Recap: A Review of Selinexor Combination Therapies in Relapsed/Refractory Multiple Myeloma

The first-in-class selective inhibitor of nuclear export, or SINE, compound, selinexor (Xpovio), in combination with dexamethasone, was granted FDA approval in 2019 for heavily pretreated patients with multiple myeloma, and subsequent regulatory actions have made this therapy available to a greater share of patients.¹ With more widespread use, additional safety and efficacy data show how this agent will shape administration going forward.

In 2021, a commentary published in Clinical Lymphoma, Myeloma, and Leukemia provided guidance on weekly dosing and supportive care solutions for selinexor in patients with multiple myeloma.² In a recent Between the Lines hosted by CancerNetwork^®, Joshua Richter, MD, director of multiple myeloma at the Blavatnik Family-Chelsea Medical Center and associate professor of medicine at the Tisch Cancer Institute of Mount Sinai in New York, New York; and Peter Forsberg, MD, associate professor of medicine-hematology at the University of Colorado School of Medicine in Aurora, focused on this commentary and weighed in on how it stands up to their own practice patterns.

Throughout the program, Richter and Forsberg focused on safety and efficacy of selinexor combination regimens, current clinical trials, and ongoing research.

Mechanism of Action

Selinexor helps to block the protein exportin 1 (XPO1), which is responsible for the nuclear export and functional inactivation of tumor suppressor pathways. Blocking of XPO1 results in nuclear preservation and tumor suppressor protein activation; this prevents messenger RNA translation of oncoproteins, in turn leading to apoptosis induction.

“It is definitely a unique mechanism that may translate into a unique effectiveness profile, but it also may have some impact on some of the toxicities and [adverse] effects that we deal with and work through,” Forsberg said.

Richter described the mechanism of action differently, specifically focusing on the role selinexor plays in cell death. He described how malignant cells typically work around programmed apoptosis to allow proliferation and how inhibition of XPO1 can be useful for outsmarting this process.

“When you trigger a cell to undergo apoptosis, you get a signal that travels to the nucleus and then you get a cascade of events—A, B, C, D, and E—that leads to cell death. The cancer cells will get smart and [find a way around that by kicking out C] through these little holes in the nucleus called XPO1…you’ll get A, B, but no C, so the cascade doesn’t follow through, the cell does not die, and the cancer cell proliferates. What selinexor does is it blocks those XPO1 channels and prevents the cancer cell from kicking out part of that cascade.”

BOSTON and STOMP Trials

Two key trials investigating selinexor in patients with relapsed/refractory multiple myeloma were examined in the commentary. One is the phase 1/2 STOMP trial (NCT02343042), which is composed of 11 treatment arms across various combinations containing selinexor plus dexamethasone and including pomalidomide (Pomalyst), bortezomib (Velcade), lenalidomide (Revlimid), daratumumab (Darzalex), carfilzomib (Kyprolis), ixazomib (Ninlaro), and belantamab mafodotin (Blenrep). The other is BOSTON, a phase 3 trial (NCT03110562) analyzing selinexor with bortezomib and dexamethasone (Vd) vs Vd alone.

However, it was the phase 2 STORM study (NCT02336815) that paved the way for use of selinexor in multiple myeloma.³ This study looked at oral selinexor at 80 mg plus 20 mg of dexamethasone given on days 1 and 3 weekly. Despite robust efficacy, high-dose selinexor totaling 160 mg weekly led to high rates of adverse effects (AEs), leading investigators to explore more optimal dosing strategies to maintain efficacy and reduce toxicity.

STOMP Trial

Currently, the most mature data sets for STOMP include those related to selinexor/dexamethasone in combination with pomalidomide, daratumumab, or carfilzomib. Richter and Forsberg began by discussing selinexor/dexamethasone plus pomalidomide for patients with relapsed/ refractory multiple myeloma.⁴

Two dosing schedules of selinexor were used for examining selinexor/ dexamethasone plus pomalidomide: selinexor either weekly at 60 mg, 80 mg, or 100 mg, or twice weekly at 60 mg or 80 mg; plus escalating doses of pomalidomide at 2 mg, 3 mg, or 4 mg given with the selinexor; and dexamethasone at 20 mg twice weekly or 40 mg each week.

