Introduction: Despite treatment (tx) advances in multiple myeloma (MM), patients (pts) continue to face shortened survival compared with the general population, highlighting the persistent unmet need. Available therapies remain insufficient due to heterogenous population, prior exposure, disease biology, and increasing attrition with each line of therapy (LOT). In real-world practice, tx-limiting toxicities often result in discontinuation, even when disease progression is not evident. However, most data on tx discontinuation stem from clinical trials, with limited insights from the broader MM population. This study aims to assess reasons for and rates of tx discontinuation across LOT cohorts to better understand and address unmet needs of pts with MM.

Methods: This prospective, observational cohort study used data collected via the PREAMBLE registry (NCT01838512) to assess demographic and clinical characteristics, tx patterns, and rates and reasons for tx discontinuation in pts with MM. Pts were evaluated within overlapping LOT cohorts (first-line [1L]–fifth-line [5L]) from Jan 1, 2015, and followed until end of available data (Sep 5, 2024). Index was the start of therapy for each cohort. Index date was defined as initiation of therapy for each respective LOT cohort. Pts were included in a LOT cohort if the therapy continued beyond their enrolment in the study (LOTs captured prior to enrolment in retrospective chart review were not included). Those lacking date information for LOTs were excluded from the analysis. Outcomes were analysed using descriptive statistics.

Results: Of 1718 PREAMBLE pts included, 656 had prospective data for 1L; 905 2L; 663 3L; 451 4L; 240 5L. Median age across cohorts was ~70 y (SD, ~10). with a slightly higher proportion of male to female pts. Most pts were White (72–79%). Median follow-up ranged from 10.9 to 40.5 mo (1L, 40.5 mo [SD, 22.7]; 2L, 28.3 mo [SD, 20.9]; 3L, 17.8 mo [SD, 16.5]; 4L, 12.4 mo [SD, 15.6]; 5L, 10.9 mo [SD, 12.0]). Approximately 70% of pts were outside the US across 2L–5L, with an equal proportion from Europe and the US in 1L and enrolled from Jan 1, 2018. Most pts received autologous stem cell transplant during 1L–2L (16% 1L, 18% 2L). High-risk status (per R-ISS stage III and cytogenetic features) was similar across LOTs (18–23%).

Prior exposure to all main tx classes increased with LOTs (immunomodulatory drug [IMiD®] agents: 54% 2L, 99% 5L; proteasome inhibitors [PIs] 82% 2L, 98% 5L; anti-CD38 monoclonal antibodies (mAbs) 3% 2L, 40% 5L; alkylating agent-based therapies 43% 2L, 79% 5L). At index: IMiD agent + PI exposure was seen in 39% of pts who experienced 2L, 78% 3L, 90% 4L, 98% 5L; IMiD agent + anti-CD38 mAb in 2% 2L, 15% 3L, 26% 4L, 40% 5L; PI + anti-CD38 mAb in 2% 2L, 16% 3L, 28% 4L, 40% 5L. IMiD agent + PI + anti-CD38 mAb exposure was seen in 1% 2L, 14% 3L, 26% 4L, 40% 5L.

The top 3 most common index line regimens (± corticosteroids) were: 1L lenalidomide (LEN) + bortezomib (BORT) (RVd, 22%), BORT + cyclophosphamide (CyBorD, 18%), BORT (12%); 2L LEN (18%), daratumumab (DARA) + BORT (DVd, 8%), DARA + LEN (DRd, 7%); 3L LEN (11%), pomalidomide (POM) (8%), DVd (6%); 4L POM 10%, DARA (9%), carfilzomib (CFZ) (6%); 5L DARA (11%), POM (8%), CFZ (6%).

The proportion of pts discontinuing tx due to death or disease progression increased with later LOTs (12% of pts died on or after 1L, 23% on or after 5L; 9% discontinued at 1L due to disease progression, 24% at 5L). Across LOT cohorts, 5–9% discontinued due to toxicity. Fewer pts in later LOTs discontinued due to tx completion/maximum clinical benefit (1L: 23%/9%, 5L: 4%/5%). Tx discontinuation reasons remained undocumented in 29–39% of cases due to study completion/study discontinuation/loss to follow up.

Conclusions: Understanding reasons for tx discontinuation in pts with MM can offer valuable insights into pt burden and tx choices. The increasing prevalence of discontinuation due to death and progression across successive lines of therapy, along with the inability to complete tx, reflect a continued unmet need in these pts. Reasons for discontinuation observed in this study highlight ongoing challenges related to maintaining tx. These results emphasize the need for more tolerable and effective tx promoting sustained adherence and better long-term outcomes in MM. Ongoing research to understand how tx discontinuation impacts pt outcomes in the real world is warranted to improve outcomes and guide tx strategies.

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2025
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