Faculty Bibliography

BACKGROUND/UNASSIGNED:Frontline (1L) treatment for transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM) has shifted from triplet (e.g. bortezomib [V], lenalidomide [R], dexamethasone [d]) to quadruplet (e.g. daratumumab with VRd [DVRd]) regimens, based on improved efficacy demonstrated in pivotal trials. This real-world study compared progression-free survival (PFS) in TE patients with NDMM treated with DVRd plus DR or R maintenance (DVRd-DR/R) versus VRd plus R maintenance (VRd-R). METHODS/UNASSIGNED:Adult TE patients with NDMM who initiated DVRd-DR/R or VRd-R between 1 January 2020 and 30 June 2022 were identified through a retrospective chart review at 10 US sites. PFS was assessed using Kaplan-Meier analyses and propensity score-weighted hazard ratios (HR) were estimated using Cox regression. RESULTS/UNASSIGNED:= 0.006). CONCLUSION/UNASSIGNED:Findings aligned with pivotal trials, demonstrating the significant PFS benefit of 1L DVRd over VRd and supporting its real-world use for TE NDMM.

Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma (MM). To comprehensively investigate somatic drivers in relation to inherited genetics in MM, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing MM between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiological data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop MM at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes.

The H3K36me2 methyltransferase NSD2 is deleted in Wolf-Hirschhorn syndrome and aberrantly expressed in 10-15% of multiple myeloma (MM) due to a t(4;14) translocation. Although NSD2 is thought to be a primary driver in MM, the exact molecular mechanisms by which it regulates transcription remain unclear. We applied the dTAG system to acutely degrade NSD2 and used this, in combination with time-resolved SLAM-seq, to identify 307 transcriptional targets of NSD2. Reconstitution with either wild-type NSD2 or a catalytically inactive mutant (NSD2Y1179A) showed that NSD2's transcriptional effects are almost exclusively dependent on its SET domain activity. Mechanistically, H3K36me2 deposition by NSD2 antagonizes H3K27me3 levels, and treatment with two distinct PRC2 inhibitors demonstrated that approximately half of NSD2 target genes are regulated in an H3K27me3-dependent manner. CUT&Tag analysis showed that upon NSD2 depletion there was an increase in H3K27me3 that occurred at genome-wide intergenic regions, rather than at the promoters or gene bodies of NSD2 target genes. These data suggest that NSD2, via H3K36me2, antagonizes H3K27me3 deposition likely at distal regulatory elements including enhancers, creating a chromatin landscape favorable for target gene transcription. Importantly, NSD2 target genes were enriched for key oncogenic pathways, and 24 transcription factors implicated in neurodevelopment and acute leukemia, consistent with its role in Wolf-Hirschhorn syndrome and MM. Eight of these transcription factors are known oncogenic drivers in acute leukemia or MM, highlighting a novel molecular mechanism for NSD2's role in t(4;14) MM.

INTRODUCTION/BACKGROUND:Standardized incidence rates of multiple myeloma (MM) are higher among males than females, suggesting that male sex is an important risk factor for MM, which may affect disease etiology, pathogenesis, and clinical presentation. METHODS:The association of sex with the prevalence of clinical features and chromosomal abnormalities was evaluated among 850 patients with newly diagnosed MM enrolled in the Integrative Molecular And Genetic Epidemiology (IMAGE). Risk estimates were calculated using prevalence odds ratios (OR) and corresponding 95% CIs from logistic regression adjusted for confounders. RESULTS:Male patients with newly diagnosed MM by comparison with females, were more likely to have International Staging System stage III disease (odds ratio [OR] = 2.05; 95% CI, 1.22-3.46; p = .007), high serum monoclonal protein (≥3 g/dL; OR = 1.72; 95% CI, 1.15-2.56; p = .008), κ light chain disease (OR = 1.60; 95% CI, 1.11-2.30; p = .01), and more end-organ damage (OR = 1.24; 95% CI, 1.02-1.50; p = .03) including impaired renal function (OR = 1.71; 95% CI, 1.12-2.61; p = .01) and lytic lesions (OR = 1.97; 95% CI, 1.01-3.85; p = .05) and were less likely to have osteopenia (OR = 0.59; 95% CI, 0.36-0.98; p = .04) and light chain only disease (OR = 0.63; 95% CI, 0.41-0.95; p = .03) after adjusting for race, age, body mass index, education, income, smoking, and alcohol use. Significant interactions of age on the association of male sex with the prevalence of involved to uninvolved free light chain ratio ≥100 (p = .01) and any copy number abnormality (p = .04) were also observed. CONCLUSION/CONCLUSIONS:These novel findings suggest that male patients with newly diagnosed MM have a greater tumor burden.

