Phase 3 BOSTON Trial for RRMM
An expert hematologist-oncologist reviews the randomized, phase 3 BOSTON trial of a selinexor-based triplet regimen for the treatment of multiple myeloma.
Clifton C. Mo, MD: Selinexor was initially FDA approved for patients with penta-refractory disease in July of 2019 in combination with low-dose dexamethasone, and with a twice-weekly dosing of selinexor. This was an accelerated approval with the understanding that full approval would be predicated upon the results of the randomized phase 3 BOSTON study of once-weekly selinexor, Velcade [bortezomib], and dexamethasone vs Velcade [bortezomib] and dexamethasone alone.
The BOSTON study recently met its primary end point of progression-free survival [PFS] in 2020, and fortunately, it confirms the superiority of this triplet regimen over Velcade [bortezomib] and dexamethasone alone. There was a statistically significant improvement in median progression-free survival of approximately 14 months with a selinexor-based regimen vs a little over 9 months with Velcade [bortezomib] and dexamethasone alone.
An important thing to note about this study is that it was the first of its kind to lower the dose of the backbone regimen, in the sense that patients in the control arm received twice-weekly Velcade [bortezomib], and only once-weekly Velcade [bortezomib] in the selinexor, Velcade [bortezomib], and dexamethasone arm, which equated to about a 40% reduction in total Velcade [bortezomib] exposure, as well as a 25% reduction in total dexamethasone exposure in the triplet arm. Despite these lower doses, there was still a significant improvement in PFS. Importantly, this held up across multiple subgroups, including subgroups of patients with cytogenetically high-risk disease and specifically with patients with the 17p or TP53 deletion, as well as patients who were more elderly or over 65 years old.
The No. 1 thing that we’ve learned from the BOSTON study is that the XVd [selinexor, bortezomib, dexamethasone] regimen is superior to Velcade [bortezomib] and dexamethasone alone, and provides a clinically meaningful benefit to patients with relapsed/refractory myeloma who have received at least 1 prior line of therapy. The other important thing we’ve learned from the BOSTON trial is that the toxicity or potential for higher grade toxicity of selinexor is considerably lower when given once weekly, according to the BOSTON trial schedule, as opposed to twice weekly, which is how it was initially FDA approved. When it was given twice weekly in a more heavily treated patient population, we saw a fairly high incidence of high-grade hematologic toxicity, predominantly thrombocytopenia, as well as anemia and neutropenia, although the incidence of febrile neutropenia remained low.
Perhaps more importantly, there was not a high, but a significant incidence of grade 3 nonhematologic toxicities on the STORM trial in the more heavily pretreated patient population, most notably nausea, anorexia, fatigue, and hyponatremia. We see a significant reduction in the rates of high-grade toxicities, both hematologic and nonhematologic, in the BOSTON study compared to the STORM study, which means that, when given only once weekly as opposed to twice weekly, selinexor is generally a much better-tolerated drug. In fact, in the BOSTON study, the only nonhematologic toxicity that we saw at greater than 10% incidence at a higher grade, meaning grade 3 or higher, was fatigue. Every other nonhematologic toxicity was less than 10%, demonstrating that the once weekly dosing of selinexor makes arguably all the difference in the world in terms of a patient’s likelihood of being able to tolerate it in both the short and long term.
Transcript edited for clarity.
Case: A 79-Year-Old Woman with Multiple Myeloma
Initial Presentation
- A 79-year-old woman presented with intermittent nausea, decreased appetite and tingling and numbness in her feet bilaterally
- PMH: HTN, medically controlled
- PE: thin, tired appearing woman, otherwise unremarkable; grade I peripheral neuropathy
- ECOG PS 0
Clinical Workup
- Labs: Hb 9.6 g/dL, calcium 10.5 mg/dL, LDH 210 U/L, creatinine 1.1 mg/dL, albumin 3.8 g/dL, beta-2 microglobulin 3.2 mcg/mL, M-protein 2.9 g/dL, serum free kappa light chains 4.4 mg/dL, CLCr 35mL/min
- Hepatitis B and C negative
- Skeletal survey and MRI showed a lytic lesion in her spine L3/L4
- Bone marrow shows 45% clonal plasma cells IgG k
- FISH: hyperdiploid
- Diagnosis: R-ISS stage I MM
Treatment
- Initiated lenalidomide + bortezomib + dexamethasone for 8 cycles + lenalidomide maintenance for 9 months
- Follow-up at that time revealed disease progression
- Initiated selinexor + bortezomib + dexamethasone
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