Video Summary
Clinical outcomes and optimal therapy for Black patients with newly diagnosed multiple myeloma (NDMM) remain to be defined. In the United States, standard-of-care induction and consolidation regimens include lenalidomide, bortezomib, and dexamethasone (RVd) [1, 2]. The phase 2 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) evaluated the addition of the anti-CD38 monoclonal antibody daratumumab to RVd (D-RVd) induction and consolidation with lenalidomide (R) maintenance, in conjunction with autologous stem cell transplant (ASCT) in patients with NDMM in the United States [3]. The primary results of GRIFFIN were previously reported; D-RVd significantly improved the rate of stringent complete response (sCR) by the end of post-ASCT consolidation (D-RVd, 42.4% vs RVd, 32.0%; 1-sided P = 0.068 at the pre-specified 1-sided α level of 0.1), as well as the rates of minimal residual disease (MRD) negativity (10−5) [3]. Responses deepened with longer follow-up (median, 27.4 months); the rate of sCR continued to improve, and rates of MRD negativity (10−5) were also higher in the D-RVd group versus RVd group [4]. Here, we report a post hoc subgroup analysis of the GRIFFIN study examining the efficacy and safety of D-RVd in Black patients after all patients completed ≥12 months of maintenance therapy or discontinued at the median follow-up of 27.4 months.
The full study design of the randomized phase of the GRIFFIN study has previously been published [3]. Briefly, patients with NDMM who were eligible for ASCT received 4 cycles of D-RVd or RVd induction, high-dose therapy and ASCT, followed by 2 cycles of D-RVd or RVd consolidation, and D-R or R maintenance for up to 24 months. The primary endpoint was the sCR rate by the end of the post-ASCT consolidation treatment and was previously reported [3]. Secondary analyses were evaluated using 2-sided α of 0.05, not adjusted for multiplicity.
This analysis included 32 (D-RVd, n = 14 and RVd, n = 18) Black patients (15% of those enrolled) and 161 (D-RVd, n = 85 and RVd, n = 76) White patients (78% of those enrolled). Race was identified at study enrollment and recorded in the case report form; no Black patient self-identified with multiple races. Overall baseline demographics were previously published [3] and are shown by race in Table 1. Baseline characteristics were generally similar, except Black patients were slightly younger (median age: D-RVd, 58.5 years; RVd, 57.0 years) compared with White patients (D-RVd, 59.0 years; RVd, 61.5 years), and fewer Black males enrolled (D-RVd, 35.7% [n = 5]; RVd, 44.4% [n = 8]) compared with White males (D-RVd, 61.2% [n = 52]; RVd, 60.5% [n = 46]). Similar proportions of Black patients (D-RVd, 21.4% [n = 3]; RVd, 12.5% [n = 2]) and White patients (D-RVd, 15.0% [n = 12]; RVd, 13.7% [n = 10]) had high cytogenetic risk. Bone marrow involvement with ≥60% plasma cells was seen in a similar proportion of evaluable Black patients (D-RVd, 42.9% [n = 6]; RVd, 38.9% [n = 7]) and White patients (D-RVd, 43.5% [n = 37]; RVd, 36.8% [n = 28]).
Treatment delivery was similar among randomized Black and White patients. The median lenalidomide relative dose intensities for Black patients were 81.6% (range, 48.1–100.0%) in the D-RVd group and 80.2% (range, 33.9–100.0%) in the RVd group. The median lenalidomide relative dose intensities among White patients were 87.7% (range, 26.1–101.6%) in the D-RVd group and 96.6% (range, 30.2–100.0%) in the RVd group. Lenalidomide cycle delays occurred in similar proportions of Black patients (D-RVd, 42.9% [n = 6]; RVd, 50.0% [n = 9]) and White patients (D-RVd, 43.4% [n = 36]; RVd, 45.9% [n = 34]). Similar proportions of Black patients (D-RVd, 14.3% [n = 2]; RVd, 50.0% [n = 9]) and White patients (D-RVd, 20.0% [n = 17]; RVd, 46.1% [n = 35]) discontinued study therapy; however, discontinuation rates were higher for both Black and White patients in the RVd group. Among Black patients, most patients discontinued therapy for the primary reason of withdrawal by patient (D-RVd, 0%; RVd, 16.7% [n = 3]) and adverse event (D-RVd, 7.1% [n = 1]; RVd, 11.1% [n = 2]). Among White patients, most patients discontinued therapy for the primary reason of progressive disease (D-RVd, 7.1% [n = 6]; RVd, 11.8% [n = 9]) and adverse event (D-RVd, 2.4% [n = 2]; RVd, 11.8% [n = 9]).
