Faculty Bibliography

BACKGROUND:Infections are a common reason for hospitalization and death in multiple myeloma (MM). Although pneumococcal vaccination (PV) and influenza vaccination (FV) are recommended for MM patients, data on vaccination status and outcomes are limited in MM. MATERIALS AND METHODS/METHODS:We utilized data from the global, prospective, observational INSIGHT MM study to analyze FV and PV rates and associated outcomes of patients with MM enrolled 2016-2019. RESULTS:Of the 4307 patients enrolled, 2543 and 2500 had study-entry data on FV and PV status. Overall vaccination rates were low (FV 39.6%, PV 30.2%) and varied by region. On separate multivariable analyses of overall survival (OS) by Cox model, FV in the prior 2 years and PV in the prior 5 years impacted OS (vs. no vaccination; FV: HR, 0.73; 95% CI, 0.60-0.90; P = .003; PV: HR, 0.51; 95% CI, 0.42-0.63; P < .0001) when adjusted for age, region, performance status, disease stage, cytogenetics at diagnosis, MM symptoms, disease status, time since diagnosis, and prior transplant. Proportions of deaths due to infections were lower among vaccinated versus non-vaccinated patients (FV: 9.8% vs. 15.3%, P = .142; PV: 9.9% vs. 18.0%, P = .032). Patients with FV had generally lower health resource utilization (HRU) versus patients without FV; patients with PV had higher or similar HRU versus patients without PV. CONCLUSION/CONCLUSIONS:Vaccination is important in MM and should be encouraged. Vaccination status should be recorded in prospective clinical trials as it may affect survival. This trial was registered at www. CLINICALTRIALS/RESULTS:gov as #NCT02761187.

PURPOSE/OBJECTIVE:Molibresib is a selective, small molecule inhibitor of the BET protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851). EXPERIMENTAL DESIGN/METHODS:Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR). RESULTS:There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg QD (for MDS) and 60 mg QD (for CTCL) were selected. Most common Grade 3+ AEs included thrombocytopenia (37%), anemia (15%) and febrile neutropenia (15%). Six patients achieved complete responses (three in Part 1 [two AML, one NHL], three in Part 2 [MDS]), and seven patients achieved partial responses (six in Part 1 [four AML, two NHL], one in Part 2 [MDS]). The ORRs for Part 1, Part 2, and the total study population were 10% (95% CI: 4.8-18.7), 25% (95% CI: 7.3-52.4), and 13% (95% CI: 6.9-20.6), respectively. CONCLUSIONS:While anti-tumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.

Early alterations within the bone marrow microenvironment that contribute to the progression of multiple myeloma (MM) from its precursor stages could hold the key to identifying novel therapeutic approaches, yet the intrinsic variability in cellular populations between patients together with differences in sample processing and analysis methods have made it difficult to identify consistent changes between datasets. Here, we used single-cell RNA sequencing of BM cells from precursor stages, monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM) and newly diagnosed MM and analyzed our data in combination with a previously published dataset that used a similar patient population and sample processing. Despite vast interpatient heterogeneity, some alterations were seen consistently in both datasets. We identified changes in immune cell populations as disease progressed that were characterized by a substantial decrease in memory and naïve CD4 T cells and an increase in CD8+ effector T cells and T-regulatory cells. These alterations were further accompanied by an enrichment of non-clonal memory B cells and an increase of CD14 and CD16 monocytes in MM compared to its precursor stages. These results provide crucial information of the immune changes associated with the progression to clinical MM and can help to develop immune based strategies for patient stratification and early therapeutic intervention.

IgD myeloma is a subtype often considered to have adverse features and inferior survival but there is a paucity of data from large clinical studies. We compare the clinical characteristics and outcomes of IgD myeloma patients from UK Phase III myeloma trials analysed in two groups; old (1980-2002) and recent (2002-2016) clinical trials, based on the time of adoption of novel myeloma therapies. IgD myeloma patients comprised 44/2789 (1.6%) and 70/5773 (1.2%) of the old and recent trials respectively. Overall, IgD myeloma was associated with male predominance, low-level paraproteinemia (<10g/l) and lambda light chain preference. The frequency of ultra-high risk cytogenetics was similar in IgD myeloma compared with other subtypes (4.3% vs 5.3%, p>0.99). Despite the old trial series being a younger group (median age: 59 years vs 63 years, p=0.015), there was a higher frequency of bone lesions, advanced stage at diagnosis, worse performance status and severe renal impairment compared with the recent trials. Furthermore, the early mortality rate was significantly higher for the old trial series (20% vs 4%, p=0.01). The overall response rate following induction therapy was significantly higher in the recent trials (89% vs 43%, p<0.0001) and this was consistent with improved median overall survival (48 months; 95% CI 35-67 months vs 22 months, 95% CI 16-29 months). Survival outcomes for IgD myeloma have significantly improved and are now comparable to other myeloma types due to earlier diagnosis, novel therapies and improved supportive care. (Myeloma IX International Standard Randomised Controlled Trial Number: 68454111, Myeloma XI International Standard Randomised Controlled Trial Number: 49407852).

Deciphering Multiple Myeloma evolution in the whole bone marrow is key to inform curative strategies. Here, we perform spatial-longitudinal whole-exome sequencing, including 140 samples collected from 24 Multiple Myeloma patients during up to 14 years. Applying imaging-guided sampling we observe three evolutionary patterns, including relapse driven by a single-cell expansion, competing/co-existing sub-clones, and unique sub-clones at distinct locations. While we do not find the unique relapse sub-clone in the baseline focal lesion(s), we show a close phylogenetic relationship between baseline focal lesions and relapse disease, highlighting focal lesions as hotspots of tumor evolution. In patients with ≥3 focal lesions on positron-emission-tomography at diagnosis, relapse is driven by multiple distinct sub-clones, whereas in other patients, a single-cell expansion is typically seen (p < 0.01). Notably, we observe resistant sub-clones that can be hidden over years, suggesting that a prerequisite for curative therapies would be to overcome not only tumor heterogeneity but also dormancy.

The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.