Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma.

Multiple myeloma (MM) remains an incurable disease and there is an unmet medical need for novel therapeutic drugs that do not share similar mechanisms of action with currently available agents. Sphingosine kinase 2 (SK2) is an innovative molecular target for anticancer therapy. We previously reported that treatment with SK2 inhibitor opaganib inhibited myeloma tumor growth in vitro and in vivo in a mouse xenograft model. In the current study, we performed a phase I study of opaganib in patients with relapsed/refractory multiple myeloma (RRMM). Thirteen patients with RRMM previously treated with immunomodulatory agents and proteasome inhibitors were enrolled and treated with single-agent opaganib at three oral dosing regimens (250 mg BID, 500 mg BID, or 750 mg BID, 28 days as a cycle). Safety and maximal tolerated dose (MTD) were determined. Pharmacokinetics, pharmacodynamics, and correlative studies were also performed. Opaganib was well tolerated up to a dose of 750 mg BID. The most common possibly related adverse event (AE) was decreased neutrophil counts. There were no serious AEs considered to be related to opaganib. MTD was determined as at least 750 mg BID. On an intent-to-treat basis, one patient (7.7%) in the 500 mg BID dose cohort showed a very good partial response, and one other patient (7.7%) achieved stable disease for 3 months. SK2 is an innovative molecular target for antimyeloma therapy. The first-in-class SK2 inhibitor opaganib is generally safe for administration to RRMM patients, and has potential therapeutic activity in these patients. Clinicaltrials.gov: NCT02757326.

A cross-sectional observational study of health-related quality of life in adults with multiple myeloma.

BACKGROUND: The purpose of this manuscript is to describe health-related quality of life (HRQoL) outcomes in a United States (US)-based sample of multiple myeloma (MM) patients and identify characteristics associated with poor HRQoL. PATIENTS AND METHODS: MM patients identified through the Tumor Registry of a Southeastern US medical center were mailed surveys assessing patient characteristics and HRQoL outcomes. HRQoL outcomes were measured using PROMIS short form instruments which included measures of global health (global physical health and global mental health), physical function, and ability to participate in social roles and activities (social function). HRQoL domain scores were summarized, and best subset linear regression was used to identify predictors of HRQoL. RESULTS: A total of 690 patients completed and returned surveys for a response rate of 64.7%. Respondents reported global physical health (44.9), global mental health (47.5), and physical function (44.1) significantly worse than the general population mean of 50 (p < .0001). Social function (49.5) did not differ significantly (p = .09). Worse socioeconomic status, higher comorbidities, not being in remission, and past receipt of radiation therapy were significantly associated with worse HRQoL. Treatment status and time since diagnosis were not associated with HRQoL outcomes. CONCLUSIONS: Patients with MM have significantly worse HRQoL than the general population. These findings warrant increased attention from clinicians and researchers. More research is needed to better describe the relationship between treatment patterns and HRQoL in patients with MM, and to identify effective interventions.

Phase II study of dose-attenuated bortezomib, cyclophosphamide and dexamethasone ("VCD-Lite") in very old or otherwise toxicity-vulnerable adults with newly diagnosed multiple myeloma.

OBJECTIVES: Multiple myeloma (MM) primarily strikes older adults, but full-dose chemotherapy such as bortezomib (Velcade), cyclophosphamide and dexamethasone (VCD) is often excessively toxic to very old or frail adults and those with substantial comorbidities. We piloted dose-attenuated VCD ("VCD-Lite") in such vulnerable adults with newly diagnosed MM (NDMM). MATERIALS AND METHODS: Subjects with NDMM and a high risk of therapy-related toxicity due to factors above received bortezomib 1.3mg/m2 subcutaneously, cyclophosphamide 300mg/m2 and dexamethasone 40mg orally, all on days 1, 8, and 15 of a 28day cycle for eight cycles, followed by indefinite, alternating bortezomib and lenalidomide maintenance. Toxicity, overall response rate (ORR), progression-free and overall survival (PFS and OS) were determined. The Cancer and Aging Research Group geriatric assessment (CARG GA) was administered at baseline in an exploratory manner as a predictor of severe toxicity. RESULTS: 14 patients went on the study, which was closed early due to slow accrual. Intention-to-treat ORR was 64%. 64% of patients experienced grade ≥3 adverse events, the majority of which were unlikely therapy-related. Median PFS was 24.2months and OS 29.7months, with 14%, 36% and 29% of patients discontinuing study drugs due to toxicity, MM progression and other reasons respectively. Baseline CARG GA was successfully completed by all subjects but one. CONCLUSION: VCD-Lite is a viable option for vulnerable adults with NDMM. CARG GA is feasible. Further studies to optimize therapy and to explore CARG GA as a toxicity predictor are vital.