Renal response of selinexor,  bortezomib, pomalidomide, and dexamethasone in newly diagnosed multiple myeloma patients with renal impairment: A phase 2, prospective, multicenter study

Abstract

Abstract Renal impairment (RI) is a common complication of multiple myeloma (MM), accounting for ~40% of newly diagnosed MM (NDMM), which associated with higher mortality, increased hospitalization, and poorer prognosis. Rapid and effective intervention to reverse renal dysfunction is critical for the management of these patients. In our previous study, the triplet combination of pomalidomide with bortezomib and dexamethasone (PVD) showed a renal response rate of 78.8% in patients with clearance of creatinine (CrCL)≤40ml/min. However, 21.2% of patients did not respond to the regimen. Selinexor is an oral selective inhibitor of nuclear export compound, with no contraindications based on renal dysfunction. Here we reported efficacy and safety of SPVD (Selinexor, pomalidomide, bortezomib, dexamethasone) as first-line therapy in NDMM with CrCL≤40ml/min. Methods This was a prospective, multicenter, phase 2 study (ChiCTR2200064695) in NDMM with RI. Patients with myeloma-defined RI [CrCL by MDRD ≤40ml/min] were enrolled. Patients received SPVD (Cycles 1-2: Selinexor 40mg on days 1,8,15, pomalidomide 4mg on days1-14, bortezomib 1.3mg/m2 on days 1,4,8,11, and dexamethasone 20mg on day of and after bortezomib, 21days/cycle; Cycles 3-9: Bortezomib 1.3mg/m2 weekly, the other drugs was given as before, 28 days/cycle). ASCT was administered after 3-6 SPVD cycles for transplant-eligible patients. Primary endpoint was the renal ORR at 3 months. Secondary endpoints included major renal response (≥ partial response) at 3 months, hematological ORR, survival and safety profile. Results Between Oct 28, 2022, and May 7, 2025, 66 patients were enrolled across 20 centers with a median age of 62.5 years (range: 44-80). The proportion of R-ISS III was 37.9%. Median serum creatine and CrCl were 357.5 μmol/L [interquartile range (IQR): 204.4-584.3] and 14.5 mL/min (IQR: 8.5-26.6), respectively. Ten (15.15%) patients requiring dialysis at diagnosis and 5 (50%) of whom were dialysis-independent after induction therapy. Nineteen (28.8%) patients had high-risk cytogenetic abnormalities [t (4;14), t (14;16), or del(17p)]. Patients with paraskeletal plasmacytomas and peripheral blood plasma cell accounted for 7 (10.6%) and 7(10.6%), respectively. At the data cut-off date, 63 enrolled patients who received ≥1 treatment cycle and documented response evaluation was defined as the IIT population. The median follow-up time was 16.6 (IQR: 12.3-24.9) months. The median SVPD cycles were 5 (IQR: 4-8) cycles and 55 patients completed at least 3 cycles treatment. Twenty-one (31.8%) patients received first-line ASCT. The renal ORR at 3 months was 87.3%, including 39.7% renal CR, 12.7% renal PR and 34.9% renal MR. Best renal response was 88.9% (41.3% CR and 15.9% PR). The ORR of the hematological response was 93.6% (61.9% CR or better, 20.6%VGPR and 19.3% PR). For 55 patients who received ≥3 cycles SVPD, the renal ORR at 3 months was 89.5% (42.1% CR, 14% PR) and the best renal ORR was 91.2% (43.9% CR and 17.5% PR). The ORR of hematological response was 96.8%. The most common treatment emergent adverse events (TEAEs) (incidence >10%) were myelosuppression (63.6%), infection (57.6%), nausea (28.8%), peripheral neuropathy (25.8%), fatigue (19.7%)，hypokalemia (13.6%), hyponatremia (13.6%), vomiting (12.1%), constipation (12.1%). Grade ≥3 toxicity included myelosuppression (33.3%), infection (31.8%). It should be noted that 4 patients experienced hepatic failure during 1st cycle, and one patient died. Dose reduction or interruption of pomalidomide occurred in 19 (28.8%) patients due to myelosuppression and infection and 22 (33.3%) patients had dose reduction of Selinexor due to infection or vomiting, which occurred mainly during the early cycles. Seven patients adjusted their regimen for adverse TEAEs: 1 for bone marrow suppression, diarrhea and infection; 1 for heart failure; 1 for erythroderma; 1 for severe rash; 1 for liver failure and 2 for severe gastrointestinal events. The median PFS and OS were not reached. There were 13 patients who experienced disease progression. Three patients had died: one due to liver failure and severe infection; one due to severe infection; and one with the cause of death being unclear. Conclusion The treatment of SVPD has demonstrated a robust renal response rate and hematological response rate, with acceptable safety. Given the complexity of this population of patients, supportive care needs to be strengthened in the early stages of treatment.