Salvage Transplant Versus Continuous Therapy: Insights From the Myeloma ReLApsE Trial

For patients with multiple myeloma (MM) that has relapsed following autologous hematopoietic cell transplantation (AHCT), a standard salvage therapy approach involves high-dose chemotherapy and AHCT. However, the role of transplant in the era of continuous treatment with novel agents is in question. At the 2018 ASH Annual Meeting, investigators presented results from ReLApsE, the first randomized clinical trial comparing reinduction, salvage AHCT, and lenalidomide maintenance therapy with continuous lenalidomide-dexamethasone (Rd) therapy in this setting.

In the first presentation, principal investigator Hartmut Goldschmidt, MD, from the University Hospital Heidelberg and National Center of Tumor Diseases in Germany, shared the overall findings from the trial; in the second presentation, coinvestigator Marc-A. Baertsch, MD, also from the University Hospital Heidelberg, discussed results from a subgroup analysis of patients with low-risk disease.1,2

ReLApsE is a randomized, open, multicenter trial that enrolled patients in first to third relapse who had received induction with Rd. Patients were excluded if they had prior salvage AHCT or were refractory to lenalidomide or had progressive disease within six months of lenalidomide treatment.

All patients received cycles of Rd; patients with no available stem cells from earlier harvesting were scheduled to undergo peripheral blood stem cell mobilization and harvesting. Next, patients were randomized to receive continuous Rd (arm A; n=138) or high-dose chemotherapy plus AHCT (arm B; n=139). Patients were treated until disease progression (with lenalidomide maintenance in the salvage-AHCT group and Rd in the continuous-therapy group).

Patient characteristics were generally balanced between the two arms: Median ages were 62.2 years in arm A and 61.3 years in arm B; most patients received frontline high-dose chemotherapy and AHCT (94% and 93%); and most patients in each arm had International Staging System stage I disease (60% and 63%). However, “there was an imbalance in terms of cytogenetics, with a trend toward more high-risk cytogenetics in the transplant arm (43%) than the continuous arm (32%),” Dr. Goldschmidt noted.

There were no differences in overall response rate (ORR) between the two arms:

  • ORR (partial response [PR] or better): 75% in arm A vs. 78% in arm B (p=0.57)
  • very good PR (VGPR) or better: 47% vs. 49% (p=0.81)

During a median follow-up of 36 months, there also was no significant difference in progression-free survival (PFS; primary endpoint) and overall survival (OS) between the two treatment arms:

  • median PFS: 18.8 months in arm A vs. 20.7 months in arm B (hazard ratio [HR] = 0.87; 95% CI 0.65-1.16; p=0.34)
  • median OS: 62.7 months vs. not reached (HR=0.81; 95% CI 0.52-1.28; p=0.37)

To explain this surprising lack of significant differences between the arms, Dr. Goldschmidt cited the imbalance in highrisk cytogenetic features and the fact that 29 percent of patients in arm B did not receive the planned high-dose chemotherapy and AHCT intervention.

The investigators conducted a landmark analysis at the fifth Rd cycle in arm A and at high-dose chemotherapy in arm B. At this point, there was a trend for improved PFS with salvage transplant (23.3 months in arm B vs. 20.1 months in arm A; HR=0.74; p=0.09), as well as improved OS (not reached vs. 57 months; HR 0.56; p=0.05).

The toxicity was “as expected” in patients receiving highdose chemotherapy and AHCT, Dr. Goldschmidt reported.

Grade ≥3 adverse events (AEs) were reported in 75 percent of patients in arm A and 83 percent of patients in arm B, and incidence of grade ≥3 cytopenias was higher in the high-dose chemotherapy and AHCT group (leukopenia/neutropenia: 62% vs. 25% [p<0.001], thrombocytopenia: 45% vs. 11% [p<0.001]).

Approximately one-fourth of the patients completed treatment per protocol (26% in arm A and 20% in arm B). The most common reasons for treatment discontinuation in either arm was progressive disease (54% and 42%). Six patients died during the study, five in arm A and one in arm B; the authors noted that no deaths occurred during the high-dose chemotherapy and AHCT phase. Also, “there was more treatment discontinuation due to AEs and less due to progressive disease in the transplant arm,” he added.

Multivariate analyses revealed that AHCT was associated with a significant survival benefit in patients with high-risk cytogenetics (HR=2.71 for PFS and 4.22 for OS; p<0.001 for both). In his presentation, Dr. Baertsch shared results of another subgroup analysis, looking specifically at time to progression after frontline AHCT (TTP1).

These findings confirmed earlier data showing that length of TTP1 is a prognostic factor in the salvage setting: In both arms, patients who had a long TTP1 (≥48 months) had longer PFS than those with shorter TTP1 (12-24 months; p<0.04) but did not predict benefit from salvage AHCT or continuous Rd.

In summary, the analyses identified groups of patients who are more likely to derive benefit from salvage transplant than continuous Rd, including those with:

  • revised ISS stage I disease (HR=0.08 for OS [p=0.02])
  • standard-risk cytogenetics (HR=0.21 for OS [p=0.01])

There also were no significant differences in survival benefit according to “traditional risk factors,” like baseline ISS, age, renal function, response to reinduction, prior therapy lines, and single or tandem frontline AHCT.

Although these data should provide guidance on the choice between salvage AHCT or continuous Rd therapy in patients with relapsed MM, they suggest that its value may not be as high as previously assumed. Dr. Goldschmidt noted that the trial had better-than-expected efficacy in the Rd control arm. Dr. Baertsch added that the comparator in this trial (Rd) was not one of the more effective triplet regimens that have now become standard of care for relapsed MM, so definite conclusions on the role of salvage AHCT in [the modern era] cannot be drawn.”

The ReLApsE investigators report relationships with Celgene, the manufacturer of lenalidomide.

References

  1. Goldschmidt H, Baertsch M-A, Schlenzka J, et al. Salvage autologous transplant and lenalidomide maintenance versus continuous lenalidomide/dexamethasone for relapsed multiple myeloma: results of the randomized GMMG phase III multicenter trial relapse. Abstract #253. Presented at the 2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.
  2. Baertsch M-A, Schlenzka J, Habermehl C, et al. Subgroup analyses of the randomized GMMG phase III multicenter trial relapse suggest survival benefit of salvage autologous transplant primarily in low risk multiple myeloma. Abstract #254. Presented at the 2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.

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