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

Abstract

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.

Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development, Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance

“…Additional phase I studies with selinexor-containing combinations were also initiated but have no results yet, namely to study selinexor plus ixazomib plus low dose of dexamethasone in refractory MM [ 180 ]. Phase II and III studies testing selinexor plus bortezomib plus dexamethasone for refractory MM [ 181 , 182 , 183 , 184 , 185 , 186 ] were also started, and additional phase II trials with selinexor plus bortezomib plus dexamethasone plus daratumumab [ 187 ] and selinexor plus carfilzomib [ 188 , 189 ] in refractory MM were also registered.…”

The molecular mechanism and challenge of targeting XPO1 in treatment of relapsed and refractory myeloma

“…In addition, SelVd conferred benefits to patients over Vd regardless of cytogenetic risk [ 178 ]. Furthermore, SelVd is safe and effective in patients regardless of age and frailty scores [ 179 ].…”

Geriatric assessments and frailty scores in multiple myeloma patients: a needed tool for individualized treatment?

“…This led to low CCI values, therefore, the simplified IMWG-frailty index heavily relies on age and performance status alone [ 27 ]. Consequently, retrospectively performed ‘ad hoc’ analyses of the Alcyone, Icaria and Boston trials have suggested alike to the FIRST study [ 40 ], that fit and frail multiple myeloma patients profit from Dara-VMP, Isa-Pd and SVd similarly, albeit differences in the risk groups were small and prospective frailty assessment should have preferably been incorporated upfront into these clinical trials (Table 1 ) [ 39 – 41 , 42 ▪ , 43 ▪ ]. Frailty scores, should therefore, be prospectively planned to be included in research projects to get a much better understanding of how novel agents and treatment interventions can serve both fit and frail multiple myeloma patients [ 9 ], like ongoing representative studies do as summarized in Table 1 .…”