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3237 Outcomes of MRD-Adapted Treatment Modulation in Patients with Newly Diagnosed Multiple Myeloma Receiving Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd) and Autologous Transplantation: Extended Follow up of the Master TrialClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research, Plasma Cell Disorders, Combination therapy, Diseases, Therapies, Lymphoid Malignancies, Minimal Residual Disease
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Luciano J. Megala Costa, MD, PhD1, Saurabh Chhabra, MD, MS2, Eva Medvedova, MD3*, Timothy Martin Schmidt, MD4, Bhagirathbhai Dholaria, MBBS5, Kelly N. Godby, MD6*, Rebecca Silbermann, MD, MMS7, Susan Bal, MD8, Anita D'Souza, MD, MS9, Smith Giri, MD, MHS10, James L. Omel, MD11*, Parameswaran Hari, MD, MRCP12, Natalie Callander, MD13 and Binod Dhakal, MBBS14

1University of Alabama at Birmingham, Birmingham, AL
2Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
3Knight Cancer Institute, Oregon Health & Science University, Portland, OR
4Carbone Cancer Center, University of Wisconsin, Madison, WI
5Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN
6Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL
7Knight Cancer Institute, Oregon Health and Science University, Portland, OR
8O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
9Division of Hematology Oncology, CIBMTR (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI
10Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL
11Myeloma Research Advocate/Advisor, Grand Island, NE
12Medical College of Wisconsin, Department of Medicine, Milwaukee, WI
13University of Wisconsin Carbone Cancer Center, Madison, WI
14Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI

Background: Quadruplet induction and consolidation therapy in the setting of autologous hematopoietic cell transplantation (AHCT) leads to high rates of minimal/measurable residual disease (MRD) negativity in patients (pts) with newly diagnosed MM (NDMM), enabling MRD response-adapted therapy. The outcomes of patients ceasing therapy guided by MRD assessment have not been described.

Methods: Eligible pts in the MASTER trial had NDMM requiring treatment, CrCl≥40 ml/min, adequate liver and heart function, ECOG performance status 0-2 with no age limit. There was a planned enrichment for pts with high-risk cytogenetic abnormalities (HRCA). Pts received 4 cycles of Dara-KRd as induction, AHCT, and received 0, 4 or 8 cycles of Dara-KRd consolidation, according to MRD status as previously reported. MRD was evaluated by next generation sequencing (NGS, ClonoSEQ®) in all pts at end of induction, post-AHCT, and during each 4-cycle block of Dara-KRd consolidation. Primary endpoint was achievement of MRD negativity (<10-5 as defined by IMWG) in the intent-to-treat (ITT) population. Pts received therapy until achievement of two consecutive MRD <10-5 (i.e., post-induction and post-AHCT or post-AHCT and during consolidation). Pts with 2 consecutive MRD negative assessments entered treatment-free observation and MRD surveillance (“MRD-SURE”) with MRD testing 6 months after treatment cessation and yearly thereafter. Pts completing consolidation without 2 consecutive MRD-negative assessments received lenalidomide maintenance. Results are reported by risk profile based on the presence of 0, 1 or 2+ HRCA [gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)].

Results: The study accrued 123 participants. Fifty-three (43%) had no HRCA, 46 (37%) had 1 and 24 (20%) had 2+ HRCA. Median age was 60 y (36-79), 23% of pts were non-white, 20% had ECOG 2, 21% had high LDH, and 20% R-ISS3. Median follow up is 34.1 mo. Overall (N=123) 3-year PFS was 91%, 87% and 51% (Panel A, P<0.001) and 3-year OS 96%, 91% and 75% (P=0.004) for patients with 0, 1 and 2+ HRCA respectively. Disease was trackable by NGS-MRD in 118 (96%) pts. Of these, 81% achieved MRD negativity, and 71 % MRD < 10-6. Among these 118 pts, 8% discontinued therapy prematurely (death, progression or withdraw of consent), 20% completed treatment and transitioned to lenalidomide maintenance and 71% reached 2 consecutive MRD negative assessments and entered MRD-SURE. Odds of reaching MRD-SURE was 66%, 82% and 63% for patients with 0, 1 or 2+ HR abnormalities respectively. Among the 84 patients who reached MRD-SURE, after median follow up post treatment cessation of 24.8 mo, 7 (8%) initiated lenalidomide-based therapy for MRD resurgence and 11 (13%) started treatment for disease progression. Sixty-six pts (79%) have remained off therapy, including 88%, 83% and 47% of patients with 0, 1 and 2+ HRCA. Four patients died after entering MRD-SURE, 2 from MM (21 and 24 mo. after progression) and 2 from unrelated causes (COVID-19 pneumonia and accidental fall). Two-year PFS from treatment cessation is 91%, 89% and 54% (Panel B, P=0.008) and 2-year OS 100%, 92% and 100% (P=0.51) for patients with 0, 1 or 2+ HRCA, respectively.

Conclusion: MM pts. with 0 or 1 HRCA reaching confirmed MRD negativity after quadruplet induction, AHCT and MRD-adapted consolidation have excellent PFS and OS in absence of maintenance therapy. Although the odds of achieving MRD-SURE were similar across risk strata, the risk of progression was higher among patients with ultra-high-risk MM (2+ HRCA) indicating the need for novel consolidation strategies. For the majority of patients with NDMM, quadruplet therapy, AHCT and MRD response-adapted treatment modulation provides the opportunity of durable treatment cessation without compromising disease control.

Disclosures: Megala Costa: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genentech: Research Funding. Chhabra: Sanofi: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Honoraria; Amgen: Research Funding. Schmidt: Sanofi: Consultancy; Janssen: Consultancy. Dholaria: Vanderbilt University Medical Center: Current Employment; Gamida Cell: Consultancy; Orca Bio: Research Funding; Arivan: Consultancy; Molecular Templates: Research Funding; Wugen: Research Funding; BEAM Therapeutics: Consultancy; Janssen: Research Funding; Angiocrine: Research Funding; MJH Biosciences: Honoraria; Pfizer: Research Funding; Takeda: Research Funding; Poseida: Research Funding; BMS: Research Funding; MEI Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy. Silbermann: Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Bal: Adaptive Biotechnologies: Consultancy. D'Souza: Takeda, Sanofi, TeneoBio, Prothena, Caelum Biosciences, Janssen Oncology, Regeneron, AbbVie: Research Funding; Pfizer, Janssen Oncology, Bristol Myers Squibb/Celgene, Prothena: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giri: Pack Health: Research Funding; OncLive: Honoraria; CareVive: Honoraria, Research Funding. Hari: Millennium: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Incyte: Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Kite: Consultancy, Honoraria; Pharmacyclics: Consultancy; AbbVie: Honoraria; Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Spectrum Pharmaceuticals: Research Funding; Iovance: Current Employment. Dhakal: Karyopharm Therapeutics: Honoraria, Speakers Bureau; Natera: Consultancy; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding; Arcellx: Research Funding; Carsgen: Research Funding; Cartesian: Research Funding; Fate: Research Funding; Takeda: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: Use of carfilzomib for newly diagnosed multiple myeloma

*signifies non-member of ASH