Session: 653. Myeloma: Therapy, excluding Transplantation: Improving the Outcomes of Newly Diagnosed Multiple Myeloma
Hematology Disease Topics & Pathways:
Diseases, multiple myeloma, Biological, antibodies, Therapies, Plasma Cell Disorders, immunotherapy, Lymphoid Malignancies, transplantation
Methods: Eligible patients (pts) had NDMM requiring treatment, creatinine clearance >40 ml/min, adequate liver and cardiac function, ECOG performance status 0-2 with no age limit. Treatment cycles consisted of daratumumab 16 mg/kg IV days 1,8,15,22 (with typical reduction in frequency with subsequent cycles), carfilzomib 56 mg/m2 IV days 1,8,15, lenalidomide 25 mg PO days 1-21 and dexamethasone 40 mg PO/IV days 1,8,15,22 repeated every 28 days. Patients received 4 cycles of Dara-KRd as induction, autologous transplantation, and received 0, 4 or 8 cycles of Dara-KRd consolidation, according to MRD status at each phase of therapy. MRD was evaluated by clonoSEQ® (NGS-MRD; Adaptive Biotechnologies, Seattle, WA) at end of induction, post-transplant, and during each 4-cycle block of Dara-KRd consolidation. Primary endpoint was achievement of MRD negative remission (<10-5) as defined by IMWG consensus. Secondary endpoints included MRD <10-6, complete response (CR) by IMWG criteria at end of induction and upon completion of consolidation, and rate of imaging (assessed by PET/CT scan) plus MRD-negative CR. Patients received therapy until achievement of two consecutive MRD reads <10-5 (confirmed MRD-negative remission; e.g., post-induction and post-transplant or post-transplant and during consolidation). Confirmed MRD-negative pts received no further therapy and were observed with surveillance for MRD resurgence 6 and 18 months after treatment discontinuation. Patients completing consolidation without confirmed MRD-negative remission received standard lenalidomide maintenance (NCT03224507).
Results: Currently 69 pts have been enrolled, 38 have completed induction and 22 have completed post-transplant assessment. Median age was 61 (range 38-79) years, 13 (19%) had ISS 3, and 20 (29%) had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. Sixty-six (96%) pts had MRD trackable by clonoSEQ® and 100% of the expected MRD datapoints were successfully obtained. All patients responded by end of induction cycle 2, 92% of pts obtained VGPR or better after induction and 91% of patients who have reached transplant obtained CR/sCR as best response on therapy (Figure). MRD-negative remission (<10-5) rate was 34%, 70% and 80% after induction, transplant and at best response, respectively (Figure). Rates of MRD <10-6 were 28%, 45% and 65% respectively. No patient discontinued therapy due to toxicity. One patient died from metapneumovirus pneumonia post-transplant, considered not related to investigational agents. Most common grade 3 and 4 AEs were neutropenia (n=7), infection (n=6), insomnia (n=4), hyperglycemia (n=2) and rash (n=2). There were 15 serious AEs including pneumonia (n=5), fever and neutropenia (n=2), pulmonary embolism (n=1), and atypical hemolytic uremic syndrome (n=1). All 11 patients who have achieved confirmed MRD-negative remission and discontinued therapy also achieved imaging plus MRD-negative CR and none had relapse or resurgence of MRD with short follow up (0.8-7.3 months). Longer follow-up, post-induction and post-transplant MRD assessment for at least 69 and 41 pts, respectively, will be presented at the meeting.
Conclusion: This is the first report of monoclonal antibody-based quadruplet regimen with MRD-based response-adapted therapy in NDMM. Dara-KRd induction, autologous transplant and Dara-KRd consolidation guided by MRD is feasible, safe and leads to high proportion of patients achieving CR/sCR, IMWG MRD-negative CR, imaging plus MRD-negative CR and MRD <10-6. This approach can form the basis for clinical efforts to reduce the burden of continuous therapy in those with confirmed MRD-negative remissions.
Disclosures: Costa: Karyopharm: Consultancy; Janssen: Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Celgene: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy. Cornell: Takeda: Consultancy; KaryoPharm: Consultancy. Silbermann: Janssen, Sanofi: Other: Consultant/Advisor. Dhakal: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Omel: Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Hari: Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria; Amgen: Research Funding; AbbVie: Consultancy, Honoraria; GSK: Other: Grant.
OffLabel Disclosure: Carfilzomib for newly diagnosed multiple myeloma
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