Selinexor Improves Late-Stage Treatment Options for Multiple Myeloma

Sundar Jagannath, MBBS

Treatment options for patients with multiple myeloma have expanded in recent years, leading to significantly better outcomes, but an unmet need has existed for patients with disease that is relapsed or refractory to multiple lines of therapy.

In July 2019, late-stage treatment options improved with the FDA’s approval of selinexor (Xpovio) in combination with low-dose dexamethasone for the treatment of adult patients who have received ≥4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.

The approval was based on efficacy data in a subgroup of patients from the phase IIB STORM trial (NCT02336815) who had previously received 3 or more multiple myeloma regimens, including an alkylating agent, glucocorticoids, bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), and an anti-CD38 monoclonal antibody. Selinexor is a first-in-class agent that supports the retention of tumor suppressor proteins in the cell nucleus and induces tumor cell apoptosis.

Responses were seen in roughly a quarter of the patients, whose characteristics suggest that these results can be replicated in real-world populations, said Sundar Jagannath, MBBS, director of the multiple myeloma program; professor of hematology and medical oncology at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York, New York; and principal investigator of the trial.

“The characteristics of the patients in the STORM study, including being heavily pretreated, yet still experiencing rapidly progressing disease, are consistent with the growing population of patients who have exhausted available myeloma therapies but still desire to continue therapy,” he said.

In an interview with OncologyLive^®, Jagannath discussed the significance the selinexor approval has for this patient population, the tolerability of the agent, and the management of related adverse events (AEs).

OncologyLive^®: Please describe the patient characteristics in this trial.

The patients who participated in the phase II portion of STORM trial had already tried all available treatment options for myeloma, including 2 proteasome inhibitors, bortezomib and carfilzomib; 2 immunomodulatory molecules, lenalidomide and pomalidomide; alkylating agents; and the monoclonal antibody daratumumab [Darzalex]. In order for patients to be eligible for this trial, their disease had to be triple-class refractory, meaning refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and daratumumab. The only options left for these patients included recycling of the same drugs in different combinations or hospice.

Can you discuss the efficacy data that led to the approval of selinexor?

A total of 122 patients were treated; 39% had minimal response or better. The overall response rate [ORR] was 26% including 2 stringent complete responses. To put this in perspective of recent accelerated approvals in multiple myeloma: Carfilzomib in patients with single-class refractory disease had an ORR of 23%, pomalidomide and low-dose dexamethasone in the single- and double-class refractory setting had an ORR of 29.2%, and daratumumab had an ORR of 29.2% in double- refractory disease.

Can you describe the mechanism of action?

Selinexor is a selective inhibitor of exportin 1, a chaperone protein responsible for transport of protein from the nucleus into the cytoplasm. Exportin 1 is the sole nuclear exporter of tumor suppressor proteins, the glucocorticoid receptor, and oncoprotein messenger RNAs. Use of selinexor results in the retention of tumor-active suppressor proteins in the nucleus and prevention of oncoprotein messenger RNA translation in the cytoplasm. This results in apoptosis of the tumor cells. Exportin 1 is overexpressed in myeloma cells, thereby making them vulnerable to selinexor.

What do we know about selinexor’s tolerability?

Selinexor is administered orally. The major nonhematologic AEs include nausea/vomiting, fatigue, decreased appetite, weight loss, diarrhea, and hyponatremia. Severe AEs were encountered in fewer than 1 in 5 patients. The major hematologic AEs include thrombocytopenia and neutropenia. Prophylactic prevention of nausea and anorexia is more successful in controlling the symptoms.

All patients should be started with a 5-HT3 receptor antagonist, and adding low-dose olanzapine and/or a neurokinin receptor antagonist, such as rolapitant [Varubi], significantly reduces the incidence and severity of nausea and vomiting. These measures are particularly helpful in the first 1 or 2 cycles. Salt tablets can mitigate hyponatremia. Dose reduction and modification would also help in mitigating the AEs. Methylphenidate has been studied in cancer-related fatigue and is useful in a subset of patients and should be considered.

How does selinexor fit into the current treatment paradigm?

Currently, oral selinexor with dexamethasone is approved for the treatment of patients who are currently failing proteasome inhibitor, immunomodulatory molecule, and daratumumab. This is an orally administered drug. As MM is still an incurable disease and more patients are failing the available agents, there will be an increased demand for selinexor.

What are the next steps for selinexor?

We are anxiously awaiting the final results of BOSTON trial [NCT03110562], a phase III randomized trial comparing bortezomib and dexamethasone with or without selinexor. The trial is fully accrued, another indication that the drug is well tolerated. Once the results are out and [if] selinexor gets full approval for relapsed myeloma, it is likely to be used either alone or in combination for patients with relapsed and or refractory myeloma.

Is there anything else you would like to highlight about the drug?

Selinexor is the first-in-class oral selective inhibitor of exportin 1. As shuttling of tumor suppressor proteins and oncoprotein messenger RNAs in and out of the nucleus is very critical for all cancer cells, it is more than likely that selinexor will prove to be effective in other hematologic malignancies, such as lymphoma, and nonhematologic cancers.