Faculty Bibliography

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.

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.

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.

Functional high-risk (FHR) multiple myeloma (MM) is defined as an unexpected, early relapse (ER) of disease in the absence of baseline molecular or clinical risk factors (RF), making FHR MM inherently dependent on which RFs were assessed at diagnosis, but also on what treatment patients received. To establish the true incidence of FHR, we analysed uniformly treated, transplant-eligible (TE) patients from the UK NCRI Myeloma-XI trial that had been profiled for IMS/IMWG defined high-risk cytogenetic aberrations (HRCA) and the SKY92 gene expression HR signature (GEP-HR). 135 TE MyXI patients meeting these criteria were studied, with a median follow-up of 88 months. 25 patients (18.5%) experienced ER, defined as relapse <18 months from maintenance randomization post-autologous stem-cell transplantation. Hereof, 15 (60%) were classified as IMS/IMWG-HR at diagnosis, of whom 8 were also GEP-HR. Another 6 patients were GEP-HR only and would have been missed by IMS/IMWG-HR. Among 4 patients with both IMS/IMWG- & GEP-standard risk (SR), 2 had isolated HR markers at diagnosis, leaving only 2 patients (8% of ER; 1.5% of all) truly meeting all FHR criteria. The combination of IMS/IMWG-HR and GEP-HR profiling identified 84% of ER, and differentiated long-term outcome across all 135 patients: co-occurring IMS/IMWG-HR and GEP-HR was associated with very short overall survival compared to the absence of both (HR=13.1, 95%-CI: 6.5-26.1, P<0.0001), followed by GEP-HR only (HR=5.1, 95%-CI: 2.4-11.1, P<0.0001) and IMS/IMWG-HR only (HR=3.2, 95%-CI: 1.6-6.2, P=0.0007). Our results support more comprehensive baseline diagnostic profiling to identify those at risk of ER upfront. ISRCTN49407852, NCT01554852.

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.

We carried out a single-cell (sc) multiomic analysis on a series of MYD88 mutated Waldenström macroglobulinemia (WM) cases and identified two distinct subtypes of disease, memory B-cell-like (MBC-like) and plasma cell-like (PC-like), based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully towards a plasma cell (PC) and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the memory B-cell (MBC) stage, upregulates key MBC genes, and is characterized by upregulated BCR and AKT/mTOR signaling. In contrast, the PC-like subtype can partially differentiate towards a PC, upregulates key PC genes, has enhanced NF-kB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined scRNA-sequencing and scATAC-sequencing supports the variable differentiation capacity of each subtype and implicate key transcription factors SPI1, SPIB, BCL11A, and XBP1 in these features. The existence and generalizability of the two disease subtypes were validated further using hierarchical clustering of bulk RNA-seq data from a secondary set of cases. The biological significance of the subtypes was further established using whole genome sequencing, where it was shown that CXCR4, NIK, and ARID1A mutations occur predominantly in the MBC-like subtype and 6q deletions in the PC-like subtype. We conclude that the variable differentiation blockade seen in WM manifests itself clinically as two disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features with potential implications for WM treatment strategies.

Ionizing radiotherapy (RT) is a widely used treatment strategy for malignancies. In solid tumors, RT-induced double-strand breaks lead to the accumulation of indels, and their repair by non-homologous end-joining has been linked to the ID8 mutational signature in surviving cells. However, the extent of RT-induced mutagenesis in hematologic malignancies and its impact on their mutational profiles and interplay with commonly used chemotherapies has not yet been explored. Here, we interrogated 580 whole-genome sequence samples (WGS) from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet, ID8 was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum and melphalan). Using WGS of single-cell colonies derived from treated lymphoma cells, we revealed a dose-response relationship between RT and platinum and ID8. Finally, using ID8 as a genomic barcode we demonstrate that a single RT-surviving cell may seed distant relapse.

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.