The rate of sCR by the end of post-ASCT consolidation was higher for the D-RVd group versus the RVd group in both Black patients (71.4% [n = 10] vs 33.3% [n = 6]; P = 0.0353) and White patients (42.7% [n = 35] vs 32.4% [n = 23]; P = 0.1923; Fig. 1A, B). With continued therapy, responses continued to deepened; after 12 months of maintenance therapy (median follow-up, 27.4 months), the rates of sCR were higher in the D-RVd versus RVd groups among both Black patients (85.7% [n = 12] vs 38.9% [n = 7], P = 0.0085) and White patients (62.2% [n = 51] vs 49.3% [n = 35], P = 0.1099). Notably, at last follow-up, the sCR rate doubled with the addition of daratumumab to RVd in Black patients, and 100% (n = 14) of Black patients who received D-RVd achieved complete response or better (≥CR) compared with 55.6% (n = 10) of Black patients who received RVd.
The MRD-negativity (10−5) rates at last follow-up were higher in the D-RVd group versus the RVd group among both Black patients (64.3% [n = 9] vs 22.2% [n = 4], P = 0.0293) and White patients (63.5% [n = 54] vs 27.6% [n = 21], P < 0.0001; Fig. 1C, D). The rate of MRD negativity (10−6) was also higher in the D-RVd group versus the RVd group for both Black patients (21.4% [n = 3] vs 5.6% [n = 1], P = 0.2951) and White patients (29.4% [n = 25] vs 11.8% [n = 9], P = 0.0070).
Median CD34+ cell yield among Black patients was 11.2 × 106/kg for the D-RVd group and 9.4 × 106/kg for the RVd group, and among White patients was 7.9 × 106/kg for the D-RVd group and 9.4 × 106/kg for the RVd group. The median number of CD34+ cells transplanted was similar for Black and White patients among treatment groups (Black: D-RVd, 4.9 × 106/kg vs RVd, 4.8 × 106/kg; White: D-RVd, 4.2 × 106/kg vs RVd, 5.4 × 106/kg), and hematopoietic reconstitution was comparable (median number of days for neutrophil engraftment [Black: D-RVd, 11.5 vs RVd, 11.5; White: D-RVd, 12.0 vs RVd, 11.5] and platelet engraftment [12.0 vs 13.0; 13.0 vs 12.0]).
The 3 most common treatment-emergent adverse events (TEAEs) of any grade for Black patients were upper respiratory tract infections (D-RVd, 78.6% [n = 11]; RVd, 50.0% [n = 9]), peripheral edema (64.3% [n = 9]; 50.0% [n = 9]), and peripheral neuropathy (57.1% [n = 8]; 66.7% [n = 12]) and the 3 most common for White patients were fatigue (72.3% [n = 60]; 60.8% [n = 45]), diarrhea (68.7% [n = 57]; 60.8% [n = 45]), and peripheral neuropathy (63.9% [n = 53]; 75.7% [n = 56]; Supplementary Table 1). Neutropenia was the most common TEAE of grade 3/4 in both Black patients (D-RVd, 50.0% [n = 7]; RVd, 22.2% [n = 4]) and White patients (43.4% [n = 36]; 18.9% [n = 14]), followed by lymphopenia in Black patients (28.6% [n = 4]; 38.9% [n = 7]) and also White patients (22.9% [n = 19]; 16.2% [n = 12]; Supplementary Table 2). Serious TEAEs were reported in Black patients with an incidence of 35.7% (n = 5) for D-RVd and 55.6% (n = 10) for RVd, with the most common being pneumonia (D-RVd, 21.4% [n = 3]; RVd, 16.7% [n = 3]). In White patients, serious TEAEs occurred in 43.4% (n = 36) of D-RVd patients and 48.6% (n = 36) of RVd patients; the most common was also pneumonia (D-RVd, 9.6% [n = 8]; RVd, 14.9% [n = 11]). TEAEs leading to treatment discontinuations in Black patients occurred in 35.7% (n = 5) of D-RVd patients and 27.8% (n = 5) of RVd patients. Among White patients, TEAEs leading to treatment discontinuation occurred in 19.3% (n = 16) and 23.0% (n = 17) of D-RVd and RVd patients, respectively. Peripheral neuropathy was the most common TEAE leading to discontinuation among both Black patients (D-RVd, 28.6% [n = 4]; RVd, 11.1% [n = 2]) and White patients (D-RVd, 3.6% [n = 3]; RVd, 5.4% [n = 4]), followed by neuralgia in Black patients (D-RVd, 7.1% [n = 1]; RVd, 5.6% [n = 1]) and upper respiratory tract infections (D-RVd, 2.4% [n = 2]; RVd, 1.4% [n = 1]) and pneumonia (D-RVd, 1.2% [n = 1]; RVd, 2.7% [n = 2]) in White patients. There were no other trends observed in TEAEs leading to treatment discontinuation (Supplementary Table 3). No deaths occurred due to TEAEs among Black patients, and 1 White patient in the D-RVd group had a TEAE leading to death. Infusion-related reactions occurred in 28.6% (n = 4) of Black D-RVd patients and 45.8% (n = 38) of White D-RVd patients, and the majority were grades 1/2.
Prior studies indicate disparities in outcomes for Black patients with multiple myeloma versus White patients [5, 6]; however, recent evidence suggests that Black and White patients can have comparable outcomes when Black patients are provided access to the same healthcare opportunities [5]. The present subgroup analysis of GRIFFIN indicates that Black patients can derive as great of a clinical benefit from the addition of daratumumab to RVd in the frontline setting as White patients and do not experience an increase in adverse events; these data have important implications for real-world practice [7], and in particular for specific toxicities, such as peripheral neuropathy [8]. Specifically, D-RVd versus RVd as induction and consolidation therapy improved depth of response, including rates of sCR and MRD negativity, in Black patients with NDMM. Additionally, continued treatment including daratumumab plus lenalidomide as maintenance therapy further improved depth of response. The efficacy outcomes and safety profiles of D-RVd in both Black and White patients were comparable and consistent with outcomes for the overall study population [3]. Although our analysis is limited by the sample size (32 Black patients total), these results suggest that Black patients with multiple myeloma experience similar outcomes as White patients when provided the same access to clinical studies and therapeutic options, underscoring the importance of appropriate representation of this patient population in clinical trials [9]. Historically, clinical study enrollment of Black patients has been low (~3%) in cancer clinical trials that led to cancer therapy approvals by the US Food and Drug Administration [10], particularly compared with Census data that estimate people of Black race to comprise 13% of the US population [11]. In GRIFFIN, Black patients comprised 15% of those enrolled, which marks a more accurate representation of this racial group in the general population as well as among multiple myeloma patients, 17% of whom are Black in the United States [12]. Despite this improvement, further studies enrolling larger numbers of Black patients are needed to confirm and better define the magnitude of daratumumab benefit in this patient population.
Data sharing statement
The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.
References
Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679–86.
Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389:519–27.
Voorhees PM, Kaufman JL, Laubach J, Sborov DW, Reeves B, Rodriguez C, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136:936–45.
Kaufman JL, Rodriguez C, Reeves B, Nathwani N, Costa LJ, Lutska Y et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 12 months of maintenance therapy. Blood. 2020. https://doi.org/10.1182/blood-2020-137109.
Fillmore NR, Yellapragada SV, Ifeorah C, Mehta A, Cirstea D, White PS, et al. With equal access, African American patients have superior survival compared to white patients with multiple myeloma: a VA study. Blood. 2019;133:2615–8.
Costa LJ, Brill IK, Omel J, Godby K, Kumar SK, Brown EE. Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States. Blood Adv. 2017;1:282–7.
Richardson PG, San Miguel JF, Moreau P, Hajek R, Dimopoulos MA, Laubach JP, et al. Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting. Blood Cancer J. 2018;8:109.
Richardson PG, Delforge M, Beksac M, Wen P, Jongen JL, Sezer O, et al. Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia. 2012;26:595–608.
Gormley N, Fashoyin-Aje L, Locke T, Unger J, Little RF, Nooka A, et al. Recommendations on eliminating racial disparities in multiple myeloma therapies: a step toward achieving equity in healthcare. Blood Cancer Disco. 2021;2:119–24.
Tharakan S, Zhong X, Galsky MD. The impact of the globalization of cancer clinical trials on the enrollment of Black patients. Cancer. 2021;127:2294–301.
United States Census Bureau. QuickFacts United States 2021. https://www.census.gov/quickfacts/fact/table/US/PST045219. Accessed Sept 2021.
Ailawadhi S, Aldoss IT, Yang D, Razavi P, Cozen W, Sher T, et al. Outcome disparities in multiple myeloma: a SEER-based comparative analysis of ethnic subgroups. Br J Haematol. 2012;158:91–8.
Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328–e46.
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–e48.
Acknowledgements
We acknowledge the patients and investigators who participated in this study, in addition to the staff members at the study sites, the Data Review and Safety Monitoring Committees, Alliance Foundation Trials (AFT; https://acknowledgments.alliancefound.org [study AFT-29]), and the Janssen Team. We also acknowledge Daniela Hoehn, Yana Lutska, and Padma Bobba for their contributions to this study. This work was funded by Janssen Oncology. The study was sponsored by Janssen Oncology and designed in partnership with AFT. Editorial and medical writing support were provided by Laura Weber, PhD, of Cello Health Communications/MedErgy, and were funded by Janssen Global Services, LLC.
Author information
Authors and Affiliations
Contributions
AKN identified eligible patients, treated patients, collected data, and wrote/reviewed the manuscript. JLK identified eligible patients, treated patients, collected data, and wrote/reviewed the manuscript. CR supervised the study, identified eligible patients, treated patients, collected data, and wrote/reviewed manuscript. AJ identified eligible patients, treated patients, collected data, and wrote/reviewed the manuscript. YE identified eligible patients, enrolled patients, treated patients, collected data, and reviewed/edited the manuscript. BR identified eligible patients, treated patients, and wrote/reviewed the manuscript. TW identified eligible patients, treated patients, and wrote/reviewed the manuscript. SAH identified eligible patients, treated patients, and wrote/reviewed the manuscript. LDA identified eligible patients, treated patients, and wrote/reviewed the manuscript. AB enrolled patients, collected data, and wrote/reviewed the manuscript. LS identified eligible patients, treated patients, and wrote/reviewed the manuscript. ACh identified eligible patients, treated patients, collected data, performed analyses, and wrote/reviewed the manuscript. HP participated in generation of analyses and wrote/reviewed the manuscript. ACo supervised the study, performed analyses, and wrote/reviewed the manuscript. SP supervised the study, performed analyses, and wrote/reviewed the manuscript. BB performed analyses and wrote/reviewed the manuscript. JV interpreted analyses and wrote/reviewed the manuscript. TSL designed and supervised the study, performed analyses, and wrote/reviewed the manuscript. PGR designed and supervised the study, identified eligible patients, treated patients, collected data, performed analyses, and wrote/reviewed this manuscript. PV designed the study, identified eligible patients, treated patients, and wrote/reviewed the manuscript.
