Introduction: While multiple myeloma (MM) remains incurable, proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and novel therapies like CAR-T have improved overall survival (OS). Lenalidomide (Len) is commonly used in first line (1L) therapy, leading to a population of patients (pts) who are Len-refractory as early as the second line of therapy (LoT). Bortezomib (Bor) is also widely used, and daratumumab (Dara) is increasingly being incorporated into 1L. Optimal treatment strategies in 2L+ remain unclear. This real-world (RW) study was conducted to characterize demographic and clinical characteristics, treatment patterns, and clinical outcomes in Len-exposed pts with RRMM who received 1–3 prior LoT. Multiple data sources (COTA for US; IQVIA Oncology Dynamics for 5 European countries [IQVIA]) were considered to assess treatment patterns.

Methods: This retrospective cohort study used the COTA electronic health record database, last abstracted in May 2025, representing pts from diverse treatment settings in the US. Adults with RRMM who received 1–3 prior LoT, including ≥1 line of a Len-containing regimen, were included. The index date was the start of each LoT of interest (ie, 2L, 3L, or 4L), post-Len exposure on or after Jun 2006. Sensitivity analysis, restricting the index date to postdate Nov 2015 (approval for Dara), was performed. Demographics, clinical characteristics, and index treatment regimens were summarized descriptively. RW progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Response rates were based on COTA's International Myeloma Working Group algorithm. For treatment patterns in IQVIA, regimens were reported by patient counts and percentages.

Results: Overall, 2535 pts with Len-exposed RRMM who initiated next line therapy were identified. Pts were stratified by mutually exclusive cohorts: 1270 (50%), 876 (35%), and 389 (15%) pts in 2L, 3L, and 4L, respectively. Overall, the mean age (range) at index date was 67 (28–95) years; 13% were Black/African American; 62% were from community sites; 62% had an Eastern Cooperative Oncology Group performance status score ≤2 (36% missing); and 21%, 28%, 24%, and 27% were International Staging System stage I, II, III, or missing, respectively. At index date, 1927 (76%) pts were Len-refractory, and 255 (10%) and 132 (5%) had prior exposure to Dara and pomalidomide (Pom), respectively. Median follow-up time for 2L, 3L, and 4L pts was 66.1, 65.4, and 64.9 months, respectively.

Almost 50 regimens for RRMM included in US-based clinical practice guidelines were observed and the proportions of all regimens within each line and across 2L–4L were all <10%. Among pts with a known reason for discontinuation of the last regimen (n=1817), 55%, 22%, and 10% discontinued due to disease progression, toxicity, or doctor preference, respectively. Median PFS (95% CI) in months decreased with LoT (2L: 10.9 [9.5–12.2]; 3L: 8.1[7.0–9.7]; 4L: 7.3 [6.5–8.1]), as did OS in months (2L: 46.0 [42.4–49.7]; 3L: 36.4 [32.8–40.9]; 4L: 27.3 [23.7–31.7]). Overall response rates were 32%, 29%, and 30% for 2L, 3L, and 4L pts, with 41%, 42%, and 42% having insufficient lab data to determine response status, respectively; across 2L–4L, complete responses were observed in <1% pts.

Sensitivity analysis of RW PFS and OS among pts who initiated 2L+ therapy after Nov 2015 showed approximately similar results to the primary analysis, also with shorter median PFS and OS observed with each subsequent LoT received. When restricting the data from 2020–2025 (n=461), Dara-containing triplets were the most common index regimens in 2L: Dara+Pom+dexamethasone (dex) [DPd, 21%], Dara+Len+dex [DRd, 12%], Dara+carfilzomib+dex [DKd, 11%], and Dara+Bor+dex [DVd, 9%]. For 2L MM pts in IQVIA from 2021−2024, only 3 regimens were utilized in >10% of pts: Rd (19%), DRd (19%), and DVd (12%).

Conclusions: These RW data reveal a highly fragmented treatment landscape for Len-exposed pts with RRMM who have received 1–3 prior LoT in the US. This fragmentation was similarly observed in RW data from IQVIA and will be presented at a future conference. Despite the abundance of treatment options, suboptimal outcomes are consistently observed across LoT. Clinical research to advance novel therapies and improve effectiveness, safety, and treatment accessibility in the RW is warranted to address the significant prevailing unmet needs.

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2025
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