Patients with relapsed/refractory multiple myeloma (RRMM) for whom prior treatment with lenalidomide, pomalidomide, bortezomib, and carfilzomib fail have few treatment options. These “quad refractory” patients will eventually become “penta refractory” after further treatment with anti-CD38 monoclonal antibodies such as daratumumab or isatuximab.1
With further treatment, median overall survival (OS) is 9 months; without further treatment median OS is 3 months.2 Treatment options for these heavily pre-treated patients must include agents with non-overlapping mechanisms of action, so that toxicities are minimized and synergistic efficacy with any ongoing therapy is maximized to effect deep responses.
Selinexor (KPT-330) is a selective inhibitor of nuclear export (SINE) under development for the treatment of RRMM and other advanced hematologic malignancies. Selinexor induces cell death through apoptosis and autophagy.3 This dual mechanism is both novel and potentially synergistic with mechanisms already acted upon by drugs used in the treatment of patients with RRMM.
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The recent phase 2 STORM study evaluated twice weekly 80 mg oral selinexor plus 30 mg dexamethasone for 6 or 8 doses per 38 day cycle in both quad- and penta-refractory RRMM patients.1 Common hematological treatment-related adverse events (TRAEs) included thrombocytopenia (72%, grade 3/4: 58%), anemia (48%, grade 3: 25%) and neutropenia (29%, grade 3 or worse: 21%).
Non-hematological TRAEs included nausea (72%), fatigue (62%), anorexia (49%), vomiting (43%), asymptomatic hyponatremia (42%), diarrhea (42%), and weight loss (33%). TRAEs were manageable with supportive care and dose interruptions or reductions.
The primary endpoint of overall response rate, defined as at least a partial response (PR), was 21% for patients with quad-refractory disease and 20% for patients with penta-refractory disease. This promising response in heavily pre-treated patients was associated with longer survival. This is also the first study to demonstrate a response in penta-refractory myeloma patients.
Selinexor was also recently investigated with low-dose dexamethasone in combination with pomalidomide, lenalidomide, or bortezomib in the STOMP study (NCT02343042).4 The safety profile of the 3 treatment combinations was deemed to be consistent with, or less toxic than, what was previously reported with single-agent selinexor. Common grade 1/2 AEs in this study included nausea, diarrhea, and thrombocytopenia (50% in the arm receiving bortezomib plus selinexor), and were manageable. Overall responses in each arm that included either pomalidomide or bortezomib with selinexor were very promising at 57% and 69%, respectively, in these heavily pre-treated RRMM patients.
Further studies of treatment combinations with unique mechanisms of action that may result in additive or synergistic anti-myeloma effects are much needed. It will be of interest to determine if the high response rates with the selinexor plus bortezomib combination can be replicated or improved upon with a combination of selinexor and the proteasome inhibitor, carfilzomib. Two studies, 1 planned (NCT02628704) and 1 ongoing (NCT02199665), will reveal the efficacy and safety of the combination of carfilzomib, selinexor, and dexamethasone in the treatment of RRMM.
Inhibition of nuclear export and subsequent cell death through apoptosis and/or autophagy provides a novel mechanism of action that may synergize with agents with non-overlapping mechanisms. Non-overlapping toxicities should allow patients to stay on therapy longer to achieve more durable and deeper responses and, in turn, to improve overall survival.
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The clinical experience with selinexor demonstrates robust responses and non-overlapping toxicities in these difficult to treat patients. Given the high unmet need for novel agents in quad- and penta-refractory patients, selinexor represents a much-needed therapeutic addition to the available agents for the treatment of heavily pre-treated patients with few options.
References
- Vogl DT, Dingli D, Cornell RF, et al. Selinexor and low dose dexamethasone (Sd) in patients with lenalidomide, pomalidomide, bortezomib, carfilzomib and anti-CD38 Ab refractory multiple myeloma (MM): STORM Study. Paper presented at: American Society of Hematology (ASH) 58th Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA.
- Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26(1):149-157.
- Rosebeck S, Kandarpa M, Alonge MM, et al. Effects of inhibition of XPO1/CRM1-dependent nuclear export by selinexor (KPT- 330), alone and in combination with carfilzomib (cfz), on apoptosis and autophagy in multiple myeloma (MM). Blood. 2013;122(21):279.
- Bahlis N, Chen C, Sebag M, et al. A phase 1B/2 study of selinexor in combination with backbone therapies for treatment of relapsed/refractory multiple myeloma. Paper presented at: 21st Congress of the European Hematology Association; June 9-12 2016; Copenhagen, Denmark.
