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4564 Peri-Transplant and Maintenance Daratumumab for Minimal Residual Disease (MRD) Eradication in Transplant-Eligible Multiple Myeloma (MM) Patients

Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Poster III
Hematology Disease Topics & Pathways:
Biological therapies, Antibody Therapy, Plasma Cell Disorders, Diseases, Therapies, Immunotherapy, Lymphoid Malignancies, Monoclonal Antibody Therapy, Minimal Residual Disease
Monday, December 12, 2022, 6:00 PM-8:00 PM

Sikander Ailawadhi1, Ricardo D Parrondo, MD2, Gabriela Perez, MS3*, Mohamed A. Kharfan-Dabaja, MD, MBA4, Hemant S. Murthy, MD4, Ernesto Ayala, MD5, Patrick J O'Brien6*, Vivek Roy, MD7, Victoria R. Alegria7*, Ashley Zimmerman8*, Dustin Chapin9*, Stephanie Lanier10*, Carly Kasik9*, Schannon Bradley9*, Taimur Sher, MD2, Aneel Paulus, MD1 and Asher Chanan-Khan, MD11

1Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL
2Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL
3Division of Biostatistics and Informatics,, Mayo Clinic, Rochester, MN
4Division of Hematology/Oncology and Blood and Marrow Transplanation and Cellular Therapy, Mayo Clinic, Jacksonville, FL
5Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL
6Mayo Clinic, Rochester, MN
7Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL
8Hematology-Oncology, Mayo Clinic, Jacksonville, FL
9Mayo Clinic, Jacksonville, FL
104500 San Pablo Road, Mayo Clinic, JAcksonville, FL
11Division of Hematology-Oncology, Mayo Clinic, Jacksonville, FL

Introduction: Achievement of MRD negativity (MRD-) in MM is associated with superior progression free survival (PFS) and overall survival (OS). This is especially true after optimal induction followed by high-dose melphalan and autologous stem cell transplant (ASCT). Furthermore, lenalidomide (Len) maintenance following ASCT can further increase conversion to MRD- in patients (pts) that are MRD+ after ASCT. Daratumumab (Dara) has emerged as an extremely effective agent and Dara-containing regimens are associated with unprecedented MRD- rates. Still, the role of Dara in pts who are MRD+ to increase conversion to MRD- has not been studied. We report data from a phase 2 trial evaluating the efficacy of pre-ASCT Dara intensification and post-ASCT Dara maintenance in pts with MM, along with alternative Dara schedule to explore optimal frequency of administration for this immunotherapy approach.

Methods: This ongoing phase 2 trial (NCT03477539) enrolled pts with MRD+ (measured at 10-5 by multiparametric flow cytometry (MPF) in bone marrow) after any induction therapy prior to ASCT. Pts then received 2-4 (4 cycles allowed due to COVID pandemic and any ensuing delay in ASCT) 28d cycles of subcutaneous Dara 1800mcg pre-ASCT followed by ASCT, and maintenance starting at day-100 post-ASCT. Maintenance therapy included monthly Dara with Len (10mg 21 days on, 7 days off) for 1 year, and then single-agent Dara every 3 months until disease progression. MRD assessment on trial was done pre-ASCT, on Day-100, and at the end of 1-year Dara-Len maintenance therapy. Key eligibility criteria included: Induction therapy for pathologically confirmed MM, MRD+, adequate marrow (absolute neutrophil count ≥1.0x109, platelets ≥50x109) and organ function (creatinine clearance ≥30 mL/min), and ECOG performance status ≤2. Primary objective was MRD- rate at day-100 post-ASCT. The trial utilized a two-stage Simon optimum design to test the null hypothesis of MRD- rate at day-100 being 45%.

Results: Of the 50-pts enrolled, 46 were evaluable for primary endpoint analysis (3 were ineligible and 1 withdrew consent prior to the start of treatment). Median follow-up was 18.1 mths. The median age was 64 years (range: 44-73), with 8 (17.4%) pts having ISS III disease at enrollment. Seven (15.2%) had high-risk cytogenetics; del17p in 2 (4.3%), t(4;14) in 4 (8.7%), and t(14;16) in 2 (4.3%). Most common induction regimens were bortezomib+len+dex (VRd; 71.7%), Carfilzomib+Rd (KRd; 8.7%), Cyclophosphamide+Vd (VCd; 4.3%), Vd (4.3%), and Rd (4.3%). 38 (82.6%) pts were enrolled after initial induction for MM and 8 (17.4%) pts had second-line induction prior to study enrollment. Pre-ASCT Dara treatment included 2 cycles in 37 pts (80.4%) and 4 cycles in 9 pts (19.6%). At the pre-ASCT testing (after Dara treatment), 7 pts had converted to MRD- (6 of the pts with 2 cycles of Dara and 1 with 4 cycles of Dara). At Day-100 post-ASCT, 30 (65.2%; 95% CI: 50.5%-77.9%) of 46 pts were MRD-, 22 pts (47.8%) who were MRD+ after 1-4 cycles of pre-ASCT Dara consolidation, became MRD- at Day-100 (Figure 1). Twenty pts (of the 46) have been evaluated for MRD after 1 year of Dara-Len maintenance; 14 (30.4%) remained MRD-, 2 (4.3%) converted to MRD- after being MRD+ at Day-100, 3 (6.5%) remained MRD+, and 1 (2.2%) converted MRD+ after being MRD- at Day-100. Forty-nine pts received at least one cycle of treatment and were evaluable for adverse event (AE) analysis. The most common treatment related grade 3/4 AEs were neutropenia (69.4%), thrombocytopenia (69.4%) and leukopenia (57.1%).

Conclusion: Treatment regimens leading to MRD- state are preferred but so far MRD- cannot be guaranteed when selecting induction regimens. Pre-ASCT Dara consolidation followed by post-ASCT Dara-based maintenance in MM pts after induction therapy is a safe and effective strategy to enhance achievement of MRD- state. We also noted an alternative Dara regimen with extended treatment interval and continued efficacy. These early findings support continued investigation of Dara-based therapy as pre-ASCT intensification and post-ASCT maintenance to achieve deep responses, especially where induction therapy fails to achieve MRD- state.

Disclosures: Ailawadhi: GSK, Sanofi, BMS, Takeda, Beigene, Pharmacyclics, Amgen, Janssen: Consultancy.

*signifies non-member of ASH