Corresponding author
Ethics declarations
Competing interests
AKN served as a consultant for, received honoraria from, and received research funding from Janssen, Amgen, Takeda, Sanofi, Karyopharm Therapeutics, Bristol Myers Squibb, Oncopeptides, Adaptive, and Spectrum. JLK has served as a consultant for, received honoraria from, or received research funding from AbbVie, Amgen, Bristol Myers Squibb, Fortis Therapeutics, Heidelberg Pharma, Janssen, Novartis, Roche/Genentech, Sutro Biopharma, Takeda, and Tecnopharma; and has served as a member on the board of directors or advisory committees for Incyte and TG Therapeutics. CR has served as an advisor or speaker for Amgen, Bristol Myers Squibb, Janssen, Karyopharm, and Takeda. AJ held membership on an entity’s board of directors or served on advisory committees for Sanofi, Karyopharm, Janssen, GlaxoSmithKline, Amgen, AbbVie, Bristol Myers Squibb, Gracell, and Celgene. YE has received honoraria from Janssen, GlaxoSmithKline, Takeda, Oncopeptide, Alnylam, and Sanofi; served on a speakers bureau and/or as an advisor for Oncopeptide, Sanofi, Janssen, Takeda, Alnylam, and GlaxoSmithKline; and received research funding from Bristol Myers Squibb/Celgene. BR has received honoraria from Takeda and Incyte; served on a speakers bureau for Bristol Myers Squibb; and provided consultancy for and received honoraria from Pharma Essentia. TW has served as a consultant for Janssen, Carevive, Sanofi, and Seattle Genetics. SAH held membership on an entity’s board of directors or served on an advisory committee for Oncopeptides, Celgene, and Takeda; received honoraria from Celgene, Genentech, GlaxoSmithKline, Janssen, Secura Bio, Sorrento, and Takeda; and received research funding from Oncopeptides. LDA has served as a consultant for, received research funding or honoraria from, held membership on an entity’s board of directors or served on advisory committees for Amgen, Bristol Myers Squibb, Celgene, Janssen, GlaxoSmithKline, Janssen, Karyopharm, AbbVie, Prothena, and Oncopeptides. AB has received research funding from Bristol Myers Squibb and GlaxoSmithKline. LS has nothing to disclose. ACh held membership on an entity’s board of directors, or participated on advisory committees for AbbVie, Amgen, Bristol Myers Squibb/Celgene, Genentech, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, Sanofi, Seattle Genetics, Secura Bio, Antengene, and Shattuck Labs; received research funding from Amgen, Bristol Myers Squibb/Celgene, Janssen, Seattle Genetics, Pharmacyclics, and Takeda/Millennium; and acted as a consultant for Amgen, AbbVie, Antengene, Bristol Myers Squibb/Celgene, Genentech, GlaxoSmithKline, Janssen, Karyopharm, Novartis, Sanofi, Secura Bio, Shattuck Labs, and Takeda/Millennium. HP, ACo, BB, and JV are current employees and stock shareholders of Janssen. SP is a current employee of Janssen. TSL is a current employee and stock shareholder of Janssen and holds stock in GlaxoSmithKline. PGR has received research funding from Celgene/Bristol Myers Squibb, Karyopharm, Oncopeptides, and Takeda; and has served on advisory committees for AstraZeneca, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, Protocol Intelligence, Regeneron, Sanofi, and Secura Bio. PV has served as a consultant for, received honoraria from, or served as an advisory board member for AbbVie, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Karyopharm, Novartis, Oncopeptides, Pfizer, Sanofi, and Secura Bio.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Nooka, A.K., Kaufman, J.L., Rodriguez, C. et al. Daratumumab plus lenalidomide/bortezomib/dexamethasone in Black patients with transplant-eligible newly diagnosed multiple myeloma in GRIFFIN. Blood Cancer J. 12, 63 (2022). https://doi.org/10.1038/s41408-022-00653-1
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41408-022-00653-1
This article is cited by
-
Addressing the disparities: the approach to the African American patient with multiple myeloma
Blood Cancer Journal (2023)