Selinexor and Multiple Myeloma

There are various treatment options for patients with multiple myeloma (MM), including autologous hematopoietic stem cell transplantation (HSCT), thalidomide, lenalidomide, bortezomib, and daratumumab. Each patient with MM is obviously not a candidate for all of these treatments, and each treatment plan needs to be tailored for the individual patient. A consistent challenge facing both health care practitioners and patients is that none of the current medication options are curative, therefore, refractory disease is inevitable.¹ However, there are new agents being developed for use in patients with MM that seek to improve outcomes in refractory disease.

One of these new agents with developing clinical trial data is a first-in-class, selective inhibitor of exportin-1 (XPO1).² XPO1 is a protein found within the nucleus of the cell and is responsible for the transport of molecules such as tumor suppressor proteins and other oncoproteins from the nucleus to the cytoplasm.³

Increased levels of XPO1 are associated with disease progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM.⁴ These changes may eventually translate into worse outcomes in patients with MM. Early preclinical and clinical data have shown that selinexor has activity in multiple hematologic malignancies, most notably in MM. Selinexor has been studied alone as well as in conjunction with additional agents such as dexamethasone and proteasome inhibitors.²

Based on early promising data, Vogl and colleagues published a larger phase 2 study evaluating selinexor in combination with dexamethasone in patients with MM that is refractory to current therapies.² This was a multicenter, open-label study that evaluated selinexor 80 mg and dexamethasone 20 mg, both by mouth twice daily, in patients with MM who were refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and anti-CD38 antibodies (daratumumab or isatuximab). The primary end point was overall response rate (ORR) which included a partial response or better (characterized as a very good partial response or complete response) and was determined by an independent review group  using modified International Myeloma Working Group (IMWG) criteria.⁵

A total of 79 patients enrolled in the study. Median time from diagnosis was 4 years, and participants had received a median of 7 previous regimens. The ORR was 21% (95% CI, 13% to 31%), and  15% of patients experienced a partial response. The ORR of 21% was not statistically significantly, but it was higher than the authors’ prespecified threshold of 15%. Thirteen percent of patients had a minimal response, which translated into a clinical benefit rate of 33%. Patients who experienced a minimal response or better did so relatively quickly; 85% of these individuals responded within the first treatment cycle. The patients who met the primary end point did so with a median duration of response of 5 months. Median progression-free survival was 2.3 months and median overall survival was 9.3 months.

Gastrointestinal problems among the most commonly reported nonhematologic treatment-related adverse events. These included nausea (73%), vomiting (44%), and diarrhea (43%). Other common adverse events included fatigue (63%) and anorexia (49%). The most common grade 3 or grade 4 hematological adverse events were thrombocytopenia (59%), anemia (28%), and neutropenia (23%).

Although the ORR was not statistically significant, some of the results are still promising. The patient population had relatively advanced MM and therefore, was challenging to treat. The authors hypothesized that these patients may have acquired mutations throughout their treatment regimens that predisposed them to lower response rates. Also, the authors believed that the preset threshold of 15% may have been too high, and that they should have considered establishing a threshold of 10% instead. Regardless, selinexor continues to be evaluated in clinical trials in MM along with multiple other disease states.

References

1. 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.
2. Vogl DT, Dingli D, Cornell RF, et al. Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36(9):859-866.
3. Gravina GL, Senapedis W, McCauley D, Baloglu E, Shacham S, Festuccia C. Nucleo-cytoplasmic transport as a therapeutic target of cancer. J Hematol Oncol. 2014;7:85. doi: 10.1186/s13045-014-0085-1.
4. Schmidt J, Braggio E, Kortuem KM, et al. Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia. 2013;27(12):2357-2365.
5. Durie BG, Harousseau JL, Miguel JS, et al; International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia 2006;20(9):1467-1473.