Despite the favorable response rates and clinical benefits seen in the STORM study, the 160 mg selinexor cumulative weekly dose resulted in high rates of adverse events (AEs) ( Table 2 ) (17). The major Grade ≥3 non-hematological toxicities reported in STORM (n=202) were fatigue (22%) and nausea (9%). Tolerability, as assessed indirectly via median duration of exposure (mDOE), was 3.8 months (9, 10). Toxicities resulted in dose reductions and modifications in 80% of patients (9).

Subsequent studies evaluated lower selinexor doses and frequencies. The phase 3 BOSTON study (NCT 031110562) compared the efficacy of once-weekly (QW) selinexor 100 mg and subcutaneous bortezomib 1.3 mg/m² combined with twice-weekly (BIW) dexamethasone 20 mg (SVd) to standard twice-weekly bortezomib and dexamethasone (Vd) in patients with MM that had progressive disease despite 1 – 3 prior lines of therapy (12). SVd received United States Food and Drug Administration (US FDA) approval in 2020 based on significantly improved PFS as determined by an independent review committee. After median follow-up of 13.2 months (SVd) and 16.5 months (Vd), median PFS was 13.93 and 9.46 months, respectively (HR 0.70 [95% CI 0.53 – 0.93], p=0.0075). The prespecified endpoint of ORR was 76.4% (SVd) versus 62.3% (Vd) (p = 0.0012), and ≥ very good partial response (VGPR) rates were 44.6% (SVd) versus 32.4% (Vd) (p=0.0082). The European Medicines Agency approved SVd in March 2021 for patients with MM who received at least one prior therapy.

Compared to twice-weekly 80 mg selinexor (Sd) in the STORM trial, the once-weekly 100 mg selinexor BOSTON regimen (SVd) showed improved tolerability, with ≥ Grade 3 non-hematologic toxicities of fatigue and nausea reduced to 13% and 8%, respectively, in the BOSTON study (9, 12). Selinexor dose reductions occurred in 65% of SVd-treated patients, with a median final dose of 71.4 mg/week. Patients who had a dose reduction compared to those before dose reduction had lower duration-adjusted AE incidence rates (18). Notably, patients in the BOSTON study who had a selinexor dose reduction had a longer median PFS compared to those who did not (16.6 versus 9.2 months), suggesting that lower selinexor doses have continued activity in RRMM (18). Furthermore, SVd treatment in the BOSTON study showed that ORR was higher among patients with dose reductions compared to those without (82% versus 67%). While some caveats to the interpretation of these results can be postulated, such as more motivation to maintain a regimen with dose reduction in patients who were already responding well, or the fact that patients with stable or slowly responding disease may have had earlier discontinuation of treatment, these data showed an emerging impact of lower dose, weekly schedules of selinexor in previously treated MM (18).

Following BOSTON, the STOMP trial, a multi-arm, open-label, Phase 1b/2 study, evaluated selinexor in various triplet and quadruplet combinations in newly diagnosed and relapsed/refractory MM. S-containing triplets comprised other commonly used anti-myeloma agents such as daratumumab (D) (15), pomalidomide (P) (19), lenalidomide (R) (13), and carfilzomib (K) (20), as outlined in Table 2 (13, 15, 19, 20).

Among patients treated with SPd in STOMP (QW selinexor 40 mg [SPd-40] or 60 mg [SPd-60]) and XPORT-MM-028 (SPd-40), ORR and ≥VGPR in the SPd-40 cohort were 50% and 29%, respectively, and 65% and 30% in the SPd-60 cohort. Despite deeper responses in the SPd-60 cohort, as of June 30, 2023, mPFS was numerically longer, however did not reach statistical significance with SPd-40 (18.4 months [95% CI: 6.5, NR]) compared to SPd-60 (9.5 months [95% CI: 7.6, NR]) (16). The mDOE was also longer with SPd-40 (28 weeks) compared to SPd-60 (22 weeks). Similar to the BOSTON experience, lower selinexor dosing led to lower AE incidence, which was observed in the context of longer mDOE and mPFS for patients that were able to stay on treatment more reliably. Patients treated with SRd in STOMP (selinexor doses of 60 mg QW, 80 mg QW, and 60 mg BIW) had an ORR of 60%, PFS of 9.6 months, and OS that was not reached ( Table 2 ), again showing activity for lower dose weekly selinexor. Overall, the total weekly selinexor dose in STORM was 1.6x higher than in BOSTON and 1.6 - 4x higher than preferred dosing in combination with other agents tested in STOMP cohorts. Taken together, lower selinexor doses, whether initiated at baseline or following dose modification, allows patients to stay on selinexor longer, thereby improving outcomes.

Most randomized trials evaluating second-generation proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), or agents with novel mechanisms of actions after early relapse have not included many patients with triple-class refractory (TCR) MM, largely due to trial-specific eligibility criteria (19, 20). However, with increasing use of frontline “quad” regimens, there is a growing need to address both non-responders and first-relapse patients with TCR MM. Recent studies in patients with RRMM treated with fewer prior lines of therapy have shown poor efficacy for triple-class exposed (TCE) or TCR MM treated with physician’s choice of subsequent therapy (24). Data from the LocoMMotion, MAMMOTH, and control arm of the KarMMa-3 trials, report that patients with at least TCE RRMM had PFS of 4.6, 3.4, and 4.4 months, respectively, and ORRs for the next line of treatment of 30 - 40% after anti-CD38 failure (24). These next line of treatments included different PIs, IMiDs, monoclonal antibodies, and alkylating chemotherapy regimens; selinexor-based combinations were used in < 1% of patients and therefore were not evaluated in the TCR MM context.

