Recap: Selinexor, Carfilzomib, and Dexamethasone for Relapsed/Refractory Multiple Myeloma

Selinexor (Xpovio) is currently an approved treatment for patients with relapsed/refractory multiple myeloma who have received at least 1 prior therapy.¹ This drug is currently involved in many combination trials, the most significant of which are the STOMP studies (NCT02343042).²

In a recent Between the Lines segment hosted by CancerNetwork®, Joseph Mikhael, MD, and Hakan Kaya, MD, spoke about selinexor in combination with carfilzomib (Kyprolis) and dexamethasone (XKd).³ Mikhael is a professor in the Applied Cancer Research and Drug Discovery Division of the Translational Genomics Research Institute in Phoenix, Arizona, an affiliate of City of Hope Cancer Center. Kaya is a senior partner of Cancer Care Northwest, director of the Inland Northwest Myeloma/Lymphoma & Transplant Program, and a clinical professor at Cancer Care Northwest in Spokane, Washington.

Throughout the program, Mikhael and Kaya discussed results of a study by Gasparetto et al. examining use of XKd, and how they implement its results into their daily practice. Additionally, they reviewed XKd’s safety and tolerability, as well as strategies to best mitigate any adverse effects (AEs).

Selinexor as a Treatment Option

Selinexor’s mechanism of action is unique. The exportin 1 (XPO1) protein is a nuclear exporter of tumor suppressor proteins. XPO is overproduced in many cancers; and XPO1 overexpression helps cancer cells escape tumor suppressor proteins-mediated cell cycle arrest and apoptosis. Selinexor, a selective inhibitor of nuclear export compounds that blocks XPO1, which ultimately helps to cause cancer cell death.

“Selinexor is a first-in-class…XPO1 inhibitor. This means we have good tumor suppressors inside the nucleus, things like P53, that we want to retain in the nucleus because that will keep the [cancer] cell in check. However, in malignancy states, [tumor suppressors] are expelled out of the nucleus through a pathway called the XPO1. When that happens, the cell can become more malignant. It is less under the care of the rest of the body, [so to speak], and it can grow and multiply,” said Mikhael.

The trial determined that the maximum tolerated doses were 80 mg or 100 mg selinexor, 56 mg/m² or 70 mg/m² carfilzomib, and 40 mg dexamethasone. This was given once a week to those not refractory to carfilzomib.

Efficacy Results With the XKd Regimen

The dosing regimen was determined by the investigators using the maximum tolerated dose (MTD) of selinexor at 100 mg with a level down of carfilzomib of 56 mg/m² weekly, or one level down from the MTD of selinexor at 80 mg with the MTD of carfilzomib at 70 mg/m². At data cutoff, 31.3% of patients continued to receive treatment; 38% and 15.6% discontinued because of progressive disease and AEs, respectively.

The overall response rate (ORR) was 78.1%. Stringent complete response was observed in 6.3% of patients, 9.4% had a complete response, 28.1% had a very good partial response, and 34.4% had a partial response. The median progression-free survival was 15.0 months (95% CI, 12.0 months to not evaluable [NE]) with a median duration of response of 22.7 months (95% CI, 11.8-NE), and the median overall survival was not reached.

“The ORR of 78% is significant in clinical practice, especially [given] that these patients were heavily treated, many of them were triple refractory, and more than 65% of them were refractory to darolutamide [Nubeqa],” said Kaya. “From the studies and from our experience, patients with multiple myeloma who are refractory to darolutamide don’t do well. It was amazing to me that they had such a good response, and the duration of response was significant as well.”

Mikhael then discussed using selinexor in everyday practice, noting the results observed when using it as a monotherapy or in combination. “Following the philosophy that we have been embracing in myeloma—which is that we don’t save the best for last, as it were—we want to [use selinexor] earlier in the disease course and expose patients to different mechanisms of action. As we’re now using carfilzomib in the earlier relapse setting, this is a natural partner. I’ve had the opportunity to pair selinexor with almost every myeloma agent. To me, this is the natural partner in almost [all scenarios] for several reasons. One is its efficacy. Also, [second], I was struck [while reading] the study by Gasparetto et al. that more than half of the patients had high-risk disease. I don’t use it [only] in my high-risk disease patients—meaning I use it in standard-risk [patients as well]—but I have been very much drawn to [selinexor], especially when patients may have a TP53 deletion or have another feature of high risk that I know is going to be more difficult to manage.”

