MRD-Guided Sequential Therapy for Deep Response in Newly Diagnosed Multiple Myeloma (NDMM)- Master-2 Trial

Background and Significance:

Autologous hematopoietic cell transplantation (AHCT) is essential for eligible patients with newly diagnosed multiple myeloma (NDMM) but associated with short-term toxicities and long term risks of genetic instability and second primary malignancies. Induction therapy with daratumumab, bortezomib, lenalidomide, and dexamethasone (dara-VRd) achieves high response rates, with 40% reaching minimal residual disease (MRD) negativity. MRD is a strong prognostic factor for progression-free survival (PFS) and overall survival (OS), regardless of baseline risk. However, the role of MRD in guiding therapeutic decisions remains under investigation. Early MRD negativity may negate the benefits of early AHCT, while MRD-positive patients post-induction therapy are at higher risk of disease progression. Teclistamab (Tec), a bispecific antibody (BsAb) targeting BCMA, shows promise in refractory MM and, when combined with daratumumab (Tec-Dara), may help eliminate residual disease. Continuous lenalidomide maintenance, although beneficial, poses cost and toxicity concerns, especially in MRD-negative patients, making fixed-duration maintenance exploration important.

Study Design and Methods:

The MASTER-2 study (NCT #05231629) is a randomized phase II trial with a response-adaptive design for NDMM patients eligible for AHCT. The trial aims to enroll 300 patients, 25% minority enforced by trial design. Eligibility criteria include documented MM per International Myeloma Working Group criteria, measurable disease, and ECOG performance status ≤2. Prior therapy exclusions apply, except for limited doses of dexamethasone, bortezomib, cyclophosphamide, lenalidomide, or daratumumab. All patients will receive six 28-day cycles of dara-VRd induction, followed by stem cell collection and MRD assessment via clonoSEQ® (MRD1). Patients will be randomized based on MRD status: MRD-negative patients to Arm A (three cycles dara-VRd intensification, 13 cycles dara-R maintenance) or Arm B (AHCT intensification, 13 cycles dara-R maintenance). The primary hypothesis for MRD-negative patients is non-inferiority of Arm A to Arm B. MRD-positive patients will be randomized to Arm C (AHCT intensification, three cycles Dara-Tec consolidation, 13 cycles Dara-Tec maintenance) or Arm D (AHCT intensification, three cycles Dara-R consolidation, 13 cycles Dara-R maintenance). Tec will be administered at 1.5 mg/kg weekly for the first cycle, followed by 3 mg/kg every four weeks. The primary hypothesis for MRD-positive patients is the superiority of Arm C over Arm D. Post-maintenance, patients with sustained MRD negativity (<10⁻⁵ at MRD2 before maintenance and MRD 3,12 months later) will enter treatment-free observation and MRD surveillance (MRD-SURE). Patients not meeting this criterion will receive standard lenalidomide maintenance. Primary endpoints include MRD negativity rate post-induction and sustained MRD <10⁻⁵ rates. Secondary endpoints encompass PFS, OS, MRD conversion, MRD kinetics, and safety. Exploratory endpoints involve MRD <10⁻⁶ rates, quality of life (EORTC-QLQ-C30, PROMIS), blood-MRD by mass spectrometry, soluble BCMA, and immune profiling.

The study seeks to determine if AHCT can be deferred in patients achieving MRD negativity after Dara-VRd without compromising the chance of reaching and sustaining MRD negativity, and whether post-AHCT Tec-Dara can enhance sustained MRD negativity rates compared to post-AHCT Dara-R in MRD-positive patients. The study is currently open for enrollment at multiple sites in the US.

Dhakal:Medical College of Wisconsin: Current Employment; Bristol Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; Sanofi: Research Funding; Carsgen: Research Funding; Genentech: Consultancy, Honoraria; C4 therapeutics: Research Funding; Karyopharm: Honoraria, Speakers Bureau; Acrellx: Research Funding; Pfizer: Consultancy, Honoraria, Speakers Bureau. Silbermann:Sanofi-Aventis, Janssen Oncology, and Oncopeptides: Consultancy; Sanofi: Research Funding. Schmidt:BiolineRx, Janssen, Pfizer, and Sanofi: Consultancy; Alexion Pharmaceuticals, Bristol Myers Squibb, and Janssen: Research Funding. Bal:Janssen: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; MJH Life Sciences: Honoraria; Beigene: Research Funding; Fate Therapeutics: Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Giri:Janssen Research & Development, LLC: Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Research Funding, Speakers Bureau. Bumma:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Khan:Amgen: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau. Chakraborty:Janssen: Consultancy; Sanofi: Consultancy; Adaptive: Consultancy. Ravi:Guidepoint: Consultancy. Baljevic:Janssen Biotech, BMS/Celgene, Sanofi-Genzyme: Other: advisory board; Parexel: Other: IRC; AbbVie, Pfizer: Consultancy. Afrough:Sanofi: Honoraria, Other: Data safety monitoring/advisory board; Bristol-Myers Squibb: Honoraria, Other: Data safety monitoring/advisory board; Karyopharm: Honoraria, Other: Data Safety Monitoring/Advisory Board; Janssen: Research Funding; K36 Therapeutics: Research Funding; AbbVie: Research Funding; Adaptive Biotechnology: Research Funding. Kaur:Kedrion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectar Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Arcellx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Banerjee:Novartis, Pack Health: Research Funding; Adaptive Biotech, BMS, Caribou Biosciences, Genentech, GSK, Janssen, Karyopharm, Legend Biotech, Pfizer, Sanofi, SparkCures: Consultancy. D'Souza:Kedrion, Pfizer, Janssen, Bristol Myers Squibb, BMS, Janssen, and Prothena.: Consultancy; AbbVie, Sanofi, Novartis, Janssen, Regeneron, Takeda, TeneoBio, Caelum, and Prothena: Research Funding. Mohan:Sanofi: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; BMS: Consultancy; Janssen: Consultancy; Legend biotech: Consultancy. Matous:BeiGene; Pharmacyclics: Consultancy. Anderson:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectar Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Prothena: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Costa:Pfizer: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive biotechnoligies: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Caribou: Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria.