Real World Data on Outcomes of Anti-CD38 Antibody Refractory, Including Triple Class Refractory, Patients with Multiple Myeloma: A Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

Introduction: Despite the routine use of novel therapeutic agents multiple myeloma (MM) remains an incurable malignancy. The MAMMOTH study reported that patients refractory to anti-CD38 monoclonal antibodies (mAbs) have particularly dismal outcomes in the United States (Gandhi et al. Leukemia 2019). Given the differences in drug accessibility with our publicly funded healthcare model, there is a need to understand the real-world outcomes of patients refractory to anti-CD38 mAbs, particularly those that are triple class refractory (TCR), in the Canadian context. We performed a retrospective cohort study to describe the characteristics, progression free survival (PFS), and overall survival (OS) of patients treated for MM refractory to anti-CD38 mAb therapy.

Methods: Patients were identified using the Canadian Myeloma Research Group Database (CMRG-DB), a prospectively maintained national database comprised of more than 8700 patients across 16 sites. Included patients were refractory to an anti-CD38 mAb based index regimen and were subsequently treated with standard of care (SoC) regimens. Patients discontinuing anti-CD38 mAb therapy for reasons other than progressive disease or treated with an anti-CD38 mAb for a plasma cell disorder other than MM were excluded. TCR patients were examined as a distinct cohort and were defined as those refractory to an immunomodulatory drug (IMID), proteosome inhibitor (PI), and an anti-CD38 mAb. Kaplan Meier survival analysis was used to determine the PFS and OS from the initiation of subsequent therapy post anti-CD38 mAb progression. The data cutoff date was June 2022.

Results: The CMRG-DB includes 8700 patients with MM, of whom 663 progressed on anti-CD38 mAb therapy. In total, 466 (70%) anti-CD38 mAb refractory patients initiated a subsequent regimen. Of those, 120 patients were treated on clinical trial and were excluded, and 346 patients were treated with SoC regimens and were included in this study. Sixty-three percent of patients previously received an autologous stem cell transplant, and the majority of patients were refractory to lenalidomide or bortezomib (88% and 53%, respectively), as shown in Table 1. The median age at initiation of subsequent therapy was 67.9 (range 39.6-89.6) years. The median time from diagnosis to initiation of subsequent therapy post-anti-CD38 mAb progression was 54 (range 3.6-283.2) months, and the median number of prior treatment lines was 3 (range 1-9). The median PFS from start of subsequent therapy was 4.6 (95% CI 4.1-5.6) months, and the median OS was 13.3 (95% CI 10.6-16.6) months. The overall response rate (ORR) to first subsequent therapy was 38%, and 5% achieved at least a complete response (CR).

Of the 346 anti-CD38 mAb refractory patients, 199 (58%) patients were TCR and treated with SoC regimens after progression on anti-CD38 mAb. Next line of therapy among TCR patients was most commonly a combination of PI/steroid (n=53, 27%), IMID/alkylator (n=46, 23%), PI/alkylator (n=29, 15%), or PI/IMID (n=24, 12%). No patients received anti-BCMA therapy or an XPO1 inhibitor at progression as these are not available as SoC in Canada. The ORR was 40% to the first subsequent line of therapy, with 4% of patients achieving a CR or better. Among TCR patients, the median PFS from start of subsequent therapy was 4.4 (95% CI 3.6-5.3) months, and the median OS was 10.5 (95% CI 8.5-13.8) months.

We compared non-TCR to TCR patients and the median PFS and OS from start of first subsequent therapy was significantly longer among anti-CD38 mAb refractory patients who were non-TCR (median PFS 6.0 versus 4.4 months, respectively, p=0.009; median OS 17.5 versus 10.5 months, respectively, p=0.003 [see Figure 1]). Outcomes of TCR patients treated with a second subsequent SoC regimen after anti-CD38 mAb progression were even poorer (n=50 TCR patients, ORR 31%, CR 2%; median PFS and OS from start of second subsequent SoC treatment were 2.8 (95% CI 1.8-4.6) months versus 6.4 (95% CI 3.7-18) months, respectively).

Conclusion: This is the largest study reporting outcomes of patients with MM refractory to anti-CD38 mAb. Similar to prior reports, we show that anti-CD38 mAb refractory patients have a short PFS and OS when treated with SoC regimens. This study provides a real-world context for novel therapies being studied in this refractory patient population and highlights the urgent need for the development of and access to effective therapeutics for our patients.

White:Takeda: Honoraria; Forus: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; BMS: Honoraria; GSK: Honoraria; Amgen: Honoraria; Antengene: Honoraria. Jimenez-Zepeda:Pfizer: Honoraria; Sanofi: Honoraria; FORUS Therapeutics: Honoraria; Takeda: Honoraria; GSK: Honoraria; BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria. McCurdy:Janssen: Honoraria; BMS: Honoraria, Research Funding; Sanofi: Honoraria; GSK: Honoraria; Forus: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Leblanc:BMS: Honoraria; Janssen: Honoraria; FORUS Therapeutics: Honoraria; Sanofi: Honoraria; Amgen: Honoraria. Song:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Mian:Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Louzada:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Sebag:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Stakiw:BMS: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Honoraria; FORUS Therapeutics: Honoraria; Sanofi: Honoraria. Kotb:Celgene: Honoraria; BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Merck: Honoraria, Research Funding; Karyopharm: Current equity holder in private company; Amgen: Honoraria; Akcea: Honoraria. Venner:Takeda: Honoraria; Janssen: Honoraria; FORUS Therapeutics: Honoraria; Pfizer: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Kaedbey:Janssen, BMS, Sanofi, FORUS, Beigene, Pfizer: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Advisory boards; Jewish General Hospital, Montreal, QC, Canada: Current Employment; BMS. Janssen: Honoraria; BMS. Janssen: Honoraria; Beigene: Other: Advisory boards; FORUS Therapeutics: Other: Advisory boards; Sanofi: Other: Advisory boards; BMS: Honoraria, Other: Advisory boards; Janssen: Honoraria, Other: Advisory boards; Janssen, BMS, Sanofi, FORUS, Beigene, Pfizer: Membership on an entity's Board of Directors or advisory committees. Reece:Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding; BMS: Research Funding; Millenium: Research Funding; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy; Sanofi: Honoraria; GSK: Honoraria.