A Phase III Randomized Trial for Frail Newly Diagnosed Multiple Myeloma Patients Comparing Bortezomib- Lenalidomide-Dexamethasone (VRd-Lite followed by Len maintenance) with Daratumumab-Lenalidomide- Dexamethasone (DRd followed by Len+/- Dara Maintenance): SWOG S2209

Multiple myeloma (MM) is an incurable cancer of plasma cells with nearly 70% of all new diagnoses occurring in adults aged ≥ 65 years. For older adults, medical comorbidities and functional deficits become increasingly more prevalent with increased age and can impact disease outcomes and survival. There are unmet medical needs in this vulnerable patient population who are not eligible for autologous stem cell transplantation to optimize the frontline therapy for better survival and less toxicity. This randomized phase 3 clinical trial is designed to focus on real world patient population to identify an optimal frontline three drug regimen in frail or a subset of intermediate fit newly diagnosed MM patients. Diagnostic criteria and response criteria will be based on IMWG guidelines. Participants must have a calculated myeloma frailty index (Myeloma Frailty Score Calculator (http://www.myelomafrailtyscorecalculator.net/) categorized as frail or intermediate fit (regardless of age) within 28 days prior to registration (NCT05561387).

The two most commonly used induction/maintenance regimens in this patient population will be compared, including RVd-Lite (lenalidomide (R), bortezomib (V), and dexamethasone (dex) followed by R maintenance) and DRd (Daratumumab, lenalidomide, and dex followed by R or R-daratumumab maintenance). The study will include three cohorts: (1) RVd-Lite induction followed by Rev maintenance (2) DRd induction followed by Rev maintenance (3) DRd induction followed by D-R maintenance. Induction phases will be 9 cycles in total of 28 days each, followed by maintenance for cycle 10 and beyond in all cohorts until disease progression: V 1.3 mg/m² on days 1, 8, 15, 22, R 15 mg days 1-21, dex 20 mg days 1, 8, 15, 22 for induction phase and R 10 mg days 1-21 for maintenance phase in cohort 1 (VRd-Lite); SubQ Dara 1800 mg (on days 1, 8, 15, 22 for C1-2, on days 1, 15 for C3-6, on day 1 for C7-9), R 15 mg day 1-21, dex 20 mg days 1, 8, 15, 22 for induction phase and R 10 mg days 1-21 for maintenance in cohort 2 (DRd-R); SubQ Dara 1800 mg (on days 1, 8, 15, 22 for C1-2, on days 1, 15 for C3-6, on day 1 for C7-9), R 15 mg day 1-21, dex 20 mg days 1, 8, 15, 22 for induction phase and Dara 1800mg on day 1 and R 10mg days 1-21 for maintenance in cohort 3 (DRd-DR).

The dual primary objectives are (A) to compare progression free survival (PFS) between cohorts 1 (VRd-Lite) and 2 (DRd-R); (B) to compare overall survival (OS) between cohorts 1 (VRd-Lite) and 3 (DRd-DR). Quality of life objectives are to compare patient reported global health status between treatment arms at the end of induction therapy using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire.

A total of 459 eligible patients will be enrolled in this randomized three cohort trial. It is hypothesized that Cohort 1 will have a median PFS of 2.667 years and a median OS of 5 years. With 153 eligible participants per cohort accrued over 5 years, and an additional follow-up period of 3 years, this trial has 80% power to detect an increase in the median PFS in Cohort 2 from 2.667 years to 4 years, and 83.4% power to detect an increase in the median OS in Cohort 3 from 5 years to 8.5 years, each with a one-sided type I error rate of 2%.

This trial will be conducted among the NCI cooperative groups SWOG, ALLIANCE, and ECOG/ACRIN and incorporate substantial involvement from NCORP and VA member sites. This study is anticipated to provide practice changing data for this transplant-ineligible real world population to achieve deeper and longer remissions with less side effects and better quality of life.

Ailawadhi:Sanofi: Consultancy; Abbvie: Research Funding; Cellectar: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Takeda: Consultancy; Regeneron: Consultancy; Johnson and Johnson: Consultancy, Research Funding; Xencor: Research Funding; GSK: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacuclics: Consultancy, Research Funding. Lipe:Janssen, karyopharm, bms, Sanofi, Pfizer, and abbvie: Consultancy, Honoraria; Janssen and amgen: Research Funding. Holstein:BMS: Research Funding; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Usmani:Sanofi: Consultancy, Research Funding; Pharmacyclics: Research Funding; Sanofi: Consultancy, Research Funding; EdoPharma: Consultancy; Merck: Research Funding; Bristol-Myers Squibb - Celgene:: Consultancy, Research Funding; Oncopeptides: Consultancy; Pfizer: Consultancy; Gilead: Research Funding; Array Biopharma: Research Funding; GSK: Consultancy, Research Funding; SecuraBio: Consultancy; Takeda: Consultancy, Research Funding; Gracell: Consultancy; Genentech: Consultancy; Johnson & Johnson - Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Bristol-Myers Squibb - Celgene: Consultancy, Research Funding; SeaGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; TeneoBio: Consultancy. Orlowski:Sanofi, Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; DEM BioPharma, Inc., Karyopharm Therapeutics, Lytica Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Myeloma 360, Nanjing IASO Biotherapeutics, Neoleukin Corporation, Oncopeptides AB, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sporos Bio: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asylia Therapeutics Inc.: Current equity holder in private company, Patents & Royalties; Bristol Myers Squibb, CARsgen Therapeutics, Exelixis Inc, Heidelberg Pharma, Janssen Biotech Inc, Sanofi, Takeda Pharmaceuticals USA Inc; Laboratory Research Funding: Asylia Therapeutics Inc, BioTheryX Inc, Heidelberg Pharma: Research Funding; AbbVie Inc, Adaptive Biotechnologies Corporation, Asylia Therapeutics Inc, BioTheryX Inc, Bristol Myers Squibb, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Nanjing IASO Biotherapeutics, Neoleukin Therapeutics, Oncopeptides, Pf: Membership on an entity's Board of Directors or advisory committees.