Salvage ASCT Shows No Long-Term PFS or OS Benefit in Relapsed Myeloma

Multiple Myeloma |
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Long-term follow-up data from the phase 3 GMMG ReLApsE trial (NCT01086403) demonstrated no significant progression-free survival (PFS) or overall survival (OS) benefit with salvage high-dose chemotherapy (sHDCT) followed by autologous stem cell transplant (ASCT) compared with continuous lenalidomide (Revlimid) plus dexamethasone maintenance in patients with relapsed/refractory multiple myeloma.

After a median follow-up of 99 months (95% CI, 94-105), the median PFS was 20.5 months (95% CI, 15.9-27.2) in the ASCT arm vs 19.3 months (95% CI, 14.9-25.4) in the control arm (HR, 0.98; 95% CI, 0.76-1.27; P = .90). Median OS was 67.1 months (95% CI, 59.2-85.4) and 62.7 months (95% CI, 49.6–86.0), respectively (HR, 0.89; 95% CI, 0.66-1.20; P = .44).

“The GMMG ReLApsE trial does not support sHDCT [plus] ASCT at relapse after previous frontline HDCT [and] ASCT,” lead study author Marc Andrea Baertsch, MD, and colleagues wrote in a publication of the data.

GMMG ReLApsE Trial Design and Eligibility Criteria

The GMMG ReLApsE trial was a multicenter, randomized, phase 3 study designed to evaluate the efficacy of sHDCT and ASCT following reinduction therapy in patients with relapsed or refractory multiple myeloma. Patients were enrolled across 16 academic trial sites in Germany and were required to be 75 years of age or younger with 1 to 3 prior lines of therapy.

Key inclusion criteria required eligibility for high-dose therapy and transplant, and have measurable disease after prior treatment. Patients with prior salvage ASCT, lenalidomide-refractory disease, or a time to progression of less than 12 months after initial high-dose chemotherapy and ASCT were excluded from the trial.

Participants were randomly assigned 1:1 to receive either lenalidomide at 25 mg daily on days 1 to 21 and dexamethasone at 40 mg weekly in 4-week cycles as reinduction, followed by sHDCT with melphalan at 200 mg/m² and ASCT (≥2 × 10⁶ CD34+ cells/kg), and then lenalidomide maintenance at 10 mg daily until disease progression or unacceptable toxicity (transplant arm); or continuous lenalidomide and dexamethasone at the same induction doses until progression or toxicity (control arm).

The primary end point of the trial was PFS. Secondary end points included OS, posttrial treatment—including subsequent receipt of sHDCT/ASCT in the control arm—and subgroup analyses.

Initial results from the primary analysis indicated no statistically significant improvement in PFS or OS in the transplant arm compared with continuous lenalidomide/dexamethasone. Notably, 29% of patients in the transplant arm did not proceed to transplant. A landmark analysis among patients who did undergo sHDCT suggested a potential survival benefit, although OS data were not mature at the time of reporting.

The current analysis reports long-term follow-up data, including updated survival outcomes and post hoc subgroup analyses. Details of the statistical methodology used for these analyses are provided in the supplemental appendix published on the Blood journal website.

Baseline Patient Characteristics

The phase 3 trial enrolled 282 patients with relapsed or refractory multiple myeloma (RRMM) across 16 sites in Germany between December 2, 2010, and March 18, 2016. The intention-to-treat population consisted of 277 patients. Baseline characteristics were well balanced between the transplant (n = 139) and control (n = 138) arms.

The median age at enrollment was 61.3 years (range, 32.9-74.7) in the transplant arm and 62.2 years (range, 41.9–-4.5) in the control arm. Most patients were male—57% in the transplant arm and 61% in the control arm. The median interval from diagnosis to randomization was 3.9 years in the transplant cohort and 4.1 years in the control cohort.

The majority of patients had a good performance status, with 69% and 76% in the transplant and control arms, respectively, having a WHO performance status of 0. The International Staging System (ISS) distribution at diagnosis was similar between groups: ISS stage I in 63% vs 60%, stage II in 24% vs 31%, and stage III in 13% vs 9% of patients in the transplant and control arms, respectively.

Most patients had IgG (57% vs 52%) or IgA (24% vs 24%) heavy chain isotypes, with light chain disease present in 19% and 24% of the transplant and control groups, respectively. The kappa light chain was more frequent in both cohorts—63% in the transplant arm vs 75% in the control arm.

Cytogenetic data revealed a relatively high incidence of del(13q14), present in 61% and 43% of patients in the transplant and control arms, respectively. Other common abnormalities included t(11;14) (19% vs 21%) and del(17p13) (14% in both groups). High-risk cytogenetic features were detected in 43% of transplant and 32% of control arm patients.

Renal function was preserved in most patients, with 82% and 79% having an eGFR ≥60 mL/min/1.73 m² in the transplant and control arms, respectively. Lactate dehydrogenase (LDH) levels were elevated in 17% of patients in both groups.

Nearly all patients (94%) had received only 1 prior line of therapy. Prior frontline HDCT/ASCT was administered to 93% in the transplant arm and 94% in the control arm, with 36% and 45% of patients, respectively, having received tandem transplants. Thirty patients (11%) had prior exposure to lenalidomide.

Efficacy Analysis Continued

Subgroup analyses from the phase 3 GMMG ReLApsE trial confirmed the absence of a PFS or OS benefit with salvage high-dose chemotherapy followed by sHDCT/ASCT across all key clinical and biologic subgroups.

The PFS and OS outcomes were comparable between the transplant and control arms in the intention-to-treat population, with no statistically significant differences observed (PFS HR, 0.98; 95% CI, 0.76-1.27; P = .9; OS HR, 0.89; 95% CI, 0.66-1.20; P = .44). These findings remained consistent across disease and patient subgroups, including those defined by frontline HDCT/ASCT status (yes vs no; single vs tandem), age, ISS/revised ISS stage, cytogenetic risk classification, baseline LDH level, renal function, number of prior lines of therapy, and receipt of maintenance treatment post frontline HDCT/ASCT.

Patients with longer time to progression after frontline therapy demonstrated better PFS and OS compared with those with shorter intervals between frontline therapy and relapse. Specifically, patients with time to progression after frontline therapy more than 48 months had the most favorable survival, followed by those with time to first progression of 24 to 48 months, and those with time to progression after frontline therapy of 12 to 24 months had the poorest outcomes (PFS, P = .001; OS, P = .009).

Reference

Baertsch MA, Schlenzka J, Hielscher T, et al. Salvage autologous transplant in relapsed multiple myeloma: long-term follow-up of the phase 3 GMMG ReLApsE trial. Blood. Published online April 17, 2025. doi:10.1182/blood.2024027342