Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial.

Background: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis.
Methods: GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA. Patients had newly diagnosed multiple myeloma with measurable disease by M protein or free light chain, were aged 18-70 years, had an ECOG performance score of 0-2, and were eligible for autologous haematopoietic stem-cell transplantation (HSCT). Patients were randomly assigned (1:1) to four D-RVd or RVd induction cycles, autologous HSCT, two D-RVd or RVd consolidation cycles, and lenalidomide with or without daratumumab maintenance therapy for 2 years. Patients received 21-day cycles of oral lenalidomide (25 mg on days 1-14), subcutaneous bortezomib (1·3 mg/m ² on days 1, 4, 8, and 11), oral dexamethasone (40 mg weekly) with or without intravenous daratumumab (16 mg/kg weekly, cycles 1-4; day 1, cycles 5-6). Maintenance therapy (28-day cycles) was oral lenalidomide (10 mg on days 1-21) with or without daratumumab (16 mg/kg intravenously every 4 or 8 weeks, or 1800 mg subcutaneously monthly). Patients could continue lenalidomide maintenance after study treatment completion. The primary endpoint was stringent complete response rate by the end of consolidation in the response-evaluable population, and has already been reported. Here we report updated stringent complete response rates and secondary outcomes including progression-free survival and overall survival. The trial is registered with ClinicalTrials.gov (NCT02874742) and ended on April 8, 2022.
Findings: Between Dec 20, 2016, and April 10, 2018, 104 patients were randomly assigned to the D-RVd group and 103 were randomly assigned to the RVd group; most patients were White (85 [82%] in the D-RVd group and 76 [74%] in the RVd group) and male (58 [56%] in the D-RVd group and 60 [58%] in the RVd group). At a median follow-up of 49·6 months (IQR 47·4-52·1), D-RVd improved rates of stringent complete response (67 [67%] of 100] vs 47 [48%] of 98]; odds ratio 2·18 [95% CI 1·22-3·89], p=0·0079), and 4-year progression-free survival was 87·2% (95% CI 77·9-92·8) for D-RVd versus 70·0% (95% CI 55·9-80·3) for RVd, with a hazard ratio (HR) of 0·45 (95% CI 0·21-0·95, p=0·032) for risk of disease progression or death with D-RVd. Median overall survival was not reached for either group (HR 0·90 [95% CI 0·31-2·56], p=0·84). The most common grade 3-4 treatment-emergent adverse events in the D-RVd versus RVd groups were neutropenia (46 [46%] of 99 vs 23 [23%] of 102), lymphopenia (23 [23%] vs 23 [23%]), leukopenia (17 [17%] vs eight [8%]), thrombocytopenia (16 [16%] vs nine [9%]), pneumonia (12 [12%] vs 14 [14%]), and hypophosphataemia (ten [10%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 46 (46%) of 99 patients in the D-RVd group and in 53 (52%) of 102 patients in the RVd group. One patient in each treatment group reported a treatment-emergent adverse event that resulted in death (bronchopneumonia in the D-RVd group; cause unknown in the RVd group); neither was related to study treatment. No new safety concerns occurred with maintenance therapy.
Interpretation: Addition of daratumumab to RVd improved the depth of response and progression-free survival in transplantation-eligible patients with newly diagnosed multiple myeloma. These results justify further evaluation in phase 3 studies.
Funding: Janssen Oncology.
