The End of an Era: Does Transplant Still Have a Role in Multiple Myeloma Treatment?

With the rapid pace of drug discovery in multiple myeloma (MM), the role of autologous hematopoietic cell transplantation (AHCT) has been called into question recently. However, according to research presented at the 2015 ASH Annual Meeting that compared patient outcomes among patients treated with conventional chemotherapy with or without AHCT, transplantation should still be the standard of care in younger patients with previously untreated MM.

“High-dose chemotherapy plus autologous transplantation is considered a standard of care for newly diagnosed myeloma patients younger than 65 years of age,” the authors of the study, led by Michel Attal, MD, from the Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France, wrote. However, “the high complete response rate achieved with the triplet combination of immunomodulatory drugs plus proteasome inhibitors plus dexamethasone has led investigators to propose this strategy upfront without immediate transplantation.”

Dr. Attal and colleagues conducted the randomized Intergroupe Francophone Du Myelome trial to determine if, in the era of new drugs and new drug combinations, AHCT was still required in the initial management of young patients.

In the trial, the researchers compared conventional treatment with and without AHCT:

  • Conventional arm: 8 cycles of lenalidomide + bortezomib + dexamethasone (RVD) plus stem cell mobilization after 3 cycles of RVD utilizing high-dose cyclophosphamide and G-CSF (n=350)
  • AHCT arm: 3 induction cycles of RVD followed by stem cell collection, then AHCT conditioned with melphalan 200 mg/m2, followed by 2 cycles of RVD as consolidation (n=350)

Maintenance treatment with lenalidomide (10-15 mg/day) was used in both arms for one year. If patients in the RVD arm relapsed, they were planned to undergo AHCT. Patients with previously untreated MM were randomized according to International Staging System (ISS) stage (I vs. II vs. III) and FISH analysis (standard vs. high-risk [del17p or t(4;14) or t(14;16)]).

Median age of the 700 patients in this study was 58 years, and patient characteristics were similar between both groups.

Ninety patients had high-risk cytogenetics, and the majority of patients were ISS stage II (I=233; II=341; III=126).

Two pre-specified interim analyses were to be performed at 33 percent and 69 percent of the estimated total number of events; the presentation at the ASH annual meeting included results from the second interim analysis.

At the time of data presentation, 346 events had occurred over a median follow-up of 39 months: 197 in the RVD arm and 149 in the AHCT arm. All patients had discontinued treatment, with 66 percent having completed planned therapy; 16 percent experienced disease progression, and 10 percent experienced adverse events (AEs) that led to discontinuation.

AHCT was found to improve progression-free survival (PFS; the study’s primary endpoint), with a three-year PFS rate of 61 percent in the transplant arm versus 48 percent in the RVD arm (hazard ratio [HR] = 1.5; 95% CI 1.2-1.9; p<0.0002).

Notably, the PFS benefit was observed and uniform across the following subgroups in the AHCT group: age (≤ or >60 years), sex, Ig isotype (IgG or others), ISS stage, standard or high-risk cytogenetics, and response after the three first cycles of RVD (complete response or not).

The complete response rate was significantly higher in the transplant arm compared with the RVD arm, the researchers noted (58% vs. 46%, respectively; p<0.01); however, three years after randomization, the “extremely high” rate of overall survival (OS) was similar between the two study groups (p=0.25), the authors noted.

Dr. Attal and colleagues also observed a correlation between AHCT and an increased rate of minimal residual disease negativity (80% vs. 65%; p<0.001) and improved time to progression (49% vs. 35%; p<0.001).

Significantly more patients in the transplant arm achieved a complete response (59% vs. 49%; P < .01). However, the high three-year post-randomization OS rate (88%) remained similar between study groups.

The researchers recorded 41 second primary malignancies in 39 patients (23 in the AHCT arm and 18 in the RVD arm). In the transplant arm, 93 percent of patients underwent AHCT and five toxic deaths occurred during mobilization or in the actual transplant phase (1.4%).

A parallel U.S. trial is currently being conducted that will add to these results; though the study has a similar design, patients in both arms are receiving maintenance lenalidomide continuously until disease progression.

For now, though, it seems like AHCT will remain the first choice for younger patients with previously untreated MM. “The rate of survival after three years remains high in both study arms,” Dr. Attal said during his presentation of the results. “However, transplantation is already associated with a reduced risk for death due to myeloma. Thus, in the era of new drugs, transplantation should remain a standard of care.”


Reference

Attal M, Lauwers-Cances V, Hulin C, et al. Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial). Abstract #391. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, Florida.

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