Kaya agreed with Mikhael on the use of the selinexor regimen for both high-risk and standard-risk patients. The study results helped to reassure Kaya and other clinicians that the results would be similar across multiple patient types.

Safety and Tolerability of Selinexor

Mikhael and Kaya then discussed AEs they have observed using selinexor in combinations. “When we started using selinexor 3 years ago, we were using 80 mg twice a week and we saw significant toxicities including nausea, vomiting, weight loss, and decreased appetite,” said Kaya. “But, after we started using it once a week [instead, the toxicities lessened].”

The most common nonhematologic grade 3 or 4 treatment-related adverse effects (TRAEs) included nausea (grade 3, 71.9%, and grade 4, 6.3%) and fatigue (grade 3, 53.1%, and grade 4, 9.4%). The most common hematologic TRAEs of grade 3 or 4 were thrombocytopenia (in 71.9% and 46.9%, respectively) and anemia (53.1% and 18.8%). Dose interruptions and dose reductions related to TRAEs occurred in 53.1% and 65.6% of the trial participants, respectively.

It is extremely important to treat patients quickly when AEs arise, as well as to educate patients on what AEs might potentially occur and how to handle them. For instance, “we treat them aggressively for potential nausea. We give them olanzapine [Zyprexa] every day and every night. We give them ondansetron [Zofran] during the first 24 to 48 hours, and we still see them very frequently and give them additional nausea medicines. The good news, though, is [that we’ve learned] from past studies and our own experience that all the AEs get better after the first month,” said Kaya.

Mikhael agreed that most often patients experience the worst AEs during the first month of treatment. He noted that guidelines have been created by the National Comprehensive Cancer Network to better understand and treat the AEs experienced by patients receiving selinexor.⁴ According to Mikhael, the guidelines’ goal was to help patients prevent anorexia and nausea, inform them about potential AEs, and educate them about hydration and food intake.

And while patient education is important, “it’s also very important to educate our staff and our nurses,” continued Kaya. “I tell my nurses that if a patient on selinexor calls you talking about nausea or decreased appetite, you must take that very seriously. If you don’t, you may find them a week later with a 10-pound weight loss, or they may be [so] sick [that they] stop taking their drug.”

Mikhael agreed, noting that if patients have significant AEs, dose reductions may be necessary. “In about two-thirds to three-fourths of my patients, I start at 80 mg, but in some I will start at an even lower dose of 60 mg. [In fact], I’ve started 2 patients over the last year at 40 mg because they were older, they were frailer, and they had significant cytopenias. Dose escalation [is always an option].”

Both Mikhael and Kaya discussed the limitations of using selinexor in practice. They agreed that AEs were the most grueling part of taking selinexor but that they lessened after the first month, and with data coming out, there may be opportunities to see selinexor used in earlier lines of therapy.

References

1. FDA approves selinexor for refractory or relapsed multiple myeloma. FDA. December 18, 2020. Accessed November 1, 2022. https://bit.ly/3U1dBXF
2. Richter J, Madduri D, Richard S, Chari A. Selinexor in relapsed/refractory multiple myeloma. Ther Adv Hematol. 2020;11:2040620720930629. doi:10.1177/2040620720930629
3. Gasparetto C, Schiller GJ, Tuchman SA, et al. Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients. Br J Cancer. 2022;126(5):718-725. doi:10.1038/s41416-021-01608-2
4. Karyopharm announces National Comprehensive Cancer Network^® adds three XPOVIO^® (selinexor) treatment regimens to its clinical practice guidelines in oncology for multiple myeloma. News release. Karyopharm Therapeutics; December 11, 2020. Accessed November 1, 2022. https://bit.ly/3fpHcLn