Selinexor‐based regimens in patients with multiple myeloma after prior anti‐B‐cell maturation antigen treatment

Abstract There is a lack of consensus on therapy sequencing in previously treated multiple myeloma, particularly after anti‐B‐cell maturation antigen (BCMA) therapy. Earlier reports on selinexor (X) regimens demonstrated considerable efficacy in early treatment, and after anti‐BCMA‐targeted chimeric antigen receptor‐T cell therapy. Here, we present data from 11 heavily pretreated patients who predominantly received BCMA‐antibody‐drug conjugate therapy. We observe that X‐containing regimens are potent and achieve durable responses with numerically higher overall response and clinical benefit rates, as well as median progression free survival compared to patients’ prior anti‐BCMA therapies, despite being used later in the treatment course. In an area of evolving unmet need, these data reaffirm the efficacy of X‐based regimens following broader anti‐BCMA therapy.

Combinations of drugs with selinexor have shown strong clinical benefit in heavily pretreated MM, including MM refractory to anti-BCMA CAR-T therapy. In a previous report of CAR-T pretreated MM, X-containing regimens led to objective responses in seven patients with one stringent complete response, three very good partial responses (VGPRs), and two partial responses (PRs) ( [11]. Importantly, a recent report of non-X-containing treatment outcomes in seven patients with MM refractory to ide-cel showed an ORR to the first subsequent therapy of 28.5% (one VGPR and one PR), a CBR of 57.1% (one additional MR, and one stable disease [SD], and median progression-free survival [PFS] of 2 months) [12].
Although selinexor is approved for use in patients with ≥1 prior therapy in combination with bortezomib and dexamethasone, to better understand the effect of X-containing regimens in patients with heavily pretreated MM, particularly in those previously treated with anti-BCMA agents not limited to CAR-T, we evaluated the responses to therapy with selinexor post-anti-BCMA therapy in the selinexor and backbone treatments of multiple myeloma patients (STOMPs) study. Here, we report treatment outcomes for eleven new patients from STOMP who were previously treated with anti-BCMA agents, including seven who received an anti-BCMA ADC.
STOMP is a multicenter, open-label, phase 1b/2 clinical study designed to assess the efficacy and safety of 10 combination therapies of selinexor with backbone agents in 11 study arms in patients with previously treated or newly diagnosed MM. The study is ongoing in the US and Canada (ClinicalTrials.gov NCT02343042). The CBR was defined as ORR plus minimal response. Minimal response was defined by the 2016 IMWG response criteria as >25% but <49% reduction of serum M-protein and reduction in 24-hr urine M-protein by 50%-89%. In addition to the above criteria, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas was also required [13].
Eleven patients who received prior anti-BCMA therapy were treated with five different selinexor-containing regimens, including nine (81.8%) with three triplets and two (18.2%) with two quadruplet regimens (Table 1)   patients assigned to selinexor, bortezomib, and dexamethasone (three each with PNA and sepsis) [5], and none of the 32 patients treated with selinexor, carfilzomib, and dexamethasone triplet regime in STOMP [14] had any infection-related deaths reported.
High rates of anti-MM activity and tolerability of the XVd, Xcarfilzomib and dexamethasone, and X-pomalidomide and dexamethasone triplets are described in heavily pretreated MM [5,[14][15][16]. The ORR, CBR, and PFS rates reported here with X-containing regimens are numerically higher compared to those recently reported after non-X-containing therapy in the similar BCMA-refractory space (albeit small comparative numbers) [12]. Nonetheless, this is promising for patients with anti-BCMA refractory MM, is consistent with earlier reports [11], and with no evidence of cross-resistance between Xbased and other MM regimens. This further reaffirms robust activity of X-containing regimens in not only CAR-T cell, but also ADC anti-BCMA pretreated MM.
Taken together, among heavily previously treated patients, the majority with MM refractory to ADC (versus CAR-T) anti-BCMA therapy, X-containing regimens had impressive potency with durable responses and ≥6 month tolerability. Notably, X-containing regimens