Competing Interests: Declaration of interests PMV served as a consultant for, served on an advisory board for, and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Novartis, Oncopeptides, Pfizer, Sanofi, and Secura Bio. DWS served as a consultant or in an advisory role for GlaxoSmithKline, AbbVie, Sanofi, Bristol Myers Squibb, Janssen, and Pfizer. JLK served as a consultant for AbbVie, Bristol Myers Squibb, Janssen, Roche/Genentech, and Tecnopharma; received research funding from AbbVie, Amgen, Bristol Myers Squibb, Fortis Therapeutics, Heidelberg Pharma, Janssen, Novartis, Roche/Genentech, Sutro Biopharma, and Takeda; received honoraria from AbbVie, Janssen, Roche/Genentech, and Tecnopharma; and served on an advisory board for Incyte and TG Therapeutics. BR received honoraria from Incyte, Bristol Myers Squibb, and PharmaEssentia. CR served as a consultant and on a speakers bureau for Janssen, Takeda, Bristol Myers Squibb, Amgen, and Karyopharm Therapeutics. ACh served as a consultant or in an advisory role for Amgen, Janssen Oncology, Seattle Genetics, Karyopharm Therapeutics, Genzyme, Oncopeptides, Takeda, Antengene, GlaxoSmithKline, Secura Bio, Shattuck Labs, Genentech, AbbVie, and Bristol Myers Squibb/Celgene; and received research funding from Celgene, Janssen, Amgen, Seattle Genetics, Takeda, and Pharmacyclics. RS served as a consultant or in an advisory role for Sanofi/Aventis, Janssen Oncology, and Oncopeptides; and received research funding from Sanofi. LJC served as a consultant or in an advisory role for AbbVie, Amgen, Celgene, Karyopharm Therapeutics, and Sanofi; served on a speakers bureau for Amgen and Sanofi; received honoraria from Amgen, Celgene, Janssen, Karyopharm Therapeutics, and Sanofi; and received research funding from Amgen and Janssen. LDA served as a consultant or in an advisory role for and received honoraria from GlaxoSmithKline, Bristol Myers Squibb, Celgene, Janssen, Amgen, Oncopeptides, Karyopharm Therapeutics, AbbVie, BeiGene, Cellectar, and Sanofi. NS served as a consultant for Amgen, CareDx, CSL Behring, GlaxoSmithKline, Indapta Therapeutics, Karyopharm Therapeutics, Kite, Oncopeptides, and Sanofi; and received research funding from bluebird bio, Bristol Myers Squibb/Celgene, Janssen, Nektar, Poseida, Precision BioSciences, Sutro Biopharma, and TeneoBio. NB received honoraria from OncLive; and served as a consultant or in an advisory role and on a speakers bureau for Janssen, Sanofi Genzyme, and Oncopeptides. YAE received research funding, received honoraria, and served on a speakers bureau for Janssen, Takeda, Oncopeptides, GlaxoSmithKline, Pfizer, Sanofi, and Bristol Myers Squibb. SAH served as a consultant for Bristol Myers Squibb/Celgene, Janssen, Takeda, Oncopeptides, GlaxoSmithKline, Secura Bio, and Sanofi; and received research funding from Oncopeptides. CC received honoraria from Takeda, Bristol Myers Squibb, Pfizer, and Janssen. AJ served as a consultant or in an advisory role for and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm Therapeutics, and Sanofi. TMW served as a consultant for Janssen, Carevive, and Sanofi. RZO holds stock and other ownership interests in Asylia Therapeutics; received honoraria from and served as a consultant or in an advisory role for AbbVie, Biotheryx, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Neoleukin Corporation, Oncopeptides, Regeneron, Sanofi, and Takeda; received research funding from Asylia Therapeutics, Biotheryx, and Heidelberg Pharma; and holds patents, royalties, or other intellectual property for Asylia Therapeutics. KHS served on an advisory board for AbbVie, Amgen, Bristol Myers Squibb, GlaxoSmithKline, and Janssen; received research funding from AbbVie and Karyopharm Therapeutics; served on a speakers bureau for Adaptive Biotechnologies Corporation, Amgen, Bristol Myers Squibb, Janssen, and Sanofi Genzyme; served as a consultant for Adaptive Biotechnologies Corporation, Novartis, and Sanofi Genzyme; and received honoraria from Karyopharm Therapeutics. AJC served as a consultant for Janssen, Bristol Myers Squibb, EUSA Pharma, AbbVie, Sanofi, Cellectar, GlaxoSmithKline, and Secura Bio; and received research funding from Janssen, AbbVie, Sanofi, Harpoon, Bristol Myers Squibb, Adaptive Biotechnologies, and Nektar. SD is the Executive Officer for Alliance Foundation Trials for Clinical Trials. HP, ACo, and SP are employees of and hold stock and other ownership in Janssen. TSL is an employee of Janssen. SZU served as a consultant or in an advisory role for Celgene, Amgen, Janssen Oncology, Seattle Genetics, Takeda, GlaxoSmithKline, Karyopharm Therapeutics, AbbVie, SkylineDx, Merck, Oncopeptides, Genentech, Gilead Sciences, and Bristol Myers Squibb/Celgene; served on a speakers bureau for Takeda, Amgen, Janssen Oncology, Sanofi, and Bristol Myers Squibb/Celgene; and received research funding from Celgene and Array BioPharma. PGR received research funding from Oncopeptides, Celgene/Bristol Myers Squibb, Takeda, and Karyopharm Therapeutics; and served on an advisory committee for Oncopeptides, Celgene/Bristol Myers Squibb, Takeda, Karyopharm Therapeutics, Janssen, Sanofi, Secura Bio, GlaxoSmithKline, Regeneron, AstraZeneca, and Protocol Intelligence. JL and NN declare no competing interests.
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