Introduction: A growing number of patients (pts) with multiple myeloma (MM) receive anti-CD38 monoclonal antibodies (mAbs) in early treatment (tx) lines. Optimal strategies following early relapse after anti-CD38 mAb exposure remain unclear. Prior studies suggest that retreatment (retx) with daratumumab (DARA) may yield comparable progression-free survival (PFS) and overall survival (OS) even in pts with MM refractory to DARA (Abdallah AO, et al. Eur J Haematol 2023;110:626–632; Souren L, et al. Ann Hematol 2025;104:1059–1067; Girvan A, et al. Blood 2022;140[Suppl 1]:5266–5267).

This retrospective observational study using the Flatiron Health MM electronic health record database describes demographics, tx patterns, and outcomes in pts with relapsed/refractory MM (RRMM) who were retreated or not retreated with an anti-CD38 mAb in the second line (2L) or third line (3L).

Methods: Eligible pts were ≥18 y, diagnosed with RRMM, and received tx with an anti-CD38 mAb. The study period was from Jan 1, 2011–Dec 30, 2024. Pts receiving any 2L tx before the date of approval of DARA as first-line [1L] tx (May 7, 2018) were excluded.

Pts were included into 4 cohorts: pts eligible for inclusion in the 2L cohorts received an anti-CD38 mAb in 1L and were retreated (2R) or not retreated (2NR) in 2L with an anti-CD38 mAb, and pts eligible for inclusion in the 3L cohorts received an anti-CD38 mAb in 1L or 2L and were retreated (3R) or not retreated (3NR) in 3L with an anti-CD38 mAb. Index date was the start date of 2L (2R and 2NR cohorts) or 3L (3R and 3NR cohorts) tx. MM was considered refractory to an anti-CD38 mAb if pts experienced disease progression during tx or ≤60 days after the tx end date, whichever came first. Descriptive statistics were used to describe pt characteristics, and tx patterns. The Kaplan-Meier approach was used to evaluate median PFS (mPFS) and median OS (mOS).

Results: Overall, 1567 pts were included in the study: 451 in the 2R, 287 in the 2NR, 475 in the 3R, and 486 in the 3NR cohorts (cohorts were not mutually exclusive). Across all cohorts, pts had comparable baseline characteristics. More pts in the 3R (40.8%) and 3NR (42.4%) cohorts had ≥1 transplant prior to index compared with pts in the 2R (22.2%) and 2NR (34.8%) cohorts.

Tx exposures prior to index date were similar across cohorts, though pomalidomide exposure varied between the 3R (N=95, 20.0%) and 3NR (N=153, 31.5%) cohorts. More than 98% of pts had prior tx with DARA. In the 2R and 3R cohorts, 90.0% and 86.3%of pts were exposed for the 2nd time to an anti-CD38 mAb within <3 mo of their 1st exposure.

Anti-CD38 mAb refractory status prior to index was higher in the 3L vs 2L cohorts and in the cohorts who were not retreated (2NR [N=49, 17.1%] and 3NR cohort [N=140, 28.8%]) compared with the cohorts that were retreated (2R [N=67, 14.9%] and 3R [N=108, 22.7%]).

The mOS was not reached (NR) (95% CI, 46.1–NR) in the 2R and 33.9 mo (95% CI, 29.6–49.7) in the 2NR cohorts. mPFS was higher in the 2R (15.4 mo [95% CI, 11.9–21.5]) compared with the 2NR cohort (7.2 mo [95% CI, 5.7–9.0]). The 3L cohorts followed a similar pattern: mOS and mPFS were 52.3 mo (95% CI, 44.5–NR) and 10.1 mo (95% CI, 8.0–11.0), respectively, for the 3R cohort, compared with an mOS of 27.5 mo (95% CI, 24.1–32.4) and mPFS of 6.3 mo (95% CI, 5.3–7.1) for the 3NR cohort.

In pts with MM that was refractory to an anti-CD38 mAb, mPFS was higher in the 2R (5.7 mo [95% CI, 3.7–10.4]) and 3R (6.0 mo [95% CI, 4.3–10.6]) cohorts when compared with the 2NR (3.3 mo [95% CI, 2.2–5.4]) and 3NR (3.7 mo [95% CI, 2.8–5.3]) cohorts. In pts with MM that was not refractory to an anti-CD38 mAb, mPFS was 20.0 mo (95% CI, 13.3–31.1) in the 2R and 10.2 mo (95% CI, 8.6–12.1) in the 3R cohorts and also lower in the 2NR (8.4 mo [95% CI, 7.0–11.6]) and 3NR (7.5 mo [95% CI, 6.0–8.7]) cohorts.

Conclusions: Retx with an anti-CD38 mAb in 2L and 3L was associated with longer mOS and mPFS compared with no retx. Even though refractoriness to an anti-CD38 mAb was associated with a shorter mPFS, retx with an anti-CD38 mAb in pts with refractory MM was associated with longer mPFS compared with no retx. Prior exposure/refractoriness to DARA may not preclude benefit from retx. These findings support consideration of retx with anti-CD38 mAbs in select pts with RRMM and highlight the need for individualized tx strategies as anti-CD38 mAb exposure becomes more common in earlier tx lines.

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2025
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