Efficacy of Daratumumab, Pomalidomide and Dexamethasone Compared to Daratumumab, Carfilzomib and Dexamethasone in High Risk Relapsed Multiple Myeloma: Multicenter Real-World Experience
Authors: Magee Gray , Mansour Razan , Chang Mark , Atrash Shebli , Ahmed Nausheen , Mushtaq Muhammad Umair , Ouchveridze Evguenia , Abdallah Al-Ola , Paul Barry , Green Kimberly M , Davis James A , Hashmi Hamza 
Published: December 2024

Background: Daratumumab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide/dexamethasone (DPd) and carfilzomib/dexamethasone (DKd) for patients with relapsed/refractory multiple myeloma (RRMM). However, high-risk cytogenetics in RRMM present a significant challenge in achieving deep and durable remission. We conducted a large multicenter retrospective study to analyze the efficacy of DPd vs DKd in RRMM patients with high-risk cytogenetics, treated in the real-world practice.

Methods: We evaluated all patients who had received either DPd or DKd for RRMM at multiple U.S. centers in collaboration with the US Myeloma Innovations Research Collaborative (USMIRC) between January 2015 and April 2024. High-risk cytogenetics were defined as the presence of one or more of the deletion 17p, t(14;16), t(4;14), t(14;20), or chromosome 1 abnormalities on FISH analysis at any point in time, including diagnosis and/or relapse prior to treatment. Doses and frequency of chemotherapy were adjusted for toxicities per the package insert and physician discretion. Using R Core Team (2024) software, a descriptive analysis was performed. Fisher's exact was used to analyze contingency tables. Wilcoxon rank-sum test was used to compare two independent samples. Responses were evaluated using IMWG criteria. Kaplan-Meier analyses were used to estimate progression-free (PFS) and overall survival (OS).

Results: A total of 117 patients with high-risk relapsed/refractory multiple myeloma (HR-RRMM) were included in the analysis; 81 (69%) patients received DPd, and 36 (31%) patients received DKd. The median age for the entire patient population was 66 years (range 41-85), 49 (42%) patients were female, 66 (56.4%) had IgG isotype, 55 (47%) had R-ISS stage III disease, and 40 (34%) patients had extramedullary disease (EMD). Both groups had a median of two prior lines of therapies (IQR 1-3). Patient and disease related characteristics in two groups appeared equally balanced except for more patients in the DKd group who were refractory to bortezomib, while the DPd group had more patients who were refractory to carfilzomib. A total of 29 (81%) patients in the DKd group were lenalidomide refractory compared to 69 (85%) in the DPd group; however, this difference was not statistically significant (p = 0.5). A total of 5 patients in the DKd group and 27 (33%) in the DPd were carfilzomib refractory (p = 0.029), while only two patients each (5.6% vs 2.5%, p= 0.6) in the DKd vs DPd groups had pomalidomide-refractory disease, respectively. In terms of prior treatment, both the DPd and DKd groups had received autologous stem cell transplantation, with 57 (70%) patients in the DPd group and 24 (67%) patients in the DKd group, respectively (p = 0.7). With a median follow up of 20 (1-77) months for the entire patient population, the overall response rates and very good partial response rates or better were 63% and 36% in the DPd group vs 62% and 34% in the DKd group, respectively (p = 0.5). Median PFS was 8.0 months (95% CI: 5.8-12) and 3.8 months (95% CI: 3.2-6.8) (p = 0.033) for the DPd and DKd groups, respectively. Similarly, median OS was 26 months (95% CI:17-34) and 19 months (95% CI: 9.3-NA) (p = 0.3) for DPd and DKd groups, respectively.

Conclusion: This study compares the effectiveness of DPd and DKd in a real-world setting, specifically focusing on HR-RRMM. The findings suggest that DPd shows an advantage in terms of PFS compared to DKd, especially for patients who may have prior exposure and refractoriness to carfilzomib. However, there was no significant difference in OS. The DPd regimen may be a favorable option in this subgroup, but it is important to have longer follow-up and more patient data.