Faculty Bibliography

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.

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.

TOURMALINE-MM3 (NCT02181413) and -MM4 (NCT02312258) were phase 3 studies of fixed-duration, single-agent ixazomib maintenance in post-transplant (TOURMALINE-MM3)/transplant-ineligible (TOURMALINE-MM4) patients with newly diagnosed multiple myeloma (NDMM) that demonstrated improved median progression-free survival (PFS) for ixazomib vs placebo. We present the final overall survival (OS) analyses for each study separately. In both studies, eligible patients were randomized 3:2 to receive ixazomib maintenance (3 mg [cycles 1-4], 4 mg [from cycle 5 if tolerated]) or matching placebo for ≤26 cycles, or until progressive disease/unacceptable toxicity. At median follow-up of approximately 8 years (TOURMALINE-MM3) and 5 years (TOURMALINE-MM4), median OS was not reached in either arm in MM3 (hazard ratio [HR], 1.025; 95% confidence interval [CI], 0.789-1.332; p = 0.850), and was 64.8 (ixazomib) vs 69.5 (placebo) months in MM4 (HR, 1.090; 95% CI, 0.861-1.381; p = 0.473). No new safety signals were identified in either study; incidence of new primary malignancies was low. Despite meeting their primary endpoints (PFS), neither final OS analysis of TOURMALINE-MM3/-MM4 showed statistically significant differences between fixed-duration ixazomib maintenance and placebo in patients with NDMM. The growing number of available, highly effective salvage treatments with novel mechanisms of action make demonstrating an OS advantage in front-line myeloma studies increasingly challenging.

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify malignant transformation in MGUS and SMM. We introduce the concept of genomic MM and genomic MGUS to differentiate the subsets of MGUS and SMM that are biologically malignant with genomic features indistinguishable from MM from the subset that is premalignant and unlikely to progress to malignancy. Importantly, we find that most SMM has biological features of malignant transformation indistinguishable from MM. As expected, this subset that we consider having genomic MM is associated with a high risk of progression to MM although some patients remained progression-free beyond 5 years. Conversely, 60% of MGUS and 10% of SMM have no evidence of malignant transformation (genomic MGUS), with no progression during follow-up. Integration of genomic features with the 2/20/20 International Myeloma Working Group model significantly improved the prediction of progression among genomic MM. These findings support the use of genomic criteria to refine the classification and the risk stratification in myeloma precursor conditions.

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.