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Background: Anti-CD38 monoclonal antibodies have become a standard treatment option for patients with either relapsed/refractory (RR) or newly diagnosed multiple myeloma (MM). There are two approved drugs in this class, daratumumab and isatuximab. These agents have become a mainstay of myeloma treatment being used in a variety of combination approaches. Although they are widely used, very little has been reported regarding the benefit they provide if they are used again in subsequent lines of therapy among patients that have already been treated with prior anti-CD38 containing regimens. Methods: MM patients that were treated at the Berenson Cancer Center and previously received either daratumumab or isatuximab and were treated with another anti-CD38-containing combination were retrospectively analyzed. Response to each anti-CD38 regimen was evaluated for responses according to the International Myeloma Working Group (IMWG) criteria. We used Kaplan-Meier curves to determine progression free survival (PFS) and overall survival (OS). Results: There were 49 patients identified as having received > 2 anti-CD38 containing regimens. Among these patients, 40, 1, and 8 received only daratumumab, only isatuximab, or a combination of both anti-CD38 regimens. 17, 19, 8, and 41 received an IMiD, PI, a combination of both, or other combinations. Overall, the median PFS was 3.9, 3.2, 2.6, 1.9, and 1.5 months for the first (n=49), second (n=49), third (n=23), fourth (n=15), and fifth (n=8) exposures, respectively. For their first anti-CD38 containing regimen (n=49), the clinical benefit rate (CBR) and overall response rate (ORR) were 44.9% and 38.8%, respectively (7.7% MR, 34.7% PR, and 4.1% CR), and 36.7% showed SD. During their second exposure (n=49), the CBR and ORR were 42.9% and 40.8%, respectively (2.0% MR, 36.7% PR, 12.0% VGPR, and 2.0% CR) and 36.7% showed SD. The PFS among patients who were exposed to a second regimen and discontinued therapy without disease progression to their first anti-CD38 containing regimen was 5.9 months compared with only 3.0 months for those who progressed during their first regimen. OS from the start of anti-CD38 treatment was a median of 36.5 months (range, 1.8-56.5). OS was longer among patients who did not progress on first exposure with a median of 26.2 months (range, 1.8-56.5) compared to patients who progressed during their first regimen (median not yet reached; range, 7.6-54.5). PFS among patients treated with a proteasome inhibitor (PI)-containing combination in their first exposure was 8.7 months versus 4.5 months among patients who were treated with an immunomodulatory agent (IMiD)-containing treatment. Additionally, the PFS among patients treated with a PI versus an IMiD with their second exposure to an anti-CD38 containing regimen was 5.9 and 2.8 months, respectively. Conclusions: Our retrospective study suggests that RRMM patients who are retreated with another anti-CD38 containing regimens can continue to respond after multiple exposures to this drug class. The ORR differs little during the first two exposures to these agents for RRMM patients. To our knowledge, this study provides support for retreatment of RRMM patients with anti-CD38 containing regimens. Additional studies are planned to further investigate this patient population. Disclosures Vescio: Janssen: Speakers Bureau; Karyopharm: Speakers Bureau; GlaxoSnithKlein: Speakers Bureau; Amgen: Speakers Bureau.