Therapeutic Outcomes of Relapsed-Refractory Multiple Myeloma Patients with 1q21+Treated with Daratumumab-Based Regimens: A Retrospective Analysis

Introduction: Gain/amplification of 1q21 (1q21+) is detected in approximately 40% of MM patients (pts) at diagnosis. There is emerging data that 1q21+ has a negative impact on prognosis in both newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) pts even when treated with highly efficacious novel agents such as bortezomib (Bor), lenalidomide (Len), pomalidomide (Pom), carfilzomib (Car), and daratumumab (Dara). However, a recent pooled subgroup analysis of the phase 3 ICARIA-MM and IKEMA trials revealed that the addition of the isatuximab (Isa) to the backbone of Pom-dexamethasone (Dex) or Car-Dex, respectively, improved progression free survival (PFS) in RRMM pts with 1q21+. The benefit of Dara-based regimens in pts with RRMM harboring 1q21+ abnormalities is currently unknown. We evaluated the efficacy of Dara-based regimens in pts with RRMM harboring 1q21+.

Methods: We identified consecutive MM pts who received a Dara-based regimen, between 1/2015 and 4/2019 at the Mayo Clinic Comprehensive Cancer Center's three sites (Rochester MN, Scottsdale AZ, Jacksonville FL). We included pts who had received any Dara-based regimen after 1-3 prior lines of therapy. 1q21+ abnormality was defined as gain of 1q21 [gain(1q21), 3 copies] and amplification (amp) of 1q21 [amp(1q21), ≥4 copies] on FISH. High-risk cytogenetics (HRCyto) was defined as FISH testing that was positive for t(4;14), t(14;16), t(14;20) or del(17p). Pt categories for analysis were: (1) with or without 1q21+, (2) standard-risk cytogenetics (SRCyto) vs. 1q21+ as the only cytogenetic abnormality, (3) HRCyto with or without 1q21+. Fisher's exact test was used to compare differences between categorial values and PFS was analyzed using Kaplan-Meier analysis.

Results: 368 pts were identified, 278 had received a Dara-based regimen after 1-3 lines and 232 had FISH testing done and were included in the analysis. All pts received either Dara single agent, Dara-Len-Dex, Dara-Pom-Dex, or Dara-Bor-Dex. No pts received Dara-Car-Dex. Baseline characteristics are shown in Table 1. 1q21+ was noted in 57 pts (1q21 amp: 4, 1q21 gain: 53). The median follow-up time for the entire cohort was 35.7 months (m) (95% CI: 25.2-NR). The median PFS for 1q21+ pts treated with a Dara-based regimen was 24.6 m (95% CI: 19.9-29.4). The overall response rate (ORR) for pts with 1q+ treated with a Dara-based regimen was 57.9%; sCR: 1 (1.75%), CR: 3 (5.26%), VGPR: 9 (15.8%), and PR: 21 (36.8%). SD was noted in 16 (28%) pts. There were no PFS differences (p=0.956) or ORR differences (p=0.776) between the different Dara-based regimens used in pts with 1q21+. There were no PFS differences for pts with 1q21+ vs. pts without 1q21+; 24.5 m (95% CI: 18.6-29.4) vs. 23.5m (95% CI: 21.1-28.1), respectively; p=0.392. There were also no differences in ORR (p=0.09) for pts with 1q21+ vs. pts without 1q21+ treated with a Dara-based regimen. There were no PFS differences amongst pts with HRCyto without 1q21+ vs. pts with HRCyto and 1q21+; 23.5 m (95% CI: 20.7-NR) vs. 24.6 m (95% CI: 18.0-HR), respectively, p=0.507. Similarly, there were no ORR differences (p=0.127) between pts with HRCyto without 1q21+ vs. pts with HRCyto with 1q21+. Lastly, looking at pts with SRCyto vs. 1q21+ as the sole cytogenetic abnormality, there were no significant PFS differences [23.1 m (95% CI: 19.4-28.1), vs. 24.6 m (95% CI: 19.8-34.8), respectively, p=0.64] or ORR differences (p=0.075).

Conclusion: Since 1q21+ is seen fairly frequently in pts with MM, its role as an independent prognostic marker as well as biomarker to guide treatment selection is being defined. While there is emerging data that Isa-based regimens can improve the PFS and ORR of patients with RRMM with 1q21+, we noted that for RRMM pts treated with Dara-based regimens, outcomes for pts with 1q21+ are similar to those with standard risk disease or other HRCyto markers. The lack of PFS and ORR differences seen regardless of 1q21+ status with Dara-based regimens could suggest that Dara-based treatment may abrogate the poor outcomes associated with the presence of 1q21+. To further explore the importance of 1q21+ as a therapeutic and prognostic biomarker in MM, existing data from large, randomized, prospective phase 3 trials needs to be pooled and analyzed to evaluate the role of anti-CD38 monoclonal antibodies in pts with 1q21+.

Kourelis:Novartis: Research Funding. Kapoor:Sanofi: Honoraria, Research Funding; X4 Pharmaceuticals: Honoraria; Regeneron: Research Funding; Amgen: Research Funding; Ichnos: Research Funding; Loxo: Research Funding; Karyopharma: Research Funding; BMS: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Research Funding; Casma: Honoraria; Pharmacyclics: Honoraria; Imedex: Honoraria; GSK: Honoraria; Cellectar: Honoraria; Oncopeptides: Honoraria. Fonseca:Pharmacyclics: Consultancy; Pfizer: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy; Novartis: Consultancy; Merck: Consultancy; Kite: Consultancy; Karyopharm: Consultancy; Juno: Consultancy; Janssen: Consultancy; H3 Therapeutics: Consultancy; GSK: Consultancy; BMS/Celgene: Consultancy; Bayer: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; OncoMyx: Membership on an entity's Board of Directors or advisory committees.