Real-World Evaluation of Outcomes in Relapsed/Refractory Multiple Myeloma Patients That Are Triple-Class Exposed after Receiving 2 or More Prior Lines of Therapy

Background: Recent studies have shown that a majority of multiple myeloma (MM) patients (pts) in the United States (US) are triple-class exposed (TCE) after four lines of therapy (LOT), with poor prognosis for TCE patients. As treatment for MM evolves to include more advanced triplet and quadruplet regimens, a growing number of US pts are likely to reach TCE status in earlier lines of treatment. Therefore, we sought to evaluate the frequency of pts reaching TCE status after receiving two or more prior LOT (3L+) and their associated clinical outcomes.

Methods: This retrospective study used de-identified health records from the ConcertAI Patient360 MM EMR database, which consists primarily of data from community-based oncology centers in the US. The primary objective was to compare real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) between 3L+ pts with TCE status to those without TCE status. TCE was defined as exposure to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Eligibility criteria included adult subjects (age ≥ 18) diagnosed with MM between January 1, 2011 and September 30, 2022, who received at least one line of therapy post-diagnosis, did not undergo stem cell transplantation prior to treatment, did not have any other primary cancer diagnosis at baseline (1 year prior to initial diagnosis), and initiated 3L therapy from January 1, 2017, to September 30, 2022. Progression-based LOT was defined using ConcertAI's proprietary regimen-based LOT, modified to advance to a new line only after discontinuation of at least 1 year or a progression event. rwPFS and rwOS by were calculated via Kaplan-Meier method, with differences evaluated using the log-rank test. Pts without physician-documented progression or survival events were censored at the subsequent LOT or latest follow-up for PFS and were censored at the latest follow-up for OS.

Results: Overall, 557 pts meeting eligibility criteria initiated 3L therapy in 2017 and beyond were included in the analysis. Of these, 297 had 3 LOT, 146 had 4 LOT, and 114 had ≥ 5 LOT. Median age at diagnosis was 67.0 years (y), 48.1% were female, and 37.3% had transplant post-diagnosis. Most frequently, ECOG status was 1 (30%), eGFR ≥ 60 (40%) and R-ISS stage 3 disease at diagnosis (29%) with 27%, 28% and 34% of data not available, respectively. Median (range) follow-up for survivors from diagnosis was 63 (10 – 141) months. Most pts were treated at community-based centers (78.3%), located in the Southern US region (53.9%), with 74.0%, 20.3%, and 4.3% white, black and Hispanic pts represented, respectively. Overall, 429 (77%) pts were TCE: 32% were TCE prior to 3L initiation, 63% prior to 4L, and 74% prior to 5L. Among TCE pts, the percentage reaching TCE status within 1L, 2L, 3L, 4L, and 5L+ of therapy was 4%, 39%, 40%, 14%, and 3%, respectively. TCE pts were frequently retreated with agents, even after prior refractory status (Figure A). Median (95% CI, Events n/N) rwPFS in 3L+ was 5.7 (5.2 – 6.4 mo, 358/464) in TCE pts vs 9.8 (8.5 – 11.8 mo, 337/498) in non-TCE pts (p<0.001). Median (95% CI, Events n/N) rwOS from time of 3L initiation was 15.9 (11.3 – 19.2 mo, 106/179) in TCE pts vs 31.5 (27.3 – 43.1 mo, 168/340) in non-TCE pts (p<0.001). Median rwPFS and rwOS were consistently lower in TCE vs non-TCE pts across 3 - 5 LOT (Figure B).

Conclusion: In this real-world cohort from predominantly community-based US oncology centers, approximately 80% of patients were TCE, with 83% reaching TCE status within 3 LOT. TCE pts experienced inferior rwPFS and rwOS compared with non-TCE pts. The inferior survival outcomes and frequent re-exposure to previously used agents after TCE status underscore the need to understand optimal sequencing of anti-myeloma agents, particularly given the advancements in modern immunotherapies.