Daratumumab, Ixazomib, Lenalidomide, and Dexamethasone for Newly Diagnosed Multiple Myeloma
Authors: Kumar Shaji K. , Kapoor Prashant , Laplant Betsy , Phuong-Dung Liang , Muchtar Eli , Buadi Francis K. , Gonsalves Wilson I , Malave Gabriella C , Vossen Alanna M. , Dingli David , Go Ronald S. , Warsame Rahma M , Kourelis Taxiarchis , Hwa Yi L. , Fonder Amie , Hobbs Miriam A. , Lust John A. , Lacy Martha Q. , Dispenzieri Angela , Hayman Suzanne R. , Leung Nelson , Rajkumar S. Vincent , Gertz Morie A. 
Published: February 2021

Background: The combination of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and dexamethasone is the current standard induction therapy for myeloma. Daratumumab (Dara), a monoclonal antibody directed against CD38, is highly effective in treating myeloma and improves response rates and progression free survival (PFS) when added to PI or IMiD. Ixazomib, lenalidomide and dexamethasone (IRd) is an effective, all oral, induction regimen that has been studied in phase 2 and 3 trials. We designed this trial to examine the feasibility and efficacy of adding daratumumab to the IRd regimen as well as early discontinuation of dexamethasone in two sequential cohorts of patients.

Patients and Methods: Patients with previously untreated MM who had measurable disease and adequate organ function were enrolled, irrespective of their autologous stem cell transplant eligibility. The primary objective was to determine the rate of complete response to IRD-Dara combination. A one-stage binomial design was utilized in each cohort independently to test the null hypothesis that the complete response rate is at most 25% against the alternative hypothesis that it is at least 45%, with 89% power and 9% type I error. Treatment involved 28-day cycles consisting of ixazomib 4 mg days 1, 8, 15; lenalidomide 25 mg days 1-21, dexamethasone 40 mg, weekly and Dara 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks thereafter during induction (12-cyles) followed by Dara-ixazomib maintenance (maximum 24 cycles). Cohorts A (n=38) and B (N=40) comprised the study population, with dexamethasone discontinued after two cycles in Cohort B.

Results: Baseline demographics and patient disposition are outlined in the table. Among those who have gone off study, 9 and 5 patients, respectively in Cohort A and B went off for progression, while 11 and 8 patients in the respective arms discontinued treatment for an alternative therapy, most frequently a transplant. Responses were rapid and deepened over the duration of treatment as shown in the figure; 32% of patients in Cohort A and 28% of patients in Cohort B achieved a complete response; 29% and 23%, respectively, achieved a marrow minimal residual disease (MRD) negative status. After a median follow up was 31.4 months for Cohort A and 18.2 months for Cohort B, median PFS has not been reached in either cohort. A grade 3 or higher adverse event at least possibly attributed to the study drugs was seen in 58% of patients in Cohort A (hematologic in 47% and non-hematologic in 26%) and 50% of patients in Cohort B (hematologic 43%, non-hematologic 20%). The most common toxicities included fatigue, neutropenia, lymphopenia, peripheral neuropathy and nausea. Stem cells were collected in 30 and 31 patients in Cohorts A and B respectively; median (range) of CD34 cells/kg were 8.5 (2.8, 15.9) x 106and 7.0 (2.9, 12.1) x 106, with plerixafor used in 83% and 94% of patients, respectively, in Cohorts A and B as per our standard of care "on-demand" approach based on blood CD34 count.

Conclusion: Dara-IRd is an active regimen in newly diagnosed MM, with high overall rates of response and deep responses that improved over time with therapy. Early discontinuation of dexamethasone does not appear to impact the depth, rate or kinetics of response. The toxicities were manageable, with dose modifications. All patients were able to collect stem cells when required, though majority needed plerixafor.

Disclosures

Kumar: Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Kite Pharma: Consultancy, Research Funding; Carsgen: Other, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Dr. Reddy's Laboratories: Honoraria; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Tenebio: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Sanofi: Research Funding; Novartis: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding. Kapoor:GlaxoSmithKline: Research Funding; Celgene: Honoraria; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy. Dingli:Apellis: Consultancy; Karyopharm Therapeutics: Research Funding; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Alexion: Consultancy; Rigel: Consultancy; Millenium: Consultancy; Sanofi-Genzyme: Consultancy. Dispenzieri:Pfizer: Research Funding; Takeda: Research Funding; Alnylam: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Intellia: Research Funding. Gertz:Abbvie: Other; Sanofi: Other; Celgene: Other; Research to Practice: Other; Physicians Education Resource: Other: personal fee; Amgen: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Appellis: Other: personal fee; Annexon: Other: personal fee; Alnylam: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Teva: Speakers Bureau; Aurora Bio: Other; Springer Publishing: Patents & Royalties; Proclara: Other; DAVA oncology: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Ionis/Akcea: Other: personal fee; Prothena: Other: personal fee.