OBJECTIVES/OBJECTIVE:To assess the effectiveness/safety of three proteasome inhibitors (PIs), plus lenalidomide-dexamethasone (Rd) triplet regimens, for the treatment of relapsed/refractory multiple myeloma (RRMM) in a real-world setting, using data from the observational INSIGHT-MM study (NCT02761187). METHODS:Adults with RRMM who received ixazomib, carfilzomib, or bortezomib plus Rd (IRd, KRd, or VRd, respectively) in the second or later line of therapy (LoT) were included. Patient characteristics, response to therapy (Kaplan-Meier analysis), and safety were reported descriptively. Multivariable Cox proportional hazards models were used to assess comparative effectiveness between regimens, whilst adjusting for cohort imbalances. RESULTS:Overall, 356 LoTs (IRd n = 181; KRd n = 96; VRd n = 79) from 348 patients were included. There was heterogeneity in patient characteristics between cohorts. Median real-world progression-free survival (rwPFS) for IRd, KRd, and VRd was 14.5, 13.2, and 9.1 months, respectively. After adjustment for baseline covariates, no significant differences in rwPFS were observed between regimens. All three regimens demonstrated a manageable safety profile. CONCLUSIONS:IRd, KRd, and VRd demonstrated comparable effectiveness and safety for the treatment of RRMM in a real-world setting, highlighting the need for a holistic evaluation of individual patients' needs and circumstances when selecting an appropriate PI. CLINICAL REGISTRATION/BACKGROUND:Clinical trial registration for the INSIGHT-MM study: NCT02761187; https://clinicaltrials.gov/study/NCT02761187.

Although obesity is an established modifiable risk factor for multiple myeloma (MM), the influence of obesity on survival among Black patients, for whom obesity and MM are more common, is less clear. We evaluated the association of body mass index (BMI) with progression free survival (PFS) and overall survival (OS) among 834 histologically confirmed cases with newly diagnosed MM (NDMM) enrolled in the Integrative Molecular And Genetic Epidemiology study between 2009 and 2020. We estimated the association of BMI with the risk of progressed disease and all-cause and MM-specific mortality using hazard ratios (HR) and corresponding 95% confidence intervals (CI) calculated from multivariable Cox proportional hazard models adjusted for prognostic factors, overall and stratified by self-reported race and sex. Compared to NDMM patients with normal BMI at diagnosis (18.5-24.9kg/m2), positive associations with all-cause mortality were observed at the extremes of diagnostic BMI with 52% and 147% increased risks of death in patients with underweight (BMI<18.5 kg/m2; HR=1.52, 95% CI 0.48-4.84) and obesity (BMI≥30.0 kg/m2; HR=2.47, 95% CI 1.26-4.85), respectively. Patients with severe obesity (BMI≥35kg/m2) had the highest risk compared to those with a normal BMI (HR=3.14, 95% CI 1.50-6.55), particularly among White (HR=3.22, 95% CI 1.30-7.94) and female (HR=4.17, 95% CI 1.20-14.47) patients with NDMM, albeit the differences by race and sex were not statistically significant (Pinteraction≥0.60). Severe obesity was also significantly associated with an 83% elevated risk of progressed disease among NDMM patients (HR=1.83, 95% CI 1.04-3.24). Findings were similar for MM-specific mortality. These findings highlight the importance of weight management as a potential strategy to improve the prognosis of all patients with NDMM.

Multiple myeloma evolution is characterized by the accumulation of genomic drivers over time. To unravel this timeline and its impact on clinical outcomes, we analyzed 421 whole-genome sequences from 382 patients. Using clock-like mutational signatures, we estimated a time lag of two to four decades between the initiation of events and diagnosis. We demonstrate that odd-numbered chromosome trisomies in patients with hyperdiploidy can be acquired simultaneously with other chromosomal gains (for example, 1q gain). We show that hyperdiploidy is acquired after immunoglobulin heavy chain translocation when both events co-occur. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra copy), but fared worse than those with late 1q gain. This finding underscores that the 1q gain prognostic impact depends more on the timing of acquisition than on the number of copies gained. Overall, this study contributes to a better understanding of the life history of myeloma and may have prognostic implications.