Carfilzomib, Lenalidomide, and Dexamethasone Followed by Salvage Autologous Stem Cell Transplant with or without Maintenance for Relapsed or Refractory Multiple Myeloma.

Marc-Andrea Baertsch,Sandra Sauer,Karin Jordan,Carsten Müller-Tidow,Mathilde Fougereau,Marc-Steffen Raab,Nicola Giesen,Thomas Hielscher,Iris Breitkreutz,Hartmut Goldschmidt,Jens Hillengass

doi:10.3390/cancers13184706

Abstract

Simple SummaryHigh-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a standard treatment in patients with newly diagnosed multiple myeloma (MM). At relapse, salvage HDCT/ASCT is a treatment option in patients with sufficient benefit from frontline HDCT/ASCT, but no evidence is currently available regarding its role in the era of triplet regimens combining the most active drug classes for relapsed MM. To evaluate the outcome after salvage HDCT/ASCT following re-induction treatment with carfilzomib/lenalidomide/dexamethasone (KRD) and to identify prognostic factors, we conducted a retrospective analysis of patients that had previously undergone frontline HDCT/ASCT. We found that deep remissions achieved with KRd followed by salvage autologous transplantation were associated with favorable PFS and were enhanced by maintenance treatment. Salvage autologous transplantation after state-of-the-art triplet re-induction was a safe and effective strategy for RRMM patients that may offer the chance to avoid refractoriness to multiple novel agents at the next relapse.Salvage high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a treatment option for relapsed and/or refractory multiple myeloma (RRMM). No data are available on salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens. We retrospectively report on 44 patients receiving salvage HDCT/ASCT following re-induction with carfilzomib/lenalidomide/dexamethasone (KRd). All patients received frontline HDCT/ASCT with median time to progression (TTP1) of 2.9 (1.2–13.5) years, enabling paired comparison of frontline and salvage HDCT/ASCT. After re-induction and before salvage transplant, 25/44 patients (57%) attained ≥ very good partial response (VGPR), which increased to 34/44 (77%) at best response after salvage HDCT/ASCT. Median progression-free survival (PFS) was 23.3 months from salvage HDCT/ASCT. Patients with ≥ VGPR at the time of salvage HDCT/ASCT and those receiving maintenance treatment post salvage HDCT/ASCT had significantly superior PFS (hazard ratio (HR) 0.19, p = 0.001 and HR 0.20, p = 0.009). In patients achieving at least an equal depth of response before salvage HDCT/ASCT as before frontline HDCT/ASCT, PFS after salvage HDCT/ASCT was comparable to the frontline situation (p = 0.3). This is the first report of state-of-the-art triplet re-induction and salvage HDCT/ASCT for RRMM after frontline transplantation. Deep remissions achieved with KRd translate into prolonged PFS following salvage HDCT/ASCT and are enhanced by maintenance treatment.

Highlights

Despite significantly improved prognosis of multiple myeloma (MM) following the approval of novel agents, including several proteasome inhibitors (PI), immunomodulators (IMiD), and monoclonal antibodies during the past decade, MM remains an incurable malignancy
We identified n = 44 patients who received salvage HDCT/ASCT after re-induction treatment with KRd between April 2016 and April 2018 at our institution, a tertiary referral center, including 3 patients (7%) in whom LEN was primarily omitted due to intolerance (n = 2) or refractoriness (n = 1)
While we are not able to assess rates of early disease progression with KRd re-induction due to selection of patients based on salvage HDCT/ASCT, we observed deep responses (≥very good partial response (VGPR)) after KRd re-induction in the majority of patients (57%) that correlated with improved progression-free survival (PFS) after salvage HDCT/ASCT

Summary

Introduction

Despite significantly improved prognosis of multiple myeloma (MM) following the approval of novel agents, including several proteasome inhibitors (PI), immunomodulators (IMiD), and monoclonal antibodies during the past decade, MM remains an incurable malignancy. The role of high-dose chemotherapy with melphalan followed by autologous stem cell transplantation (HDCT/ASCT) in frontline treatment of MM is well established and remains the standard of care for eligible patients even in the era of novel agents [2,3,4]. The only randomized controlled phase III trial (GMMG ReLApsE) that compared a novel agent regimen including salvage HDCT/ASCT versus continuous novel agent treatment (LEN/dexamethasone[DEX]) failed to show a PFS (21 vs 19 months) or OS (not reached vs 63 months) benefit in the primary analysis but was hampered by a ~ 30% discontinuation rate before the transplant step [13]. No data are available regarding the effect of salvage HDCT/ASCT after frontline transplantation in the context of re-induction with state-of-the-art triplet regimens

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