Cleaves, Travis

Abstract Background: Treatment of multiple myeloma (MM) has advanced dramatically over the past decade with median overall survival (OS) for newly diagnosed MM patients (pts) now exceeding 10 years. However, outcomes in pts with high-risk disease remain poor. While most pts with high-risk disease are identified through baseline cytogenetic risk stratification, presence of extramedullary disease, or R-ISS stage, there is also a population of pts who may or may not have these traditional high-risk factors who relapse earlier than expected and have similarly poor outcomes. These pts are often delineated as “functional high-risk,” but a standardized definition of this population in the era of modern myeloma therapy is lacking. Methods: Using the ASH Research Collaborative (ASH RC) Data Hub, we retrospectively searched 7,249 pts across 10 participating institutions for those with newly diagnosed multiple myeloma (NDMM) treated with a triplet or quadruplet induction regimen (with or without autologous stem cell transplant) who had response data available. We evaluated duration of response from first line therapy (PD1) on post-PD1 clinical outcomes such as: time to next treatment (TTNT), time to subsequent progression and/or death (PFS2), and OS. We also analyzed characteristics of those who did vs. did not progress at prespecified time points of interest (12-, 18-, 24-, and 36-months) from the start of induction. We utilized recursive partitioning analyses to iteratively explore all possible cutpoints and identify which one(s) provide the greatest differentiation in the risk of subsequent progression and/or death. Results: We identified 1,305 pts who met the eligibility criteria. Of these, 264 had PD1 data including 201 who had response follow-up (f/u) after PD1. Median f/u after PD1 in this population was 3.2 years, and median PFS2 f/u after PD1 (n=201) was 4.4 years. Months to PD1 was significantly associated with PFS2 (p=0.038). All prespecified time points examined showed inferior PFS2 compared to those with PD1 >36 mos, although each subgroup was not statistically significant, likely due to limited numbers in each group: PD1 <12 mos HR=1.44 (n=43; 95% CI: 0.90 – 2.30; p=0.126), PD1 12-24 mos HR=1.65 (n=30; 95% CI: 0.95 – 2.85; p=0.073), and PD1 24-36 mos HR=1.58 (n=52; 95% CI: 0.98 – 2.53; p=0.059). Similarly, timing of PD1 was also associated with OS post-PD1; pts with PD1 <12 mos had significantly lower OS compared to those with PD1 >36 mos (HR=2.35, 95% CI: 1.27 – 4.32; p=0.006). Our recursive partitioning analysis identified 30-months at the cutoff that produced the greatest differential in outcomes between those above vs. below the landmark. Approximately 23% of the pts analyzed had PD1 within 30 mos, and these pts had significantly lower OS compared to those with PD1 ≥30 mos (HR=1.99, 95% CI: 1.21 – 3.27; p=0.006). Similarly, pts who progressed within 30 mos of starting 1L therapy (n=98) had significantly shorter PFS2 (median=12.5 mos vs 22.8 mos; HR=1.55, 95% CI: 1.09 – 2.20; p=0.014) than those who did not (n=103). Those pts who progressed within 30 mos were more likely to have a higher R-ISS stage at diagnosis (p=0.048), but were not more likely to have high-risk cytogenetics (p=0.66) compared to pts with PD1 ≥30 mos. Interestingly, receiving SCT as part of 1L therapy was not significantly associated with improved PFS2 (HR=0.89, 95% CI: 0.62 – 1.29; 0.54) but was significantly associated with improved OS (HR=0.53, 95% CI: 0.31 – 0.90; 0.018) by univariate analysis. Conclusion: Our study is the first to use a large, multicenter, cohort to evaluate the definition of functional high-risk MM in the era of novel induction therapies. Our data suggest that pts who progress within 30 mos of induction on triplet or quadruplet regimens (irrespective of whether they underwent stem cell transplant) have poorer outcomes than those who progress at 30 mos or later, and that progression prior to 30 mos represents functional high-risk disease. These pts represent a clear unmet medical need, and additional focus should be taken to identify them early with the goal of designing trials to optimize their subsequent therapies.

