Background Outcomes for patients (pts) with transplant-ineligible newly diagnosed multiple myeloma (TI-NDMM) have improved with the introduction of anti-CD38 monoclonal antibodies (mAbs) and quadruplet regimens (proteosome inhibitors, immunomodulatory drugs, anti-CD38 mAbs, and dexamethasone). Outcomes in frail TI-NDMM pts, however, remain poor. These differences are driven by advanced age, comorbidities, increased infection rates, treatment toxicity, and therapy discontinuation among frail versus fit individuals. Several tools have been developed to assess frailty, yet operationalizing in practice remains challenging. This study estimates the proportion of the TI-NDMM population that is elderly or frail and evaluates real-world (RW) outcomes among those receiving standard of care (SoC) regimens (bortezomib-lenalidomide-dexamethasone [VRd], daratumumab-lenalidomide-dexamethasone [DRd], or daratumumab-bortezomib-lenalidomide-dexamethasone [DVRd]).

Methods This retrospective observational study used the COTA Vantage MM database, a US-based oncology electronic health record (EHR) database (cotahealthcare.com/data-services/). Included pts were diagnosed with MM and initiated treatment between January 1, 2018, and April 30, 2023, within 120 days of diagnosis. To mimic a TI-NDMM population, pts with any record of transplant or melphalan use were excluded. Index date was defined as the date of initiation of SoC. Pt demographics, clinical characteristics, and RW outcomes were assessed.

Where possible, a simplified frailty score (Facon et al., 2019) based on Eastern Cooperative Oncology Group Performance Status/Karnofsky Performance Status, age, and Charlson Comorbidity Index was calculated; high-risk cytogenetics based on t(4;14), t(14;16), t(14;20), del(17p), del(1p), and TP53 deletions/mutations were assessed. For both, a window of 180 days prior to 30 days after index was used.

Time-to-event outcomes were estimated using unadjusted Kaplan-Meier methods. RW progression-free survival (PFS) was defined as the time from first-line (1L) initiation to the earliest of International Myeloma Working Group-based progression, physician-reported progression, or death; censoring occurred at the earliest of second-line (2L) start, diagnosis of a secondary cancer, last activity date + 365 days, or the administrative end of follow up (July 1, 2024).

Results A total of 645 pts were considered transplant-ineligible, with a median follow-up of 31.8 (IQR: 19.0, 51.9) months (mo). Of these pts, 553 (86%), 68 (11%), and 24 (4%) initiated VRd, DRd, and DVRd, respectively. Over half (n=383 [59%]) were elderly (70+ years), 312 (48%) were female, 371 (58%) were White, and 544 (84%) were abstracted into the COTA provider network from a community site. A simplified frailty score could be calculated for 394 (61%) pts, of which 88 (22%), 111 (28%), and 195 (49%) were fit (0), intermediate (1), and frail (2+), respectively. A high-risk cytogenetic test was performed in 456 (71%) pts at the time of treatment initiation, of which 134 (29%) had a positive test.

In the PFS analysis, 243 pts progressed or died before the start of 2L treatment and 402 were censored. Toxicity was listed as the reason for discontinuation for 142 (22%) pts, of which 32 went on to have an event. Unadjusted median PFS (95% CI) was 37.9 (30.7–52.5) mo. In subgroup analyses, elderly and frail pts generally had shorter median PFS relative to younger and less frail pts, however, these differences were not statistically significant. Too few pts received DRd and DVRd for meaningful analyses by regimen, however, the VRd group had a slightly shorter median PFS relative to the overall population.

The validity of these outcomes may be limited by the difficulty in capturing RW disease progression in pts. Furthermore, RW algorithms for determining lines of therapy rely on clinical guidelines and knowledge of EHR data nuance, rather than being based on empirical evidence. Lastly, our definition of transplant ineligibility may include those who are either transplant non-intended or transplant deferred.

Discussion Our unadjusted results suggest that elderly and frail pts have numerically lower PFS with current SoC regimens for TI-NDMM in RW settings. These results will be further examined in adjusted analyses. At the same time, these pts are largely excluded from randomized controlled trials with new innovative treatment regimens. Unmet medical need in this pt population remains high.

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2025
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