Real-world treatment patterns and outcomes in frail and non-frail patients with newly diagnosed multiple myeloma not undergoing frontline transplant: A study using cota oncology database

Abstract Background: Multiple myeloma (MM) is commonly diagnosed at older age, when concerns about treatment tolerability often limit the use of highly efficacious therapies like stem cell transplant (SCT) or intensive multi-drug regimens. Frail patients who are unsuitable for SCT are particularly vulnerable, yet limited real-world data exists on their treatment utilization and outcomes. This study compared frontline treatment patterns and outcomes in frail and non-frail newly diagnosed MM (NDMM) patients who did not receive SCT in the real-world setting. Methods: We identified adults with NDMM who did not receive frontline (1L) SCT from the COTA oncology electronic health record database (January 1st, 2016 to July 31st, 2024). Frail patients were defined by the simplified International Myeloma Working Group (sIMWG) frailty score ≥2, based on age, ECOG performance status, and comorbidities. These patients were matched 1:1 with non-frail patients based on propensity score, which were estimated using sex, race, ethnicity, index year, high-risk cytogenetics, CRAB symptoms (excluding bone lesions), practice setting, IgG, measurable disease, and BMI category. Regimens used in 1L were descriptively summarized and real-world outcomes including progression-free survival (rwPFS) and overall survival (rwOS) were compared between frail patients and matched non-frail controls using Kaplan-Meier analysis. Results: Out of 1,622 NDMM patients who did not receive 1L SCT, 608 (37.5%) had a frailty score≥2 and 1,014 (62.5%) had a frailty score <2. The mean age was 77.1 compared to 65.3 years for non-frail patients. Among frail patients, 38.8% had ECOG PS ≥2 and 38.5% had a Charlson comorbidity index (CCI) ≥3. After matching, the cohorts included 601 frail patients and 601 non-frail controls. The mean (standard deviation [SD]) age was 77.1 (8.9) vs 65.5 (9.2) for the matched frail and non-frail cohorts, respectively. As age, ECOG, and CCI were used to defined frailty and hence not matched, 39.1% frail patients had ECOG PS ≥2 and 38.6% had CCI ≥3, while none of the non-frail patients had ECOG PS ≥2 or CCI ≥3. There were no significant differences in the matching covariates. Bortezomib-lenalidomide-dexamethasone (VRd) was the most used regimen in both frail and matched non-frail controls (32.4% vs 47.3%, p<0.001), followed by bortezomib-cyclophosphamide-dexamethasone (VCd) (16.3% vs 18.1%, p=0.408). Frail patients showed higher use of doublets such as Vd (16.1% vs 8.8%, p<0.001) and Rd (13.1% vs 4.2%, p<0.001). Overall, the utilization of triplets comprised of 64.2% in frail patients and 78.9% in non-frail patients (p<0.001). Quadruplets were used by 4.3% and 7.7% of patients in frail and non-frail cohorts, respectively (p=0.009). The median follow-up duration was 30.8 months for frail and 42.1 months for the matched non-frail cohorts (p<0.001). Frail patients experienced a higher risk of disease progression, with 2-year rwPFS rates (95% confidence interval [CI]) of 54% (49-58%) versus 58% (54-62%) for non-frail patients. Median rwPFS was 29 months for frail patients and 35 months for non-frail patients (p=0.520). Median rwOS was significantly shorter in frail patients, 39 months compared to 76 months in non-frail patients (p=<0.01). The 5-year rwOS rates (95% CI) being 34% (29-38%) for frail patients and 59% (55-64%) for non-frail patients. Conclusions: Over a third of non-transplant NDMM patients met the frailty criteria by the sIMWG categorization. The overall utilization of quadruplets was low in both frail and non-frail patients during the study period, because quadruplets containing anti-CD38 agents became available only after 2024. Our findings suggest a reluctance to use NCCN preferred triplets (VRd and DRd) upfront in frail patients, potentially due to tolerability concerns. While the risk of disease progression did not significantly differ, frail patients experienced substantially higher mortality, likely attributed to older age, poorer health status, and challenges in receiving optimal treatment. Given evolving treatment landscape in MM, recent studies suggest that frail patients treated with quadruple regimens can achieve comparable clinical benefits to non-frail patients without increased adverse events. Future studies are warranted to further evaluate the effectiveness and safety outcomes in this vulnerable population with substantial unmet needs.