Of the 52 patients in this study, a median of 3 lines of prior therapy were noted, and 84.6% had prior stem cell transplant. The overall response rate (ORR) was 65% with a median progression-free survival (PFS) of 12.3 months and an overall survival (OS) of 19.3 months. The recommended phase 2 dose with this combination was 60 mg of selinexor weekly for 3 of 4 weeks along with 4 mg of pomalidomide, and 40 mg of dexamethasone given orally on a weekly schedule.

“Some of the patients in the selinexor plus pomalidomide arm were already refractory to pomalidomide, and the selinexor resensitized them,” Richter said.

Selinexor/dexamethasone plus carfilzomib was the next arm discussed, in which 32 patients were given selinexor at 80 mg or 100 mg, plus carfilzomib at 56 mg/m² or 70 mg/m², plus dexamethasone at 40 mg.⁵ The median number of lines of prior therapy in this arm was 4. The ORR was 78.1%: 6.3% of patients had a stringent complete response (CR), 9.4% had a CR, 28.1% had a very good partial response (VGPR), and 34.4% had a PR. The median PFS was 15.0 months (95% CI, 12.0-not evaluable [NE]), with a median follow-up of 8.0 months. The median duration of response was 22.7 months (95% CI, 11.8-NE) with a median follow-up of 5.6 months. The median OS was not reached at the median follow-up of 15.1 months.

Selinexor/dexamethasone plus daratumumab was analyzed in patients who had 3 or more prior lines of antimyeloma therapy.⁶ The recommended phase 2 dose was 100 mg of selinexor, 16 mg/kg of daratumumab, and 40 mg of dexamethasone, all once weekly. For patients who were daratumumab-naive (n = 19), the ORR was 74% with 5 VGPRs, 9 PRs, and 2 instances of stable disease. Of 2 patients who were refractory to daratumumab, there was 1 patient with progressive disease and 1 with stable disease.

“This update creates a great body of foundational data for us to understand the dosages [of selinexor that were utilized], giving us a dosing structure to begin with. They’re sketching out an efficacy and a safety profile. It’s not a large phase 3 body of data, but it is enough to give us a sense of an active combination strategy in the relapsed/ refractory, heavily pretreated [space, more] than some of the other study scenarios,” said Forsberg.

BOSTON Trial

BOSTON examined selinexor plus Vd (SVd) vs Vd alone in patients with multiple myeloma who had been treated with 1 to 3 prior lines of therapy.⁷ Patients in the active treatment arm were given 100 mg of selinexor once weekly, 1.3 mg/m² of bortezomib once weekly, and 20 mg of dexamethasone twice weekly. Those in the control arm were given bortezomib at 1.3 mg/m² twice per week for the first 24 weeks and once a week thereafter, and 20 mg of dexamethasone 4 times a week for the first 24 weeks and twice a week thereafter.

“[The BOSTON trial] led to an approval [of SVd] in 2020 in patients with 1 or more prior lines of therapy.⁷ These patients are not necessarily nearly as heavily pretreated, and [the data also give us a different insight] in terms of the dosing structure,” said Forsberg.⁸

At a median follow-up of 13.2 months for the triplet regimen and 16.5 months for the doublet, the median PFS was 13.93 months (95% CI, 11.73-NE) vs 9.46 months (95% CI, 8.11-10.78), respectively (HR, 0.70; 95% CI, 0.53- 0.93; P = .0075).

Treatment Use and Dosing of Selinexor

Based on the evidence that has become available since the approval of selinexor/ dexamethasone and the STORM trial, once-weekly dosing appears to be a more favorable option when the doublet is combined with other anti-myeloma agents.

“In the original STORM study, we gave selinexor twice weekly at 80 mg. It was more toxic that way, but it had to do all the heavy lifting. When we start combining it with other agents that can share the load, we can get away with once-weekly dosing. For the most part, the maximum tolerated dose in these studies is based off the myelotoxicity of the partner drug,” Richter said.

The participants then shifted the conversation to cover situations in which they like to utilize selinexor for their patients. As evidenced by the data, selinexor/dexamethasone offers better results for patients when coupled with another multiple myeloma backbone therapy vs used alone. However, certain patients have limited treatment options after having received multiple lines of prior therapy.

