Selinexor-Based Triplet Therapy Improves Outcomes in Certain Patients with RRMM

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In the first article of a 2-part series, Sumit Madan, MD, discusses how the combination of selinexor, bortezomib, and dexamethasone shows superior survival outcomes for patients with relapsed/refractory multiple myeloma that are proteasome inhibitor naive or have high-risk cytogenetics.

CASE SUMMARY

A 70-year-old White woman was diagnosed with stage I multiple myeloma and fluorescence in situ hybridization showed deletion 17p (del17p) in her disease. The patient had a prior medical history of stage 3 chronic kidney disease and moderate renal impairment. She declined autologous stem cell transplant, and received lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd). She had a very good partial response (VGPR), so lenalidomide maintenance was continued. Two years later the patient relapsed after reporting mild fatigue but continued to work full-time​. Bone marrow plasma cells, light chains, and M protein were all rising, and her kidney function worsened to stage IV chronic kidney disease. The patient was then given daratumumab (Darzalex), pomalidomide (Pomalyst), and dexamethasone and had a VGPR. One year later she experienced a second relapse of her disease with renal function continuing to decline. The patient was started on selinexor (Xpovio), bortezomib, and dexamethasone (SVd) based on her progressive renal impairment, del17p status, and prior therapies. She achieved a VGPR.

Targeted Oncology: What led to the BOSTON trial (NCT03110562) that looked at the triplet therapy of SVd?

SUMMIT MADAN, MD: [Selinexor] initially was approved in 2019.1 It was due to the single-arm [STORM study (NCT02336815)] of extremely sick patients where selinexor was given twice a week in combination with dexamethasone. Based on the response rates, the drug was approved, but then they had to do the phase 3 BOSTON trial. The BOSTON study looked at patients with relapsed/refractory multiple myeloma, and more than 400 patients were randomly assigned to receive SVd or just Vd.2 SVd was given once a week, selinexor at 100 mg once a week, [1.3 mg/m2 of] bortezomib given once a week alongside dexamethasone. It was compared with twice-weekly Vd given [4 times a week for 1-8 cycles], and they were looking at a primary end point of progression-free survival [PFS].2

Sumit Madan, MD

Hematologist-Oncologist

Banner MD Anderson Cancer Center

Gilbert, AZ

Sumit Madan, MD

Hematologist-Oncologist

Banner MD Anderson Cancer Center

Gilbert, AZ

What were the results of this trial?

This was a positive trial that eventually led to the approval of SVd, with [efficacy results in] favor of SVd.... Essentially, by decreasing the dose of the selinexor to once a week we were also able to decrease the toxicity quite a bit. In terms of the fatigue, the nausea, the gastrointestinal adverse events [AEs], and the thrombocytopenia, all of them were significantly better compared with the STORM trial. [Further], peripheral neuropathy was significantly higher with the doublet compared with the triplet.2

Please describe the patient population of this trial.

[Looking at] the baseline characteristics of patients [on the BOSTON study], many were naive to a proteasome inhibitor [PI].2 About 100 patients were not refractory to either bortezomib or carfilzomib [Kyprolis], so it was a well-balanced group in both the triplet arm as well as the doublet. A majority of the patients received 1 or 2 prior lines of therapy, and approximately 40% of the patients had high risk, and patients with moderate renal impairment were included in the study as well.2 We are basically looking at this subgroup of patients who were naive to a PI.

What were the survival outcomes for patients naive to a PI?

I would pick SVd in a patient who is still naive to a PI, because you can clearly see the superiority of the selinexor- [based triplet].2 With the addition of selinexor to Vd, we were essentially able to triple the PFS [in this group of patients]: median PFS was 9.7 months [95% CI, 8.4-23.7] with the doublet compared with 29.5 months [95% CI, 27.5-Not reached] with the triplet with a very impressive HR of 0.29 [95% CI, 0.14-0.63, P < .001].2

This is some of the highest PFS that we see in patients in the relapsed setting. For a patient who is getting first-time daratumumab, lenalidomide, and dexamethasone, they are getting a PFS [approximately] more than 5 years, and to again give a triplet where you can expect to get a PFS of approximately 2.5 years, I think that would be a great combination to use for patients who are not yet refractory to bortezomib.

How did the triplet fare for patients with either high-risk or standard-risk cytogenetics?

How the drug works is that it's basically an XPO1 inhibitor, so it blocks the export of the nuclear proteins from inside the nucleus to the cytoplasm, so it keeps all your...tumor suppressor proteins within the nucleus. It works well in patients who have del(17p) and high-risk cytogenetics. When you look at the subgroup of patients that have higher-risk cytogenetics, especially [those patients with] del(17p) or more than 4 copies of 1q, showed significant improvement when looking at the response rate.3

The overall response rate [ORR] [for patients with higher-risk cytogenetics] was 78.6% with the triplet compared with 57.7% with the doublet with an [odds ratio of 2.68 (95% CI, 1.28-5.62)] and a significant P-value of .004. [The ORR favored the triplet] in the standard-risk cytogenetics group as well [with an ORR of 75.2% in the SVd group vs 64.7% in the Vd arm (OR, 1.65; 9% CI, 0.97-2.83, P = .033].3 For patients with high-risk cytogenetics, which we know are bad actors, we don't have too many good options for these patients, but now I think selinexor becomes a very good options for these patients.

References

1. FDA grants accelerated approval to selinexor for multiple myeloma. News release. FDA. July 3, 2019. Accessed November 22, 2023. https://tinyurl.com/3smvfssn

2. Mateos MV, Englehardt M, Lelu X, et al. Efficacy, survival and safety of selinexor, bortezomib and dexamethasone (SVd) in patients with lenalidomide-refractory multiple myeloma: subgroup data from the BOSTON trial. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract P886. Accessed November 22, 2023. https://tinyurl.com/3efvuzn8

3. 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

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