A retrospective analysis of 62 patients with RRMM from BOSTON and STOMP who had prior anti-CD38 exposure (median 4 prior lines), had ORRs of 52% (SPd), 56% (SVd), and 65% (SKd); only 6% of these patients received twice-weekly SPd dosing (22). Most patients were TCE and > 50% were TCR. Median PFS was 8.7 (SPd), 6.7 (SVd), and 15.0 (SKd) months and median OS was 20.4 months, with SPd at 9.6 months, SVd at 16.9 months, and SKd at 33.0 months (22). Adverse events for S-containing triplets were manageable with standard supportive care and dose modifications ( Table 2 ). Grade ≥3 fatigue and nausea occurred in <5% of patients with SPd and SKd receiving with once-weekly dosing. Given historically poor outcomes in TCE RRMM with PIs, IMiDs, and anti-CD38 monoclonal antibodies who undergo drug-class recycling or turn to alkylator-based chemotherapy, these data suggest that once-weekly, appropriately selected S-based triplets offer a viable alternative, especially when access to T-cell-based immunotherapies is limited (22).

Chimeric antigen receptor T cell (CAR-T) and T-cell engaging bispecific antibody therapies have revolutionized our ability to manage RRMM. The single-agent activity of T-cell redirecting therapies established a new benchmark in RRMM, achieving ORR of 80 - 90% with CAR-T, and 50 - 70% with bispecific antibodies ( Table 3 ). The two approved CAR-T cell products for MM, idecabtagene vicleucel and ciltacabtagene autoleucel, can be accessed in early lines of therapy based on the results of the KARMMA - 3 and the CARTITUDE - 4 phase 3 trials (39), while ongoing studies are generating data in the first line as well (40). This new era of MM therapeutics is welcome, however given that they are not curative, two issues must be addressed: 1) maximizing T-cell based therapy outcomes given their associated costs, logistical planning, and potential adverse effects; and 2) effectively addressing and treating a new population of RRMM that has failed bispecific antibody or CAR-T treatment. Early investigation into CAR-T efficacy has shown that factors such as T-cell exhaustion, an acquired inability for cytotoxic T-cells to target and eliminate tumors, may play a role in outcomes. A search for T-cell sparing agents to use in earlier line MM treatment to limit T-cell exhaustion and to support the efficacy of subsequent T-cell therapies is underway. IMiDs and cereblon E3 ligase modulatory drugs (CelMODs) have already been shown to increase cytotoxic T-cell activity as a downstream effect of cereblon targeting (41). Clinical data support the use of XPO - 1 inhibitors, such as low dose weekly selinexor, as potentially T-cell sparing in both the pre-apheresis stage (42) and the bridging period between apheresis and CAR-T infusion (43). Additional studies are underway to further investigate the interaction between XPO1 inhibitors, T cells, and the immune microenvironment. A retrospective study performed by the Myeloma CAR-T consortium examined the impact of various bridging regimens, as compared to no bridging, in patients with RRMM who received idecabtagene vicleucel. As reported, patients without the need for a bridge regimen to control the RRMM had the best outcomes, likely due to having more indolent disease. Amongst the patients who required bridging, those who received IMiD or S-based bridging had numerically longer PFS after CAR-T than those who received PI or alkylating chemotherapy bridging, with IMiD ± mAb combos showed comparable PFS to no-bridging (median PFS: 12.01 months vs. 11.48 months). In comparison to the IMiD ± mAb combination PFS, selinexor was 9.77 months, versus lower results with PI combos (6.41 months), and alkylator therapy (6.51 months) (43). These results suggest that S-based bridging combinations do not lead to inferior idecabtagene vicleucel outcomes, although the data specifying which doses and schedules of selinexor that were used as bridging was not reported.

A real-world evidence study reported the clinical outcomes of 45 patients treated with a selinexor regimen and subsequently received idecabtagene vicleucel, ciltacabtagene autoleucel, or another anti-BCMA CAR-T under development. The majority (75.5%) of patients received low dose selinexor (median 80mg weekly starting dose), most commonly in combination with carfilzomib (35%). The median line of selinexor exposure was seventh, while CAR-T was the ninth. An exploratory multivariate analysis determined that receiving selinexor in the line of therapy prior to CAR-T was associated with the best PFS and OS outcomes with hazard ratios of 0.4 (95% CI 0.113 – 1.09) and 0.08 (95% CI 0.02 – 0.46), respectively (42).

A report of S-containing regimens in RRMM patients who had progressed or failed anti-BCMA CAR-T showed objective responses in 6 of 7 patients, with 1 stringent complete response (treated with SKd), 3 VGPRs (2 treated with SKd and 1 with SVd), and 2 partial responses (PRs, 1 each with Sd and SVd). The ORR was 86% with a clinical benefit rate (CBR) of 100% with 1 additional minor response with SKd (44). A subsequent case series of 11 patients with progression after anti-BCMA (non-CAR-T) treatment (7 were anti-BCMA antibody drug conjugate pretreated) from the STOMP trial, all with weekly dosing of selinexor, reported ORR and CBR rates of 63.6% and 81.8%, respectively, and no cases of disease progression as a best response (23). Median DOR and PFS were not reached after median follow-up of 14.3 months and median OS was 14.8 months ( Table 2 ). Response was >6 months for 5/7 responders and up to at least 15.6 months, with 6-month PFS probability determined to be 75%.