Natural History of Patients with Multiple Myeloma Refractory to Elotuzumab and Outcomes of Subsequent Therapy with Anti-CD38 Monoclonal Antibodies

Introduction: Monoclonal antibodies (MoAbs) have shown activity in relapsed and refractorymultiple myeloma (MM). Elotuzumabis an anti- SLAMF7MoAb that synergizes with immunomodulatory agents (IMiDs) and is approved for treatment of relapsed and refractoryMM. Anti- CD38MoAbs ( daratumumab, FDA approved and isatuximab, in clinical trials) have also entered the therapeutic MM landscape but little is known about how to best sequence MoAbs and the existence of cross resistance between different classes of MoAbs. We analyzed outcomes of patients who become refractoryto elotuzumabwith emphasis on the activity of anti- CD38MoAbs in the post- elotuzumabsetting. Methods: We identified patients from 14 academic institutions within the US who were refractoryto elotuzumabadministered alone or in combination with other agents. Patients were considered refractoryto elotuzumabif treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) within 60 days of last dose. Time zero (T0) was defined as point when myeloma became refractoryto elotuzumab-containing regimen. Data were collected with an electronic platform and submitted to peer-based quality check for completeness and internal consistency. We analyzed demographics, characteristics of their myeloma and prior therapy including number and type of therapy prior to elotuzumab, duration of elotuzumabtherapy, and outcome after becoming refractoryto elotuzumab. We performed a multi-variable analysis of these factors to determine significant factors associated with survival post T0. We subsequently identified a subset of patients who received an anti- CD38MoAb alone or in combination as next or subsequent line of therapy after T0 and report their outcomes. Results: Eighty-nine patients were evaluated. Eighty-six (96.6%) had progression on elotuzumabin combination with IMiD (N=82) or another agent (N=4). Median age at T0 was 65 years (range 28-90), 51% of patients were males, 65% were White, 54% had IgG subtype, 27% had ISS stage III at diagnosis, and 27% had high-risk cytogenetics. Patients received a median of 4 prior lines of treatment (range 1-11) prior to elotuzumab-containing regimen, including 66% who underwent autologous transplant. Sixty-one patients (69%) were refractoryto at least one IMiD and one proteasome inhibitor (PI) at T0, classified as double- refractory. Twenty-one (23.6%) were quad- refractory, i.e. refractoryto 2 IMiDs and 2 PIs. Twenty-eight patients (31.5%) were refractoryto prior anti- CD38MoAb. The median time from diagnosis to T0 was 59.5 months and duration of elotuzumabtherapy was 3 months (range 0.4 - 59.5). Median OS from T0 for the entire cohort was 15.1 months (95% C.I. 9.3-20.9). In multivariate analysis, the only factors affecting OS after T0 were high-risk cytogenetics (HR 3.31, 95% C.I. 1.74-6.27, P Conclusion: Patient who become refractoryto elotuzumabhave guarded prognosis, particularly dismal among patients also refractoryto anti- CD38MoAb, defining a population with great need for novel therapies. Failure of elotuzumab-based therapy does not preclude disease control with anti- CD38MoAb, particularly in combination. Disclosures Paul:Bristol Myer Squibb: Other: Stock and pension plan (past employee). Amarendra:Amgen: Consultancy; Celgene: Consultancy. Liedtke:Caelum: Membership on an entity9s Board of Directors or advisory committees; celgene: Research Funding; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; BlueBirdBio: Research Funding; Prothena: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Hari:Kite Pharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria; Bristol-MyersSquibb: Consultancy, Research Funding; Amgen Inc.: Research Funding; Spectrum: Consultancy, Research Funding. Vij:Karyopharm: Honoraria; Jazz Pharmaceuticals: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding; Bristol MyerSquibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Kumar:Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Costa:Karyopharm: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding; Sanofi: Honoraria; Janssen: Research Funding.