BOSTON Trial Shows Efficacy of Selinexor in R/R Multiple Myeloma

Joshua Richter, MD

Associate Professor of Medicine

Tisch Cancer Institute

Director, Multiple Myeloma

Blavatnik Family-Chelsea Medical Center at Mount Sinai

New York, NY

Targeted Oncology^TM: What is the history of FDA approvals for selinexor (Xpovio) in multiple myeloma?

Selinexor had 2 FDA approvals in multiple myeloma alone. It has a third FDA approval in diffuse large B-cell lymphoma.¹ In multiple myeloma [Selinexor] received its first FDA approval on July 3, 2019 based off of the STORM study [NCT02336815], looking at selinexor plus dexamethasone in triple-class–refractory patients with myeloma, and then in December of 2020 it received a second FDA approval based on the phase 3 BOSTON study [NCT03110562].^2,3

BOSTON was a head-to-head, randomized regimen of XVd [selinexor, bortezomib (Velcade), and dexamethasone] vs Vd [bortezomib and dexamethasone].⁴ The Vd was given the way we used to give Vd, on a 3-week cycle, days 1, 4, 8, and 11 every 21 days. The XVd was given with weekly bortezomib and weekly selinexor; however, it was given on a 35-day cycle. So, in reality, this more mimicked the old RVd-lite [modified lenalidomide (Revlimid), bortezomib, and dexamethasone] paper from a number of years ago from Elizabeth K. O’Donnell, MD.⁵ Here bortezomib was given at days 1, 8, 15, and 22. The selinexor was given 100 mg weekly every week without a break, and of note, the original STORM study dosed selinexor with 80 mg twice a week.⁶ Here in BOSTON it was once a week at 100 mg.⁴

This [treatment] was for early-relapsed patients who had received 1 to 3 prior lines [of therapy with approximately 50% having 1 prior line]. The average age was in the mid 60s. There was a significant number of high-risk cytogenetic patients in this study. And, of note, about 40% of patients had prior autologous stem cell transplant and many of them were exposed to a lot of our other drugs, including IMiDs [immunomodulatory drugs], PIs [proteasome inhibitors], and daratumumab [Darzalex].

The primary end point for this study was progression-free survival [PFS], and here we saw an improvement in the median PFS between XVd and Vd of [9.46] for Vd vs [13.93] months for XVd.

Looking across a variety of different subgroup analyses, for patients with baseline ECOG of 0, it favors XVd but is not statistically significant. However, for patients with an ECOG of 1 it not only favors XVd but it is statistically significant because it does not cross the 1 line. There were several subgroups that specifically had favorable outcomes with the triplet over the doublet: those older or equal to the age of 65, patients who were non-frail, women, White patients.

Daratumumab is used earlier and earlier…. [Based on] the MAIA [NCT02252172] data, daratumumab/lenalidomide/dexamethasone [Dara-Rd] is used up front. One of the things that’s interesting is that…prior to 5 years ago, almost everyone was getting bortezomib as part of their upfront line of therapy and many patients still are. Now, given the rise of Dara-Rd, we have a new group of patients are PI naive entering early relapse. It’s nice to see some data for this group of patients who are getting daratumumab up front [though it was not statistically significant].

When it comes to overall response rates [ORRs], XVd had an ORR of approximately 76%. It also had a higher proportion of deeper responses with the triplet over the doublet. The median time to response was 1.1 months and the median duration of response [DOR] was 20.3 months with XVd [vs 1.4 months and 12.9 months, respectively, with Vd]. So XVd had quicker time to response, higher ORR, deeper response, and more durable remission.

What did analyses show about certain high-risk features?

For patients with high-risk cytogenetics, there are a number of patients with a variety of cytogenetic lesions: 17p, 1q21 gain, [t(4;14), and t(14;16)]. We saw patients with high-risk cytogenetics only getting a PFS of [8.61] months with Vd, vs [12.91] months with XVd, and still getting some deep responses and significant DORs in patients with high-risk disease.⁷

The other area that I think is important is looking at those with renal impairment. I think we start to look at a lot of these great studies coming out with great new drugs, and not a lot of them have data in patients with renal insufficiency as they’re often excluded from clinical trials. Here they grouped people into normal renal function greater than 60 mL/min, mild renal impairment 40 mL/min to 60 mL/min, and less than 40 mL/min with significant renal impairment. In the normal patients, we see the standard response that we see in the general cohort of [approximately] 13.2 months median PFS with XVd versus 9.6 months with Vd.⁸

But when we start going down into the more renally impaired patients, where we know outcomes are generally worse, we still see the improvement with the triplet over the doublet [regimen when] comparing a median PFS of 16.6 months with XVd vs 7.6 months with Vd in patients with mild renal impairment, compared to 7.6 months with XVd vs 4.3 months with Vd in the more significantly impaired patients. In terms of ORR, you look at some of the renal impairment patients getting ORR over 80% with XVd compared with the 50% to 59% with the Vd alone. There were significantly longer durations of remission, especially long median DORs in the more significantly renally impaired patients.

What were the safety outcomes of XVd vs Vd in the BOSTON trial?

In terms of adverse events [AEs], there’s a number of AEs that are known to [be related to] selinexor.⁴ One is asthenia. It does induce cytopenias and it has a predilection for the platelets, so thrombocytopenia is something that is seen in patients receiving selinexor. Decreased appetite, nausea, and vomiting are certainly on the list as well. Treatment-related AEs that led to discontinuation are slightly higher in the XVd group over the Vd group. Dose modifications were similarly high amongst both groups, and most selinexor-related AEs were reversible and mitigated with supportive care.

_REFERENCES:

_{1. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. News release. June 22, 2020. Accessed March 20, 2023. https://bit.ly/3FBxwHn}

_{2. FDA grants accelerated approval to selinexor for multiple myeloma. News release. FDA. July 3, 2019. Accessed March 20, 2023. https://bit.ly/2LBqyHt}

_{3. FDA approves selinexor for refractory or relapsed multiple myeloma. News release. FDA. December 19, 2020. Accessed March 20, 2023. https://bit.ly/3Z2NC3U}

_{4. 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}

_{5. O'Donnell EK, Laubach JP, Yee AJ, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol. 2018;182(2):222-230. doi:10.1111/bjh.15261}

_{6. 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}

_{7. Richard S, Chari A, Delimpasi S, et al. Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk. Am J Hematol. 2021;96(9):1120-1130. doi:10.1002/ajh.26261}

_{8. Delimpasi S, Mateos MV, Auner HW, et al. Efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in comparison with standard twice-weekly bortezomib and dexamethasone in previously treated multiple myeloma with renal impairment: Subgroup analysis from the BOSTON study. Am J Hematol. 2022;97(3):E83-E86. doi:10.1002/ajh.26434}