karyopharm, SkylineDx, and Takeda, and received honoraria from and served on an advisory board for Amgen, Bristol Myers Squibb, Celgene, Janssen, Karyopharm, SkylineDx, and Takeda. R.Z.O. served on advisory committees for and received honoraria from AbbVie, Amgen, AstraZeneca, Biotheryx, Bristol Myers Squibb, Celgene, EcoR1 Capital, Forma Therapeutics, Genzyme, GlaxoSmithKline, Ionis Pharmaceuticals, Janssen, Juno Therapeutics, Karyopharm, Kite Pharma, Legend Biotech, Meridian Therapeutics, Monte Rosa Therapeutics, Molecular Partners, Neoleukin Therapeutics, Oncopeptides, Regeneron, Sanofi-Aventis, Servier, and Takeda; and received research funding from Asylia Therapeutics, Inc, Biotheryx, CARsgen Therapeutics, Celgene, Exelixis, Janssen, Sanofi-Aventis, and Takeda. S.-S.Y. received honoraria from Novartis; served on advisory boards for Amgen, Antengene, Astellas, Celgene, Janssen, Novartis, and Takeda; and received research funding from Kyowa Hakko Kirin, Roche-Genentech, and Yuhan Pharma. S.Z.U. received research funding from Amgen, Array BioPharma, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDx, and Takeda; served in a consulting role for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Edo Pharma, Genentech, Gilead, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, Seattle Genetics, Secura Bio, SkylineDx, Takeda, and TeneoBio; and served as a speaker for Amgen, Bristol Myers Squibb, Janssen, and Sanofi. K.W. received research support from Amgen, Bristol Myers Squibb/Celgene, Janssen, and Sanofi; received honoraria from AbbVie, Adaptive Biotech, Amgen, AstraZeneca, Bristol Myers Squibb/Celgene, BeiGene, GlaxoSmithKline, Janssen, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, and Takeda; and received consulting fees from AbbVie, Adaptive Biotech, Amgen, Bristol Myers Squibb/Celgene, BeiGene, Janssen, GlaxoSmithKline, Karyopharm, Oncopeptides, Pfizer, Roche, Sanofi, and Takeda. D.R. received honoraria from Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, and Takeda; served in a consulting or advisory role for Amgen, Bristol Myers Squibb/Celgene, Janssen, Karyopharm, and Takeda; received research funding from Bristol Myers Squibb/Celgene, Janssen, Millennium, and Takeda; provided expert testimony for Bristol Myers Squibb/Celgene and Janssen; and serves as the voluntary chief medical officer of the Canadian Myeloma Research Network. T.A. is an employee of and owns stock and options in Genmab. H.P., X.G., and J.C. are employees of Janssen and own stock in Johnson & Johnson. W.G.M. and R.C. are employees of Janssen. M.A.D. received honoraria from Amgen, BeiGene, Bristol Myers Squibb, Janssen, and Takeda. J.B.B. declares no competing financial interests."

"These studies (NCT02136134 and NCT02076009) were sponsored by 10.13039/100005205Janssen Research & Development, LLC."

"High-risk multiple myeloma (MM) is often defined based on cytogenetic abnormalities, but patients who relapse early after initial therapy are considered a functional high-risk group. In the phase 3 CASTOR and POLLUX studies, daratumumab plus bortezomib/dexamethasone (D-Vd) or lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS), regardless of cytogenetic risk, and achieved higher rates of complete response or better (≥CR) and minimal residual disease (MRD) negativity vs that with Vd/Rd alone in relapsed/refractory MM. Post hoc analyses of CASTOR and POLLUX evaluated patient subgroups with 1 prior line of therapy based on timing of progression/relapse (early or late) after initiation of first line of therapy. PFS consistently favored the daratumumab-containing regimens across subgroups using both a 24- and 18-month early-relapse cutoff. In the CASTOR/POLLUX pooled data set, daratumumab reduced the risk of disease progression or death by 65% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.26-0.48; P < .0001) in the early-relapse (<24 months) subgroup and by 65% (HR, 0.35; 95% CI, 0.26-0.47; P < .0001) in the late-relapse (≥24 months) subgroup. OS also favored the daratumumab-containing regimens in both the early-relapse (HR, 0.62; 95% CI, 0.45-0.86; P = .0036) and late-relapse (HR, 0.67; 95% CI, 0.48-0.93; P = .0183) subgroups in the pooled population using a 24-month cutoff. Rates of ≥CR and MRD negativity (10−5) were higher with daratumumab vs control, regardless of progression/relapse timing. Although daratumumab is unable to fully overcome the adverse prognosis of early relapse, our results support the use of daratumumab for patients with 1 prior line of therapy, including for those who progress/relapse early after initial therapy and are considered to have functional high-risk MM. These trials were registered at www.clinicaltrials.gov as #NCT02136134 (CASTOR) and #NCT02076009 (POLLUX)."