Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd) Induction, Autologous Transplantation and Post-Transplant, Response-Adapted, Measurable Residual Disease (MRD)-Based Dara-Krd Consolidation in Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Background: The CD38-targeting antibody daratumumab, when combined with a proteasome inhibitor or with an immunomodulatory agent (IMiD) increases depth and duration of response in multiple myeloma (MM). Depth of remission post initial therapy as assessed by MRD predicts long term outcome in NDMM. We hypothesized that the combination of daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) would be safe and highly active in patients with NDMM. In addition, we assessed the feasibility of using MRD by next generation sequencing (clonoSEQ® method, sensitivity 10-6) to inform the use and duration of post-transplant Dara-KRd consolidation. 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 ( 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 ( 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 Download : Download high-res image (77KB) Download : Download full-size image Figure . Disclosures Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor. 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: Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Carfilzomib for newly diagnosed multiple myeloma