Abstract Background: Hematogenous extramedullary multiple myeloma (HEMM), though rare, is mainly observed in MM patients at relapse. The current study assesses the characteristics and outcomes of patients with MM who develop HEMM in the novel agent era. Methods: Consecutive patients, treated in 16 participating centers and diagnosed with HEMM, were included. Patient characteristics at diagnosis and at HEMM presentation, treatment regimens, response to therapy, response duration and survival were recorded. Factors predicting time to HEMM and survival from HEMM diagnosis were analyzed. Results: 127 patients were included. Median age at MM diagnosis was 63 years (31-94). 50% of patients had IgG MM, 26% had IgA, 23% had light chain, and 1% had other MM types. 44% had ISS 3 and 57% presented with plasmacytomas. 30% presented with high-risk cytogenetics: 19% with t(4;14),11% had 17p deletion. CD56 was expressed in 72% of cases and CD20 in 16%. 55% of the patients were treated for MM with PI, 55% with IMIDs, 62% with chemotherapy and 59% underwent autologous stem cell transplantation (ASCT) prior to HEMM. The median time to the development of HEMM was 2.8 years (95% CI 2.2-3.6). B2M levels (HR 1.04, 95% CI 1.00-1.07, p=0.03), del17p (HR 3.3, 95% CI 1.6-7.1, p=0.002) and plasmacytomas at MM diagnosis (HR 1.6, 95% CI 1.1-2.4, p=0.01) were associated with a shorter duration from diagnosis to HEMM, while upfront ASCT was associated with a longer period to the development of HEMM disease (HR 0.6, 95% CI 0.4-0.9, p=0.01). 47 patients (38%) patients had no concomitant plasmacytomas at HEMM diagnosis. 33% of patients had ≥2 HEMM sites, in 53% HEMM lesion was ≥5 cm, 20% had non-secretory disease at HEMM, and 59% had an increased LDH. 61% received at least 2 lines for MM prior to HEMM. First treatment for HEMM included PIs in 50%, IMIDs in 39%, MoAbs in 10% and chemotherapy in 53%. Overall response rate (ORR) was 49% and 51% failed to respond to first treatment for HEMM. IMIDs were associated with higher odds for ORR (OR 2.2, 95% CI 1.02-4.7, p=0.04). Median survival from MM diagnosis and from HEMM diagnosis were 4.3 (CI 95% 3-5.5) and 0.5 (CI 95% 0.4-0.6) years, respectively. 5-year OS from HEMM diagnosis was 6% (1-15%)(Figure 1A). Increased LDH level at the time HEMM (HR=2.2, 95% CI 1.3-3.8, p=0.002, Figure 1B), FISH positive for t(4;14) (HR=2.3, 95% CI 1.2-4.2, p=0.01)(Figure 1C), t(14;16) (HR=5.6, 95% CI 1.3-25, p=0.02)(Figure 1D), as well as ≤3 years between MM diagnosis and HEMM (HR=1.6, 95% CI 1.04-2.4, p=0.03(Figure 1E)), were found to be associated with a significantly shorter survival from HEMM diagnosis. The achievement of CR or VGPR to treatment administered for HEMM therapy were both associated with improved OS (HR=0.2, 95% CI 0.1-0.3, p<0.001 and HR=0.5, 95% CI 0.3-0.9, p=0.02, respectively) (Figure 1F). No specific treatment was found to be associated with improved survival in patients that develop HEMM. Conclusion: In MM patients who develop HEMM, the median time from MM to HEMM diagnosis is 2.8 years. Despite the improvement in MM therapy over the last decades, patients with HEMM diagnosis have a dismal outcome. OS is significantly shorter in patients with high-risk cytogenetic abnormalities, increased LDH and time to HEMM <3 years. Further studies assessing best therapy in patients experiencing this complication are warranted. Figure 1. Figure 1. Disclosures Cohen: Neopharm Israel: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Medisson Israel: Consultancy, Honoraria, Research Funding. Garderet:Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Niesvizky:Amgen Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Castillo:Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Millennium: Research Funding; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding.