Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial

Abstract

Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10-5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.

Conflict of interest statement

Conflict-of-interest disclosure: P.M.V. served in a consultancy or advisory role and received honoraria from Adaptive Biotechnologies, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and TeneoBio; served in a consultancy or advisory role for Novartis, and Oncopeptides; served on a speakers’ bureau for Janssen and Amgen; and received research funding from Amgen, Celgene, Janssen, GlaxoSmithKline, Takeda, and TeneoBio. J.L.K. has held membership on an entity’s board of directors or advisory committee for Pharmacyclics and Karyopharm; has received honoraria from Janssen; served as a consultant for AbbVie, Takeda, Celgene, Amgen, Bristol-Myers Squibb, Incyte, and TG Therapeutics; and is an employee of Winship Cancer Institute of Emory University. D.W.S. served in a consultancy or advisory role for Amgen, Celgene, and Janssen; and received honoraria from Celgene. B.R. has served as a consultant for Incyte, Takeda, and Seattle Genetics; received honoraria from Celgene, Incyte, Takeda, and Seattle Genetics; and served on a speakers’ bureau for Celgene. C.R. has served in a consultancy role or on a speakers’ bureau for Celgene, Takeda, Janssen, Kite, Sanofi, and Bristol-Myers Squibb. A.C. has received research funding from, served as a consultant for, and served on an advisory board for Janssen, Celgene, Novartis, and Amgen; has served in a consultancy role for Bristol-Myers Squibb; has served on an advisory board for Karyopharm, Sanofi, and Oncopeptides; has received research funding and served on an advisory board for Seattle Genetics and Millennium Pharmaceuticals/Takeda; and has received research funding from Pharmacyclics. R.S. has served on an advisory committee for Janssen and on an advisory board for Sanofi. L.J.C. has received research funding from Janssen, Celgene, GlaxoSmithKline, and Amgen; received honoraria from Amgen, Celgene, Sanofi, GlaxoSmithKline, and Janssen; has served in a consultancy or advisory role for AbbVie, Amgen, Celgene, Sanofi, GlaxoSmithKline, and Karyopharm; and has served on a speakers’ bureau for Amgen, Sanofi, and Janssen. L.D.A. has served in a consultancy or advisory role for, served on a speakers’ bureau for, and received honoraria from Celgene, Takeda, Janssen, and Amgen. N.S. has received research funding from Celgene, Janssen, Bluebird Bio, Sutro Biopharma, and Poseida; has served in an advisory role or held membership on an entity’s board of directors for Bristol-Myers Squibb, Amgen, Kite, Nkarta, TeneoBio, Genentech, Seattle Genetics, Oncopeptides, Karyopharm, Surface Oncology, Precision BioSciences, GlaxoSmithKline, Nektar, Amgen, Indapta Therapeutics, and Sanofi; owns stock in Indapta Therapeutics; and has received research funding from Celgene, Janssen, Bluebird Bio, and Sutro Biopharma. Y.A.E. has served on a speakers’ bureau for Janssen; received honoraria from and served on an independent adjudication committee for Takeda; and served on an advisory board and speakers’ bureau for Akcea. S.A.H. has served in a consultancy or advisory role for and received honoraria from Adaptive Biotechnologies, Bristol-Myers Squibb, Celgene, Genentech, Oncopeptides, Sorrento, and Takeda; and has received research funding from Oncopeptides. C.C. has received honoraria from Takeda and Celgene; has served as a consultant for Celgene; and has received research funding from Takeda, Janssen, and Celgene. A.J. served as a consultant for, received honoraria from, or held membership on an entity’s board of directors or advisory committee for AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm Therapeutics, Millennium Pharmaceuticals, Sanofi, SkylineDx, and Takeda; and has served as a consultant for and received honoraria from Adaptive Biotechnologies and Juno. T.M.W. has received research funding from Janssen and served as a consultant for Carevive. R.Z.O. has received honoraria from or held membership on an entity’s board of directors or advisory committees for Amgen, Janssen, Bristol-Myers Squibb, Kite Pharma, Celgene, Ionis Pharmaceuticals, Legend Biotech, Molecular Partners, Sanofi-Aventis, Servier, Takeda, and Pharmaceuticals North America; and received research funding from Amgen, BioTheryX, and Spectrum Pharmaceuticals. K.H.S. has received research funding from AbbVie; has served as a consultant for Adaptive Biotechnologies; and has held membership on an entity’s board of directors or served in an advisory role for Celgene, Bristol-Myers Squibb, Amgen, Takeda, Janssen, and Sanofi Genzyme. A.J.C. has received research funding from and served as a consultant for Janssen and Celgene; has received research funding from AbbVie and Juno Therapeutics, a subsidiary of Celgene; and served in a consultancy role for Cellectar and Sanofi. Y.L. is an employee of Janssen. S.M., H.P., J.U., J.V., C.d.B., D.H., and T.S.L. are employees of Janssen and have equity ownership. P.G.R. has received research funding from Oncopeptides, Celgene, Takeda, and Bristol-Myers Squibb; and has served as a member of an advisory committee or received honoraria from Karyopharm, Oncopeptides, Celgene, Takeda, Amgen, Janssen, and Sanofi. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Summary of response rates and MRD-negativity (10−5) rates over time. (A) Response rates over time are shown. Data for the end of induction, end of ASCT, and end of consolidation are from the primary analysis. Response data with longer median follow-up of 22.1 months are also shown (last follow-up). (B) MRD-negativity (10−5) rates in the intent-to-treat population by the end of induction therapy, end of consolidation, and last follow-up. All MRD data are from the analysis with a median follow-up of 22.1 months. MRD was evaluated at baseline, first evidence of suspected CR or sCR, at the end of induction and consolidation, and after 12 and 24 months of maintenance, regardless of response (per protocol amendment 2).

Figure 2.

Subgroup analysis of sCR by the end of post-ASCT consolidation (primary end point; median follow-up, 13.5 months) and subgroup analysis of MRD negativity (10−5) by last follow-up (median follow-up, 22.1 months). (A) sCR by the end of post-ASCT consolidation (primary end point; median follow-up, 13.5 months). Analysis of sCR for the primary end point in prespecified subgroups of the response-evaluable population that were defined according to baseline characteristics. (B) MRD negativity by last follow-up (median follow-up, 22.1 months). Analysis of MRD by last follow-up in subgroups of the intent-to-treat population. The ISS disease stage is derived based on the combination of serum β2-microglobulin and albumin levels, with higher stages indicating more advanced disease. The subgroup analysis for the type of multiple myeloma was performed on data from patients who had measurable disease in serum. A high-risk cytogenetic profile was defined by the detection of a del17p, t(4;14), and/or t(14;16) cytogenetic abnormality on FISH testing. ECOG performance status (PS) is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.

Figure 3.

PFS. Results of the Kaplan-Meier estimates of PFS are shown among patients in the intent-to-treat population. Median PFS was not reached for either group, and Kaplan-Meier estimates of 24-month PFS rates are shown.