Moshe Y. Levy M.D.

Delimpasi, S., Mateos, M.V., Auner, H.W., Gavriatopoulou, M., Dimopoulos, M.A., Quach, H., Pylypenko, H., Hájek, R., Leleu, X., Dolai, T.K., Sinha, D.K., Venner, C.P., Benjamin, R., Garg, M.K., Doronin, V., Levy, Y., Moreau, P., Chai, Y., Arazy, M., Shah, J., Shacham, S., Kauffman, M.G., Richardson, P.G. and Grosicki, S. (2021). “Efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in comparison with standard twice-weekly bortezomib and dexamethasone in previously treated multiple myeloma with renal impairment: Subgroup analysis from the BOSTON study.” Am J Hematol Dec 9. [Epub ahead of print].

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Patients with hematological malignancies, particularly multiple myeloma (MM), typically have a high prevalence of renal impairment (RI). When combined with the nephrotoxic risk of anticancer drugs, especially with an older patient population like that frequently observed in MM, optimizing treatment regimens that are both safe and efficacious is difficult.1 Taken together, there is a need to identify effective therapeutic options that can be used in patients with RI and do not pose or induce additional renal toxicity in patients with MM.[No abstract; excerpt from article].

Tremblay, G., P. Daniele, J. Breeze, L. Li, J. Shah, S. Shacham, M. Kauffman, M. Engelhardt, A. Chari, A. Nooka, D. Vogl, M. Gavriatopoulou, M. A. Dimopoulos, P. Richardson, N. Biran, D. Siegel, P. Vlummens, C. Doyen, T. Facon, M. Mohty, N. Meuleman, M. Levy, L. Costa, J. E. Hoffman, M. Delforge, D. Kaminetzky, K. Weisel, M. Raab, D. Dingli, S. Tuchman, F. Laurent, R. Vij, G. Schiller, P. Moreau, J. Richter, M. Schreder, K. Podar, T. Parker, R. F. Cornell, K. Lionel, S. Choquet and J. Sundar (2021). “Quality of life analyses in patients with multiple myeloma: results from the Selinexor (KPT-330) Treatment of Refractory Myeloma (STORM) phase 2b study.” BMC Cancer 21(1): 993.

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BACKGROUND: Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy – Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM. METHODS: FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders. RESULTS: Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores. CONCLUSION: The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015.

Sanchez, L., Leleu, X., Beaumont, J.L., Yu, H., Hudgens, S., Simonova, M., Auner, H.W., Quach, H., Delimpasi, S., Špička, I., Pour, L., Kriachok, I., Dimopoulos, M.A., Usenko, G., Hájek, R., Benjamin, R., Sinha, D.K., Venner, C., Illmer, T., Garg, M.K., Stevens, D.A., Jagannath, S., Levy, M., Anderson, L.D., Jr., Bahlis, N.J., Facon, T., Cavo, M., Chai, Y., Ma, X., Tang, S., Leong, H., Shah, J., Shacham, S., Kauffman, M., Richardson, P. and Grosicki, S. (2021). “Peripheral Neuropathy Symptoms, Pain, and Functioning in Previously Treated Multiple Myeloma Patients Treated with Selinexor, Bortezomib, and Dexamethasone.” Am J Hematol Jun 23. [Epub ahead of print].

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With over 34 000 new cases and ~12 400 deaths from multiple myeloma (MM) anticipated in 2021 in the United States1 and about twice as many in Europe, there is an unmet medical need for therapies in patients with previously treated MM that have progressed on available agents. Currently, there are few agents with new mechanisms of action approved for early-line treatment. Selinexor (XPOVIO, Karyopharm Therapeutics Inc.) is a potent, oral, first-in-class, selective inhibitor of nuclear export that specifically blocks exportin 1 (XPO1). [No abstract; excerpt from article].

Levy, M., Xie, L., Wang, Y., Neumann, F., Srivastava, S., Naranjo, D., Xu, J., Zhang, Q. and Dalal, M. (2021). “Comparison of incidence/occurrence of cardiovascular events between ponatinib vs bosutinib among patients with at least one prior line of tyrosine kinase inhibitors in chronic myeloid leukemia in a community setting in the United States.” Cancer Treat Res Commun 28: 100424.

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INTRODUCTION: In this real-world study, the incidence of cardiovascular events (CV) including major adverse cardiac events (MACE), arterial occlusive events (AOE), and venous occlusive events (VOE) was evaluated in chronic myeloid leukemia (CML) patients treated with ponatinib or bosutinib in a US commercial database population. MATERIALS AND METHODS: CML patients aged ≥18 years with use of 1 or 2 prior tyrosine kinase inhibitors prescribed bosutinib or ponatinib were selected from the IBM® MarketScan® Research database. Cox proportional hazard model analyses were conducted to examine any difference in CV event risk. RESULTS: Ponatinib and bosutinib was associated with similar incidence and risk of CV events, including MACEs (HR: 1.02; 95% CI: 0.35, 3.01), AOEs (HR: 0.90; 95% CI: 0.43, 1.85) and VOEs (HR: 0.92; 95% CI: 0.44, 1.94). CONCLUSION: Treatment with ponatinib or bosutinib was not associated with significant differences in the incidence of CV events in CML patients.

Richard, S., Chari, A., Delimpasi, S., Simonova, M., Spicka, I., Pour, L., Kriachok, I., Dimopoulos, M.A., Pylypenko, H., Auner, H.W., Leleu, X., Usenko, G., Hajek, R., Benjamin, R., Dolai, T.K., Sinha, D.K., Venner, C.P., Garg, M., Stevens, D.A., Quach, H., Jagannath, S., Moreau, P., Levy, M., Badros, A., Anderson, L.D., Jr., Bahlis, N.J., Facon, T., Mateos, M.V., Cavo, M., Chang, H., Landesman, Y., Chai, Y., Arazy, M., Shah, J., Shacham, S., Kauffman, M.G., Grosicki, S. and Richardson, P.G. (2021). “Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk.” Am J Hematol June 1. [Epub ahead of print].

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In the phase 3 BOSTON study, patients with multiple myeloma (MM) after 1-3 prior regimens were randomized to once-weekly selinexor (an oral inhibitor of exportin 1 [XPO1]) plus bortezomib-dexamethasone (XVd) or twice-weekly bortezomib-dexamethasone (Vd). Compared with Vd, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and lower rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. In BOSTON, 141 (35.1%) patients had MM with high-risk (presence of del[17p], t[4;14], t[14;16], or ≥4 copies of amp1q21) cytogenetics (XVd, n=70; Vd, n=71), and 261 (64.9%) exhibited standard-risk cytogenetics (XVd, n=125; Vd, n=136). Amongst patients with high-risk MM, median PFS was 12.91 months for XVd and 8.61 months for Vd (HR, 0.73 [95% CI, (0.4673, 1.1406)], p=0.082), and ORRs were 78.6% and 57.7%, respectively (OR 2.68; p=0.0041). In the standard-risk subgroup, median PFS was 16.62 months for XVd and 9.46 months for Vd (HR 0.61; p=0.0036), and ORRs were 75.2% and 64.7%, respectively (OR 1.65; p=0.0329). The safety profiles of XVd and Vd in both subgroups were consistent with the overall population. These data suggest that selinexor can confer benefits to patients with MM regardless of cytogenetic risk. ClinicalTrials.gov identifier: NCT03110562