Low Non Relapse Mortality and Good Hematological Response after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients with Renal Insufficiency at Transplant: A Prospective Société Francaise De Greffe De Moelle-Thérapie Cellulaire Observational Study

Background: High dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (ASCT) is widely used in newly diagnosed multiple myeloma (NDMM) patients as upfront therapy. However, the safety and efficacy of ASCT in patients with renal insufficiency (RI) is controversial, which have led to an inconsistent arbitrary cut-off for creatinine clearance (CrCl) for performing ASCT. Here, we analyzed prospectively the outcomes of NDMM patients with severe RI who underwent ASCT.

Methods: We enrolled prospectively, from April 2018 to Sept 2020 in 17 SFGM-TC centers, 50 NDMM patients who had a serum CrCl of <40 mL/min (CKD-EPI) at the time of ASCT. They all received bortezomib-based induction therapy and had achieved at least a partial response before proceeding to ASCT. The recommended dose of melphalan was 140 mg/m² and it was infused at least 3 x10⁶/kg autologous CD34+ cells. Consolidation/maintenance post-ASCT was according to the physician's choice. The primary endpoint was non-relapse mortality (NRM). Overall survival (OS) and progression free survival (PFS) were estimated with Kaplan-Meier method, and cumulative incidence of relapse (CIR) and NRM were estimated using cumulative incidence function to account for competing events of death without relapse or death unrelated to myeloma.

Results: At diagnosis, a renal biopsy was done in 9 (no amyloidosis, 6 cast nephropathy and 3 others). 82% were male. The median medullary plasmocytosis was 42% (11-80), light chain MM was frequent in 28 patients (56%), IgG in 13 (26%), IgA in 8 (16%) and 1 IgD. Seven (16%) had extra medullary disease. The ISS score was I (1), II (7) and III (34) (8 missing). At enrollment at the time of ASCT: median age was 56 years (33-68). Induction chemotherapies had included bortezomib plus IMiDs in 28 (56%) patients, CyBorDex in 17 (34%), bortezomib dex in 4 (8%) and 1 other (2%). Thirty nine patients (80%) had received 4 or less cycles of chemotherapy and 13 (26%) had ≥2 lines of chemotherapy. The pre-transplant disease status was sCR in =3 (6%), CR in =7 (14%), VGPR in =22 (45%), and PR in =17 (35%) of patients (1 not evaluable ( NE)). The number of days of cytapheresis was 2 or less in 93% of cases and the median number of CD34+ cells collected was 5.4 x 10⁶ (1.1-15.1) (3 missing).The HCT-CI score was 0 (4), 1 (8), 2 (11), 3 (11), missing (16) and 97% had a Karnofsky score ≥70%. HDM was 100 mg/m² in 1, 140 mg/m² in 44/50 patients and 200 mg/m² in 5/50 with 6 patients receiving a tandem ASCT. Seventy three percent received consolidation post ASCT (1 missing) and 69% had maintenance therapy (lenalidomide: 53%, thalidomide: 26%, bortezomib: 21%). Toxicity: We observed one death during the first 100 days post-ASCT, secondary to a septic shock on day 42. The median time to neutrophil engraftment (>500/mm³) was 13 days (10-136) and to platelet engraftment (>20 000/mm³) 16 days (8-136). Among patients receiving RBC transfusions (43%) and platelet transfusions (49%), the median number of RBC transfusions was 3 (2-14) and that of platelet transfusions was 2 (1-44). Response: Nine patients (60%) achieved dialysis independence from the time of diagnosis: 15 patients were on dialysis at diagnosis, 6 at the time of ASCT and 4 three months post-ASCT. At 100 days post-ASCT, the hematological response had improved in 62 % of patients, from PR to VGPR (15%), from PR to CR/sCR (15%), from VGPR to CR/sCR (30%) and from CR to sCR (2%). The best response obtained was 4 (9%) PR, 18 (39%) VGPR, 19 (41%) CR and 5 (11%) sCR with one patient relapsing and 3 NE. At 2 years, the NRM was 4% (95% CI: 0%-12%), the OS was 84% (95% CI:74%-95%), the PFS was 70% (95% CI:58%-84%) and the CIR was 30 % (95% CI:17%-43%) (Figure).

Conclusions: HDM with ASCT proved to be safe and effective in NDMM patients with RI at transplant. NRM was 4% at 2 years and 62% improved their hematological response. Renal response will be reported.

Garderet:Janssen: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Vincent:Sandoz: Other: Education course paid by sandoz; Pfizer: Other: Financing meeting participation, congress participation; Sanofi: Honoraria, Other: Financing meeting participation; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Financing meeting participation; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financing meeting participation; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Financing meeting participation; Amgen: Membership on an entity's Board of Directors or advisory committees. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Adaptive Biotechnologies: Honoraria; Celgene: Honoraria; Oncopeptides: Honoraria; Pfizer,: Honoraria; GSK: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria. Karlin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.