Effect of age and frailty on the efficacy and tolerability of once‐weekly selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma

Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once‐weekly selinexor and bortezomib with low‐dose dexamethasone (XVd) improved PFS and ORR compared with standard twice‐weekly bortezomib and moderate‐dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year‐old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM.


| INTRODUCTION
Multiple myeloma (MM) is a malignant neoplasm of clonal B cells originating in the bone marrow (BM). [1][2][3][4] Novel therapeutic approaches and drug combinations are increasingly used to achieve deeper and more durable responses and to potentially overcome mechanisms of resistance. Commonly used multi-drug combinations include immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mAbs), alkylating agents and corticosteroids. [5][6][7] The median age of MM patients at diagnosis is just under 70 years, and MM-related deaths primarily occur in patients ages 65 to 84 years. 8,9 Although there has been an increase in survival for MM patients overall, older patients have not benefitted from novel therapies to the same extent as younger patients. 10 This is highlighted by the stagnant 10-year survival rate reported for patients 75 and older of <10%, while an improvement from approximately 10% to 35% was observed in patients younger than 65. 11 While chronological age is an important factor in determining outcomes, the health status, or fitness, of a patient also plays a key role in the success of a treatment. 12 Higher chronological age is often associated with reduced organ function, such as cardiac, renal, and gastrointestinal impairment, and these comorbidities, in combination with the polypharmacy often linked to their treatment, can cause increased toxicity and decreased efficacy. 13,14 However, younger patients can also be vulnerable, and older patients can be remarkably resilient and tolerate intensive chemotherapy. 15 Thus, frailty, encompassing age and comorbidities, can be a clinically useful criterion that is predictive of survival and toxicity outcomes and is associated with increased death rate, disease progression, and treatment discontinuation. 16 Novel therapies for patients with MM, particularly those who are older and/or frail, are required.
Exportin 1 (XPO1) is a nuclear exporter that controls the nuclear and cytoplasmic localization of most tumors suppressor proteins, IκB (the inhibitor of NF-κB), numerous RNAs, and the glucocorticoid receptor. 17,18 Selinexor forces the nuclear retention of tumor suppressor proteins and other macromolecules by preventing nuclear export without affecting import. 19,20 Overexpression of XPO1 is found in a variety of cancers including MM, and has been linked to an increase in MM bone disease and poor clinical outcomes. 4,18 Selinexor is a potent, oral selective inhibitor of nuclear export (SINE) compound that binds to Cys528 in the cargo-binding pocket of XPO1 and blocks its function. Selinexor has been approved for the treatment of previously treated MM 4,18 as well as diffuse large B-cell lymphoma. 21,22 A recent FDA approval (December 18, 2020) was granted based on the phase 3 BOSTON trial in 402 patients with previously treated MM, which demonstrated that the triplet combination of once-weekly selinexor with bortezomib and low dose dexamethasone (XVd) was superior to the standard twice-weekly combination of bortezomib and moderate dose dexamethasone (Vd). 23 Due to the considerable variability of comorbidities and fitness, defining optimal treatment strategies for elderly or frail patients is challenging. 24 As a consequence, these patients are less likely to receive novel agents and less likely to be included in clinical trials. 25 A number of frailty scores that support clinical decision making in patients with MM have been described, [26][27][28][29][30] and a simplified frailty score that distinguishes frail from non-frail patients based on the Charlson Comorbidity Index (CCI), Eastern Cooperative Oncology Group performance status score (ECOG PS), and age has recently been tested and validated as a predictor of outcome. 31,32 Here we present the results of efficacy and safety analyses of subgroups from the BOSTON study based on age and the simplified frailty score.

| Study details
Details of the BOSTON trial (ClinicalTrials.gov identifier: NCT03110562) have been previously published. 23

| Safety
The majority of patients experienced at least one treatment-emergent adverse event (TEAE). Overall, both hematological and nonhematological grade ≥ 3 TEAEs were observed more frequently in patients treated with XVd compared to those treated with Vd across all age and frailty groups analyzed (Table 2). However, grade ≥ 3 TEAEs were not observed more often in older compared to younger patients, nor in the frail compared to the nonfrail group. Incidence of AEs from pneumonia in the XVd arm was 2.3% in nonfrail patients and 3.5% in <65 as compared to 5.5% in patients ≥65 and 9.1% in frail.
Rates of PN were consistently lower on XVd than on Vd:

DATA AVAILABILITY STATEMENT
Karyopharm Therapeutics agrees to share individual participant data that underlie the results reported in this article (after deidentification), including the study protocol and statistical analysis plan. Data availability will begin 9 months after publication and will be available 36 months after publication. To gain access, data requestors should submit a proposal to medicalinformation@karyopharm.com. Proposals