A same?day assay predicts apoptotic response to combined BCL?2 and MCL?1 BH3?mimetic targeting in multiple myeloma cells

Recent advances in treatment options for multiple myeloma (MM) have positive impact on patient survival. However, there is a short fall of rapid and reliable assays that can predict patient response to novel agents. The anti-apoptotic proteins B-cell lymphoma-2 (BCL-2) and myeloid cell leukaemia-1 (MCL-1), are necessary for MM survival, although most myelomas are more dependent on MCL-1. BCL-2 inhibition alone yields significant cytotoxicity in only a minority of cases, therefore targeting both proteins simultaneously, is a therapeutic option. Venetoclax and S63845 are BCL-2 and MCL-1 targeting BH3-mimetics which have demonstrated apoptotic synergy in MM. We investigated whether a novel short-term flow cytometric cytochrome c release assay could predict response to dual BH3-mimetic targeting in MM cells. Six human myeloma cell lines (HMCL) and seven primary samples were treated with venetoclax and S63845 alone or in combination. The 4-hour assay confirmed the drug combination was synergistic in all HMCL tested. Annexin-V data at 48 hours corresponded with 4-hour response verifying the assay as a predictor of drug sensitivity. All primary samples responded to the drug combination, including samples with 1q gain and t(4;14) translocation. Normal stem cells were unaffected by the drug combination. We have developed a novel assay with the potential to predict response to therapy in MM cells

Infections in relapsed myeloma patients treated with isatuximab plus pomalidomide and dexamethasone during the COVID-19 pandemic: Initial results of a UK-wide real-world study

© 2022 The Authors. Published by Taylor & Francis. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1080/16078454.2022.2082725Objectives There are no real-world data describing infection morbidity in relapsed/refractory myeloma (RRMM) patients treated with anti-CD38 isatuximab in combination with pomalidomide and dexamethasone (IsaPomDex). In this UK-wide retrospective study, we set out to evaluate infections experienced by routine care patients who received this novel therapy across 24 cancer centres during the COVID-19 pandemic. Methods The primary endpoint was infection morbidity (incidence, grading, hospitalization) as well as infection-related deaths. Secondary outcomes were clinical predictors of increased incidence of any grade (G2–5) and high grade (≥G3) infections. Results In a total cohort of 107 patients who received a median (IQR) of 4 cycles (2–8), 23.4% of patients experienced ≥1 any grade (G2–5) infections (total of 31 episodes) and 18.7% of patients experienced ≥1 high grade (≥G3) infections (total of 22 episodes). Median time (IQR) from start of therapy to first episode was 29 days (16–75). Six patients experienced COVID-19 infection, of whom 5 were not vaccinated and 1 was fully vaccinated. The cumulative duration of infection-related hospitalizations was 159 days. The multivariate (MVA) Poisson Regression analysis demonstrated that a higher co-morbidity burden with Charlson Co-morbidity Index (CCI) score ≥4 (incidence rate ratio (IRR) = 3, p = 0.012) and sub-optimal myeloma response less than a partial response (<PR) (p = 0.048) are independent predictors of ≥ G3 infections. Conclusion Our study described initial results of infection burden during IsaPomDex treatment. We recommend close monitoring particularly in elderly patients with co-morbidities, the effective use of an-infective prophylaxis, as well as optimal vaccination strategies, to limit infections

Efficacy of isatuximab with pomalidomide and dexamethasone in relapsed myeloma: Results of a UK-wide real-world dataset

This is an accepted manuscript of a paper due to be published by Lippincott, Williams & Wilkins in HemaSphere (in press). The accepted manuscript of the publication may differ from the final published versionReal-world data on the efficacy and tolerability of isatuximab with pomalidomide and dexamethasone (IsaPomDex) in relapsed/refractory myeloma (RRMM) patients have not been reported. In this UK-wide retrospective study, IsaPomDex outcomes were evaluated across 24 routine care cancer centres. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), duration of response (DOR) for patients who achieved an objective response (≥PR), and adverse events (AEs). In a total cohort 107 patients, median follow up (IQR) was 12.1 months (10.1-18.6 months), median age (IQR) was 69 years (61-77). Median (IQR) Charlson Co-morbidity index (CCI) score was 3 (2- 4); 43% had e-GFR<60 ml/min. Median (IQR) number of prior therapies was 3 (3-3). Median (IQR) number of IsaPomDex cycles administered was 7 (3-13). ORR was 66.4%, with responses categorised as ≥VGPR: 31.8%, PR: 34.6%, SD: 15.9%, PD: 15% and unknown 2.8%. Median PFS was 10.9 months. Median DOR was 10.3 months There was no statistical difference in median PFS by age (<65: 10.2 vs. 65-74 13.2 vs. ≥75: 8.5 months, log-rank p=0.4157), by CCI score (<4: 10.2 months vs. ≥4: 13.2, log-rank p=0.6531), but inferior PFS was observed with renal impairment (≥60: 13.2 vs. <60: 7.9 months, log-rank p=0.0408). Median OS was 18.8 months. After a median of 4 cycles, any grade AEs were experienced by 87.9% of patients. The most common ≥G3 AEs were neutropenia (45.8%), infections (18.7%) and thrombocytopenia (14%). Our UK-wide IsaPomDex study demonstrated encouraging efficacy outcomes in the real-world, comparable to ICARIA-MM trial

Frailty subgroup analysis of isatuximab with pomalidomide and dexamethasone in a UK-wide real-world cohort of relapsed myeloma patients

This is an accepted manuscript of an article published by Wiley on 31/01/2023, available online: https://doi.org/10.1111/bjh.18672 The accepted version of the publication may differ from the final published version.Published versio