Renal Response of Selinexor, Pomalidomide, Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients with Renal Impairment: Preliminary Analysis from a Phase 2, Prospective, Multicenter Study

Background Newly diagnosed multiple myeloma (NDMM) patients have a high prevalence of renal impairment (RI). There is a need to identify effective and less toxicity therapeutic regimens. The triplet combination of pomalidomide with bortezomib and dexamethasone (PVD) has been proven to be effective in such entity ^[1]. However, the renal overall response rate (ORR) was 78.8% and 21.2% of patients had no renal response. There is still a critical need to improve renal function in severe RI population. Selinexor is an oral selective inhibitor of nuclear export compound, which specifically blocks exportin 1, with no contraindications based on renal dysfunction. Here we reported preliminary analysis to evaluate the renal and hematologic response of quadruplet combination of SPVD (Selinexor, pomalidomide, bortezomib, dexamethasone) as first-line therapy in NDMM with RI.

Methods This was a prospective, multicenter, phase 2 study (ChiCTR2200064695) in NDMM with renal impairment. Patients with myeloma-related RI [estimated glomerular filtration rate (eGFR) by MDRD < 40ml/min)] were enrolled. RI caused by other reasons than tubular nephropathy was excluded. Sample size was designed to recruit 62 patients. Patients received SPVD (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) for a maximum of 9 cycles. Autologous stem cell transplantation (ASCT) was administrated after 3 to 6 cycles for transplant-eligible patients. Primary endpoint was renal ORR at 3 months. Secondary endpoints included major renal response (≥PR) at 3 months, hematological ORR, minimal residual disease (MRD), progression-free survival (PFS), overall survival (OS), and safety. The definition of both hematologic response and renal response was according to the IMWG criteria.

Results Between Oct 28, 2022 and Jun 30, 2024, 52 patients were enrolled across 17 centers, with a median age of 61 years (range: 44-80). Three patients enrolled in June who did not complete one cycle of treatment were not included in the analysis. The proportion of R-ISS III was 42.9%. Median serum creatine level and eGFR were 357.5 μmol/L [IQR: 201.2-588.8] and 15.5 mL/min (IQR: 8.7-26.2), respectively. There were 10/49 (20.4%) patients requiring dialysis at diagnosis and 16 (32.7%) with high-risk cytogenetic abnormalities [t(4;14), t(14;16), or del(17p)]. Patients with paraskeletal plasmacytomas and peripheral blood plasma cell (1-19%) accounted for 6 (12.2%) and 3 (6.1%), respectively. At the data cut-off date, the median number of SPVD cycles was 4 (range: 1-11). The median follow-up time was 10.9 months (0.5-20.9). Thirteen (26.5%) patients received first-line ASCT after induction therapy. The primary endpoint of renal ORR at 3 months was 85.7%, including 40.8% renal CR and 12.2% renal PR. Best renal response was 87.8%, containing 46.9% CR and 8.2% PR. The ORR of the best hematological response was 89.8% (49% CR or better, 24.5%VGPR and 16.3% PR). The most common treatment emergent adverse events (TEAEs) (incidence >10%) were infection (42.9%), myelosuppression (40.8%), nausea (26.5%), electrolyte imbalances (16.3%), peripheral neuropathy(20.4%)，fatigue (10.2%)，constipation (14.3%). Grade 3 or more hematologic toxicity was seen in 32.7% of the patients, non-hematologic toxicities were thrombocytopenia (32.7%) , infection (30.6%) and neutropenia (24.5%). It should be noted that 4/49(8.2%) patients experienced grade 3-4 hepatic impairment during first cycle. Dose reduction or interruption of pomalidomide occurred in 10 (20.4%) patients due to myelosuppression and infection and 4 (8.2%) patients had dose interruption of selinexor due to nausea or vomiting. Median PFS and OS were not reached. Three patients died from non-myeloma progression causes (1 for severe hepatic impairment and infection, 2 for infection disease).

Conclusion SPVD is an effective and tolerable combination in NDMM patients with RI. TEAEs were typically reported during first 2cycles and severe hepatic impairment should be noted with caution.

Reference

[1] JIAN Y, CHANG L, SHI M, et al. Renal Response of Pomalidomide with Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients with Renal Impairment: A Prospective, Open-Label, Multicenter, Phase 2 Study [J]. Blood, 2022, 140(Supplement 1): 10167-9. doi:10.1182/blood-2022-159361.