Selinexor combined with bortezomib + dexamethasone: the BOSTON trial

The proteasome inhibitor, bortezomib, has demonstrated clinical efficacy in combination regimens for MM. However, prolonged treatment with bortezomib is associated with high rates of peripheral neuropathy (PN). The phase III BOSTON trial (NCT03110562) aimed to compare the efficacy of selinexor + bortezomib + dexamethasone (SVd) with bortezomib + dexamethasone (Vd) and to determine if SVd reduces the rate of PN compared with Vd alone in patients with relapsed/refractory multiple myeloma (RRMM).

At this year’s virtual ASCO Annual Meeting, Meletios A. Dimopoulos outlined the initial results, summarized below.¹

Study design

• Primary endpoint: progression-free survival (PFS)
• Secondary endpoints: overall response rate (ORR), ≥ very good partial response (VGPR), Grade ≥ 2 PN
• Adult patients with progressive measurable MM (N = 402) with 1–3 lines of prior therapy underwent 1:1 randomization to receive
  • SVd (n = 195) or
  • Vd (n = 207)
• Treatment regimens are presented in Table 1

Table 1. Dosing schedules of SVD vs Vd¹

SVd, selinexor + bortezomib + dexamethasone; Vd, bortezomib + dexamethasone *35-day cycles †Vd biweekly 21-day cycles (Cycles 1–8); Vd weekly 35-day cycles (Cycles ≥ 9)
	Regimen
SVd*	Vd†
Selinexor, 100 mg orally	Days 1, 8, 15, 22, 29	—
Dexamethasone, 20 mg orally	Days 1, 2, 8, 9, 15, 16, 22, 23, 29, 30	Cycles 1–8: Days 1, 2, 4, 5, 8, 9, 11, 12 Cycles ≥ 9: Days 1, 2, 8, 9, 15, 16, 22, 23, 29, 30
Bortezomib, 1.3 mg/m2 SC	Days 1, 8, 15, 22	Cycles 1–8: Days 1, 4, 8, 11 Cycles ≥ 9: Days 1, 8, 15, 22

Results

• Patient characteristics are presented in Table 2

Table 2. Baseline characteristics of patients enrolled in the BOSTON study¹

Characteristic	SVd (n = 195)	Vd (n = 207)
PR, partial response; SVd, selinexor + bortezomib + dexamethasone; Vd, bortezomib + dexamethasone * del (17p), t(14;16), t(14;14) or amp 1q21 † Patients previously exposed to proteasome inhibitors should have achieved at least a PR
Median age, years (range)	66 (40–87)	67 (38–90)
Male, %	59	56
Median time from diagnosis, years (range)	3.8 (0.4–23)	3.6 (0.4–22)
High-risk cytogenetics*, %	50	46
Creatinine clearance 30–60 mL/min, %	27	29
Number of prior lines of therapy, % 1 2 3	51 33 16	48 31 21
Prior treatment, %
Bortezomib†	68.7	70.0
Carfilzomib†	10.3	10.1
Lenalidomide	39.5	37.2
Daratumumab	5.6	2.9

Efficacy

• When compared to Vd, SVd was associated with significantly improved
  • response rates in the overall population and by patient subgroup and PFS (Table 3)
  • depth of response (Figure 1; ≥ VGPR, p = 0.0082)
• When patients in the control arm (Vd) presented a confirmed progressive disease, they were offered to cross over to a selinexor-based treatment
• Although SVd was associated with lower overall PN rates vs Vd (p = 0.001), PN remained the most common AE resulting in treatment discontinuation:
  • SVd: 4.6%
  • Vd: 7.4%

Table 3. Patient outcomes to SVd vs Vd¹

HR, hazard ratio; PFS, progression-free survival; SVd, selinexor + bortezomib + dexamethasone; Vd, bortezomib + dexamethasone * Data cutoff: February 18, 2020.
Patient outcome*	SVd (n = 195)	Vd (n = 207)	p value
Median follow-up, months	13.2	16.5	—
PFS, months	13.93	9.46	HR 0.70, 0.0066
ORR, %	76.4	62.3	0.0012
Aged ≥ 65 years	76.1	64.4	0.0243
High-risk cytogenetics	77.3	55.8	0.0008
Creatinine clearance 30 – 60 mL/min	79.2	56.7	0.0055
1 prior line of therapy	80.8	65.7	0.0082
Prior bortezomib treatment	77.6	59.3	0.0005
Prior lenalidomide treatment	67.5	53.2	0.0354
Median duration of response, months	20.3	12.9	—

 Figure 1. ORRs to SVd vs Vd in the overall population¹

CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; SVd, selinexor + bortezomib + dexamethasone; Vd, bortezomib + dexamethasone; VGPR, very good partial response

Safety

• Treatment-related adverse events (TRAEs) were manageable and reversible
• To date, 17% and 11% of patients discontinued SVd and Vd, respectively, due to AEs or toxicities
• Common Grade 3–4 TRAEs are outlined in Table 4

Table 4. Common Grade 3–4 TRAEs observed in > 5% of patients receiving SVd vs Vd¹

TRAE, treatment-related adverse event; SVd, selinexor + bortezomib + dexamethasone; Vd, bortezomib + dexamethasone
Grade 3–4 TRAEs	SVd (n = 195)	Vd (n = 207)
Thrombocytopenia	39.5	17.2
Anemia	15.9	9.8
Fatigue	13.3	1.0
Neutropenia	8.7	3.4
Cataract	8.7	1.5
Asthenia	8.2	4.4
Nausea	7.7	0
Diarrhea	6.2	0.5

Conclusions

QW SVd demonstrated significantly superior efficacy over BIW Vd, reducing the risk of progression or death by 30%, and standing as a novel, IMiD-free triplet therapy for patients with RRMM. QW administration of SVd has the potential to reduce hospital visits by up to 40% while also reducing levels of bortezomib-associated PN.^1,2