Salvage ASCT Shows No Significant Survival Vs Lenalidomide Combo in Myeloma

"With extended follow-up we observe a lower effect of the transplant arm across survival analyses compared to the initial publication," according to the study authors.

The addition of salvage high-dose chemotherapy (sHDCT) plus autologous stem cell transplantation (ASCT) to lenalidomide (Revlimid) and dexamethasone did not significantly benefit survival among patients with relapsed/refractory multiple myeloma, according to long-term data from the phase 3 GMMG ReLApsE trial (2009-013856-61) published in Blood.¹

With a median follow-up of 99 months (95% CI, 94-105), the median overall survival (OS) was 67.1 months (95% CI, 59.2-85.4) in the transplant arm vs 62.7 months (95% CI, 49.6-86.0) with continuous lenalidomide/dexamethasone in the control arm (HR, 0.89; 95% CI, 0.66-1.20; P = .44). Additionally, data showed a median progression-free survival (PFS) of 20.5 months (95% CI, 15.9-27.2) and 19.3 months (95% CI, 14.9-25.4) in each respective arm (HR, 0.98; 95% CI, 0.76-1.27; P = .9). A lack of PFS and OS benefits with transplant appeared to be consistent across key subgroups based on factors including frontline HDCT/ASCT status, age, International Staging System (ISS) or Revised ISS (R-ISS) disease, cytogenetic risk status, and prior lines of treatment.

Investigators noted that time to progression following frontline HDCT/ASCT (TTP1) correlated with improved survival across the overall population, although no benefit occurred with transplant in any subgroups based on TTP1.

Univariate landmark analysis indicated no significant PFS differences between the transplant arm (median PFS, 23.0 months; 95% CI, 17.2-32.2) and the control arm (median PFS, 20.3 months; 95% CI, 14.1-30.1; HR, 0.91; 95% CI, 0.68-1.22; P = .52). OS outcomes did not significantly differ between the transplant arm (median OS, 76.3 months; 95% CI, 58.8-not reached [NR]) and the control arm (median OS, 66.0 months; 95% CI, 49.7-92.9) based on univariate analysis (HR, 0.8; 95% CI, 0.56-1.13; P = .2).

“The GMMG ReLApsE trial remains the only [randomized clinical trial] comparing sHDCT/ASCT with continuous novel agent treatment. With extended follow-up we observe a lower effect of the transplant arm across survival analyses compared to the initial publication,” Marc-Andrea Baertsch, MD, an academic researcher in Hematology, Oncology, and Rheumatology at University Hospital Heidelberg in Heidelberg, Germany, wrote with study coauthors.^1,2 “This reduction in effect size is most pronounced in landmark analyses for OS, likely due to smallest sample size and least mature data at the time of the initial publication.² Consequently, no significant PFS or OS difference between trial arms is observed in the overall trial population and the previously reported, significant survival benefit in patients who actually received sHDCT/ASCT is not confirmed with extended follow-up.”

Investigators of the multicenter phase 3 study assessed 282 patients who were 75 years and older with relapsed/refractory multiple myeloma and 1 to 3 prior lines of therapy at 16 sites across Germany. Patients in the transplant arm (n = 139) were assigned to receive reinduction lenalidomide at 25 mg on days 1 to 21 plus dexamethasone at 40 mg weekly for 4-week cycles, sHDCT with melphalan (Alkeran) at 200 mg/m², ASCT with at least 2 x 10⁶ CD34-positive cells/kg, and lenalidomide maintenance at 10 mg daily. Those in the control arm (n = 138) received continuous treatment with lenalidomide/dexamethasone.

The trial’s primary end point was PFS. Secondary end points were OS and post-trial treatment, which included additional sHDCT/ASCT in the control arm.

Patients with lenalidomide-refractory disease, prior sHDCT/ASCT, and TTP1 at less than 12 months following frontline HDCT/ASCT were ineligible for enrollment in the trial.

Most patients were male in the transplant (57%) and control arms (61%). Additionally, most patients in each respective arm had a World Health Organization performance status of 0 (69% vs 76%), ISS stage I disease (63% vs 60%), normal lactate dehydrogenase (83% vs 83%), 1 prior line of treatment (94% vs 94%), and TTP1 of 12 to 24 months (34% vs 36%) or 24 to 48 months (33% vs 39%). The most common prior therapies in each arm included bortezomib (Velcade; 77% vs 77%), thalidomide (Thalomid; 22% vs 18%), and lenalidomide (9% vs 13%).

Overall, 29% (n = 41/139) of patients in the transplant arm left the trial before undergoing sHDCT/ASCT, with the most common reasons for study exit including progressive disease (12%), adverse effects (6%), and withdrawal of consent (5%). Secondary primary malignancies were reported in 18% (n = 24/135) and 14% (n = 20/145) of the transplant and control arms, respectively (P = .41).

References

1. 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 January 14, 20254. doi:10.1182/blood.2024027342
2. Goldschmidt H, Baertsch MA, Schlenzka J, et al. Salvage autologous transplant and lenalidomide maintenance vs. lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE. Leukemia. 2021;35(4):1134-1144. doi:10.1038/s41375-020-0948-0