Abstract
Introduction: For patients (pts) with multiple myeloma (MM) experiencing relapsed or refractory (RRMM) disease, several novel therapies are available, including the extensively studied anti-CD38 monoclonal antibodies (mAb) such as daratumumab (dara) and isatuximab (isa). Given their effectiveness in RRMM, anti-CD38 mAbs were studied in newly diagnosed MM and have subsequently become part of the standard-of-care in first-line (1L) MM treatment. Because of their ease of administration, favorable toxicity profile, and effectiveness, pts may receive dara/isa across many lines of therapy (LOTs) and in combination with various agents. However, effectiveness of these agents for an anti-CD38 mAb-naïve RRMM population compared to one with a prior anti-CD38 exposure has not been studied in the real-world. Our study assessed the effectiveness of dara/isa in combination with dexamethasone (d) and pomalidomide (P) or carfilzomib (K) among pts who were anti-CD38 naïve compared to those who had previously received dara or isa. We examined the characteristics, treatment patterns, and outcomes for the naïve and exposed populations receiving dara/isa-Kd and dara/isa-Pd.
Methods: This observational, retrospective, cohort study used COTA's real-world, electronic health records-based database. Adult pts diagnosed with RRMM who had one of the following treatment histories within 30 days of LOT start were eligible: received a triplet of interest (isa-Pd, dara-Pd, isa-Kd, or dara-Kd) with no prior anti-CD38 receipt OR received a triplet of interest with one prior anti-CD38 exposure but no prior exposure to the same index triplet OR received a doublet of interest (Pd or Kd) with one prior anti-CD38 exposure but no prior exposure to P or K, respectively. The index date was the date of initiation of the LOT containing the doublet/triplet of interest. Real-world time to next treatment (rwTTNT) was analyzed using the Kaplan-Meier (KM) method. We performed adjusted analyses using a multivariable binomial logistic regression model to estimate propensity scores and balance baseline variables through inverse probability of treatment weighting (IPTW) comparing the anti-CD38 naïve and exposed groups. The same methods were used to compare receipt of a triplet of interest to a doublet (Pd or Kd alone) among anti-CD38 exposed pts to determine the impact of re-exposure to anti-CD38 mAb. The following variables were used to estimate propensity scores: age at diagnosis, year of diagnosis, practice setting, CCI score, index LOT, P-refractoriness, K-refractoriness, cytogenetic high-risk status, bone marrow plasma cell percentage, prior exposure to stem cell transplant, 1q gain/amplification status, and ISS stage.
Results: There were 1,192 pts in the isa/dara-Pd group (n=895 anti-CD38 naïve; n=297 exposed), and 519 pts in the isa/dara-Kd group (n=342 naïve; n=177 exposed). There were not meaningful differences in age at diagnosis, sex, or race distributions between the naïve vs. exposed populations for either triplet group; however, pts who were previously anti-CD38 exposed were more often treated in the community for both the isa/dara-Pd (exposed: 72.7% & naïve: 50.6%; p < 0.001) and isa/dara-Kd groups (exposed: 66.7% & naïve: 56.1%; p = 0.026).
After adjusting for key characteristics, anti-CD38 naïve pts who received isa/dara-Pd experienced a longer median rwTTNT (14.4 months (mos) (95% CI: 12.4, 16.5)) compared to the exposed group (11.5 mos (95% CI: 8.7, 13.8); HR: 1.23 (95% CI: 1.02, 1.49); p=0.03) and anti-CD38 naïve pts who received isa/dara-Kd experienced a longer median rwTTNT (13.7 mos (95% CI: 10.9, 17.5)) compared to the exposed group (8.2 mos (95% CI: 5.5, 13.0); HR: 1.41 (95% CI: 1.05, 1.88); p=0.02). Within the anti-CD38-exposed cohort, the addition of the anti-CD38 mAb was not associated with significant improvements in rwTTNT with either triplet (dara/isa-Pd vs. Pd: HR: 0.79 (95% CI: 0.52, 1.2); p=0.27; dara/isa-Kd vs. Kd: HR: 0.83 (95% CI: 0.57, 1.21); p=0.34).
Conclusions: In this real-world analysis, pts who were anti-CD38 exposed and received dara/isa-P/Kd experienced shorter rwTTNT compared to anti-CD38 naïve patients, and re-exposure to anti-CD38 mAb did not offer superior outcomes to doublets lacking the anti-CD38 mAb. This highlights the need for additional research to assess the relative effectiveness of re-treatment with anti-CD38 mAb compared to alternative novel regimens in both early and late LOTs.