Richter prefers to turn to selinexor during earlier lines of therapy, preferably in the second line if the first-line treatment has failed.

“If patients receive daratumumab, lenalidomide, and dexamethasone, and they underperform or relapse in a year, then they’re daratumumab refractory, immunomodulatory refractory, and proteasome inhibitor–naive. I go to [selinexor, bortezomib, and dexamethasone] as a second-line treatment,” Richter said.

However, Forsberg tends to treat patients with selinexor in later lines of therapy, particularly if the patient is on the younger side. “I tend to think about it more in the third line and [later], because my second-line [choices] in the post–lenalidomide relapse [scenario] in younger, robust patients, have currently been leaning toward the CD38 carfilzomib-based combinations,” Forsberg said.

Toxicity of Selinexor

In each trial, rates of toxicities correlated with dosing of selinexor. In the STORM trial, the most common grade 3/4 treatment-related AEs (TRAEs) with selinexor at 80 mg twice weekly were thrombocytopenia (53.7%), anemia (29.3%), fatigue (18.7%), and neutropenia (18.7%). In the BOSTON trial, grade 3/4 TRAEs with selinexor at 100 mg once weekly included thrombocytopenia (39%), anemia (16%), and fatigue (13%). In the STOMP trial, grade 3/4 TRAEs with selinexor at 60 mg once weekly were neutropenia (54%), anemia (33.3%), and thrombocytopenia (31.7%).

The commentary also highlighted that nausea was the most common AE experienced by patients overall, but incidence decreased by 50% during cycle 2; after 2 cycles or beyond, more than 90% of patients did not experience it. It was noted that patients should be educated on AEs to expect early on, that they should expect improvement after cycle 1, and that they should not be discouraged and discontinue early.

“My general approach is to try to be more proactive than reactive. An important thing is to get ahead of [AEs], especially any [gastrointestinal complications] or nausea. You want to avoid any risk of anticipatory nausea. I tend to be more aggressive early on because you have to worry about it in the first cycle or so,” Richter said.

Looking Toward the Future

Moving forward, investigations of selinexor with multiple therapies continue. The results that have been reported so far with a weekly dosing schedule have been positive.

In their closing remarks, Richter and Forsberg discussed some unmet needs in relapsed/refractory multiple myeloma.

“Our toolbox is getting deeper, and when [patients] become refractory to more and more of these agents, what do you do next?” questioned Richter.

“We can hopefully do a lot of great work to build on this robust foundation of myeloma therapies. We know we’re not where we want to be, [and] we need to cross that cure threshold with much more consistency. We just need to keep refining how we can best use the tools that we do have,” Forsberg concluded.

References

1. FDA grants accelerated approval to selinexor for multiple myeloma. FDA. July 3, 2019. Accessed October 6, 2022. https://bit.ly/2LBqyHt
2. Nooka AK, Costa LJ, Gasparetto CJ, et al. Guidance for use and dosing of selinexor in multiple myeloma in 2021: consensus from International Myeloma Foundation Expert Roundtable. Clin Lymphoma Myeloma Leuk. 2022;22(7):e526-e531. doi:10.1016/j.clml.2022.01.014
3. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738. doi:10.1056/ NEJMoa1903455
4. Chen CI, Bahlis NJ, Gasparetto C, et al. Selinexor in combination with pomalidomide and dexamethasone (SPd) for treatment of patients with relapsed refractory multiple myeloma (RRMM). Blood. 2020;136(suppl 1):18-19. doi:10.1182/blood-2020-139858
5. 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
6. Gasparetto CJ, Lentzsch S, Schiller GJ, et al. Deep and durable responses with selinexor, daratumumab, and dexamethasone (SDd) in patients with multiple myeloma (MM) previously exposed to proteasome inhibitors and immunomodulatory drugs: results of phase 1b study of SDd. Blood. 2018;132(suppl 1):599. doi:10.1182/ blood-2018-99-117201
7. FDA approves selinexor for refractory or relapsed multiple myeloma. FDA. December 18, 2020. Accessed October 6, 2022. https://bit.ly/3CCvQMH
8. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3