Abstract Introduction: While the incidence of multiple myeloma (MM) is 2-3 fold higher in Black compared to white individuals, the impact of racial differences on treatment outcomes remains unclear due to the confounding effect of socioeconomic barriers and disparities in access to effective therapies and clinical trials. In this study, we explored the relationship between race, social deprivation, and outcomes in newly diagnosed MM (NDMM) patients (pts) receiving modern therapies with triplet or quadruplet regimens. Methods: Pts with NDMM diagnosis, who received first line treatment between 2015-2025, and had data available on response and survival outcomes were identified through the ASH Research Collaborative MM Data Hub (a real-world database with pts across 11 U.S. institutions). Data on patient demographics (age, race, ethnicity, sex), disease risk status (ISS/R-ISS stage, FISH cytogenetics), treatment regimens (triplet vs quadruplet, anti CD38 monoclonal antibody-based vs not), and disparity measures were abstracted from electronic medical records. Race and ethnicity were self-reported by pts. Social Deprivation Index (SDI) score was calculated based on ZIP code, where higher scores reflect greater deprivation. Progression free survival (PFS) was defined as time from start of treatment until progression or death. Overall survival (OS) was defined as time from start of treatment until death from any cause. Kaplan-Meier methods were used to compare PFS and OS between groups, and cox regression models with log-rank tests were used to evaluate the influence of various factors on outcomes. Results: A total of 1,743 patients were identified; 1,116 (63.8%) identified as non-Hispanic White (NHW) and 402 (23.3%) as non-Hispanic Black (NHB) [note: 85 pts (4.9%) were Hispanic but not included due to limited numbers]. The median age (years) at the start of treatment (61.8 vs. 65.6) was lower for NHB compared to NHW pts (p<0.001). The proportion of females was greater in NHBthan NHW pts(53.5% vs. 41.1%, p=0.0016). Median SDI scores were significantly higher for NHBcompared to NHW pts (68.4 vs. 39.4; respectively; p<0.001), reflecting significantly higher rates of social deprivation. While NHB ptshad higher rates of advanced stage disease (ISS III 26.9% vs. 20.9%, p=0.009), lower rates of autologous stem cell transplant (ASCT) (56.7% vs. 63.6%, p=0.014), and longer median time from treatment initiation to ASCT (6.5 vs. 5.9 months, p=0.043), the rates of standard risk cytogenetics on FISH (72.3% vs. 77.6%), and utilization of CD38 monoclonal antibody-based regimen (29.9% vs. 27.7%) were similar between the two groups. Best response after treatment initiation was similar between the NHB and NHW pts (p=0.12) with complete response 45.7% vs. 52.6% and very good partial response 37.3% vs 34.7%; respectively. However, time to best response (months) was longer in NHB pts (7.2 vs. 6.5, p=0.005). Median follow-up for OS was 4.2 years (95% CI 3.9-4.4; 182 OS events) and for PFS was 1.3 years (95% CI: 1.1-1.6; 302 PFS events) across the two groups. Unadjusted PFS was similar for NHB vs NHW pts (HR=1.05, 95% CI: 0.81- 1.36; median: 5.0 vs 4.9 years; 3-year PFS: 66% vs. 71%). Similarly, unadjusted OS was not significantly different in NHB vs NHW pts (HR=1.12, 95% CI: 0.79-1.59; 5-year OS: 86.4% vs 85.6%). Higher SDI scores were significantly associated with worse OS (HR=1.07, 95% CI: 1.02-1.12; p=0.0065) but not PFS (HR=0.99, 95% CI: 0.95-1.02; p=0.46). Though not statistically significant, univariate analyses indicated a greater impact of high SDI scores (≥70, 75th percentile across all pts) in NHW (HR=1.45, p=0.068) than in NHB pts (HR=0.78, p=0.35) for OS. Adjusting for age, sex, ISS stage, and SDI, NHB did not appear to have worse OS (HR=0.75, 95% CI: 0.35-1.60; p=0.46) or PFS (HR=1.23, 95% CI: 0.78-1.96; p=0.37) compared to NHW pts. Conclusions: Our study represents a diverse population enriched for pts who received modern day standard of care frontline therapies including triplet and quadruplet regimens with or without ASCT. Based on SDI scores, higher social deprivation levels were seen in NHB compared to NHW pts without a difference in outcomes between the two races. Our analysis supports that higher social deprivation among different races rather than race and ethnicity alone may drive differential outcomes and adjustment for factors like SDI is critical to interpretation of survival outcomes by race.