Curative Strategy for High-Risk Smoldering Myeloma: Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Followed by Transplant, KRd Consolidation, and Rd Maintenance

Abstract

Purpose: Early treatment of high-risk smoldering myeloma has been shown to delay progression to multiple myeloma (MM). We conducted this trial with curative intention using a treatment approach employed for newly diagnosed patients with MM.

Methods: Patients with high-risk smoldering myeloma (>50% progression risk at 2 years) and transplant candidates were included and received induction therapy with carfilzomib, lenalidomide, and dexamethasone (KRd), six cycles, followed by high-dose melphalan (200 mg/m²) autologous stem-cell transplantation (HDM-ASCT), two KRd consolidation cycles, and Rd maintenance for 2 years. The primary end point was undetectable measurable residual disease (uMRD) rate by next-generation flow after ASCT. Sustained uMRD 4 years after ASCT was the secondary end point.

Results: Between June 2015 and June 2017, 90 patients were included, and 31% met at least one SixtyLightchain MRI (SLiM)-hypercalcemia, renal impairment, anemia, bone disease (CRAB) criterion. After a median follow-up of 70.1 months, 3 months after ASCT, in the intention-to-treat population, 56 (62%) of 90 patients had uMRD, and 4 years later, it was sustained in 29 patients (31%). Five patients progressed to MM, and the 70-month progression rate was 94% (95% CI, 84 to 89). The presence of any SLiM CRAB criteria predicted progression to MM (four of the five patients; hazard ratio, 0.12; 95% CI, 0.14 to 1.13; P = .03). Thirty-six patients showed biochemical progression, and failure to achieve uMRD at the end of treatment predicted it. The 70-month overall survival was 92% (95% CI, 82 to 89). Neutropenia and infections were the most frequent adverse events during treatment, resulting in one treatment-related death. Three second primary malignancies have been reported.

Conclusion: Although a longer follow-up is needed, this curative approach is encouraging and more effective than active MM, with 31% of the patients maintaining the uMRD 4 years after HDM-ASCT.

Trial registration: ClinicalTrials.gov NCT02415413.

FIG 1.

Disposition of patients. ASCT, autologous stem-cell transplantation; CT, computed tomography; IC, informed consent; MDE, myeloma-defining event; SMM, smoldering multiple myeloma.

FIG 2.

Kaplan-Meier estimates of (A) time to biochemical progression and (B) landmark time to biochemical progression by MRD status at the end of maintenance. MRD, measurable residual disease.

FIG 3.

Kaplan-Meier estimates of (A) TTP to myeloma; (B) TTP to myeloma by the presence of any SLiM-CRAB criteria; and (C) OS in the ITT population, which included all patients who started treatment. CRAB, hypercalcemia, renal impairment, anemia, bone disease; ITT, intention-to-treat; MRI, magnetic resonance imaging; OS, overall survival; SliM, SixtyLightchain MRI; TTP, time to progression.

FIG A1.

(A) Time to biochemical progression by the presence of HRCAs according to the International Myeloma Working Group [t(4;14), t(14;16) and/or del(17/17p). (B) Time to biochemical progression by the presence of HRCAs according to the International Myeloma Working Group [t(4;14), t(14;16) and/or del(17/17p)] plus abnormalities on 1q chromosome. HRCA, high-risk cytogenetic abnormalities; TTBP, time to biochemical progression.