High-Dose Chemotherapy Plus Transplantation Improves PFS, But Not OS, in Myeloma Patients

High-dose chemotherapy plus autologous hematopoietic cell transplantation (AHCT) has long been a standard treatment of multiple myeloma (MM), but the associated toxicity risks and the introduction of effective immunomodulatory drugs and proteasome inhibitors raise questions about the role and timing of AHCT in MM patients.

In an analysis from the Intergroupe Francophone du Myélome (IFM) 2009 study published in the New England Journal of Medicine, the combination of lenalidomide, bortezomib, and dexamethasone (RVD) followed by AHCT led to deeper and longer responses than high-dose chemotherapy alone in patients with newly diagnosed MM.

The authors, led by Michel Attal, MD, PhD, from the University Institute Cancer Toulouse Oncopole in France, also noted that the survival benefits must be weighed against the increased toxicity risks of both high-dose chemotherapy and AHCT.

This randomized, open-label, phase III trial included 700 adult patients enrolled from 69 sites in France, Belgium, and Switzerland between November 2010 and November 2012. Patients with grade ≥2 peripheral neuropathy or a history of other cancers were excluded.

All patients received induction therapy consisting of three 21-day cycles of RVD:

  • lenalidomide 25 mg orally on days 1-4
  • bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11
  • dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12

During consolidation, patients were randomized 1:1 according to
International Staging System disease stage and cytogenetic risk profile to receive either:

  • five additional cycles of RVD with dexamethasone reduced to 10 mg (RVD-alone group; n=350; median age = 59 years; range = 29-66 years)
  • melphalan 200 mg/m2 plus AHCT followed by two cycles of RVD with dexamethasone reduced to 10 mg (RVD plus AHCT group; n=350; median age = 60 years; range = 30-66 years)

Both groups then received maintenance therapy with lenalidomide for one year or until disease progression, toxicity, or patient withdrawal. Patients in the RVD-alone group were eligible for salvage AHCT at the time of disease progression.

During study follow-up, 368 patients had progressive disease or died: 211 in the RVD-alone group and 157 in the RVD plus AHCT group.

There were no significant between-group differences in the rates of treatment-related deaths, second primary cancers, thromboembolic events, or peripheral neuropathy. Grade 3/4 adverse events were more common with RVD plus AHCT, compared with RVD alone (97.1% vs. 83.4%; p value not provided). Grade 3/4 neutropenia was significantly higher in the transplant group than in the RVD-alone group (92% vs. 47%; p<0.001), as were rates of grade 3/4 gastrointestinal disorders (28% vs. 7%; p<0.001) and infections (20% vs. 9%; p<0.001).

After a median follow-up of 44 months in the RVD-alone group and 43 months in the RVD plus AHCT group, the median progression-free survival (PFS; the study’s primary endpoint) was 36 months and 50 months, respectively (hazard ratio [HR] adjusted for disease progression or death = 0.65; 95% CI 0.53-0.80; p<0.001). Patients in the RVD plus AHCT group also had higher rates of complete response and lower rates of MRD positivity (TABLE).

However, overall survival (OS) was similar between the two groups: 82 percent in the RVD-alone group and 81 percent in the RVD plus AHCT group (HR adjusted for death = 1.16; 95% CI 0.80-1.68; p=0.87). The similarity in OS results could be attributed to “the high level of activity of the new agents that were used to treat relapses,” the researchers explained.

The successful use of salvage transplantation may also have led to the comparable OS rates; of the 207 patients in the RVD-alone group who experienced progressive disease, 136 (79%) went on to receive salvage transplantation, which suggests that “delayed transplantation is feasible and is associated with no decrement in OS,” the authors noted.

Patients with undetectable MRD after consolidation and maintenance therapy had longer PFS and OS, compared with those who had MRD (HRs adjusted for disease progression or death = 0.30 and 0.34; p<0.001 for both). “These findings confirm that the absence of MRD is an important treatment target in myeloma,” the authors noted, “and suggest that the use of high-dose chemotherapy plus transplantation after induction therapy with RVD specifically among patients in whom MRD is detected could be … one approach to tailoring therapy and further improving clinical benefit.”

However, the MRD implications are limited by the sensitivity of the MRD detection method; more sensitive methods, such as next-generation flow cytometry, could have revealed more subtle differences, according to the researchers. Study results also could have been influenced by therapies received subsequent to study conduct.

The study was supported by grants from Celgene and Janssen.

Contributing authors report financial relationships with Celgene, Janssen, Takeda Oncology, and Millennium Pharmaceuticals.


Reference

Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311-20.

TABLE. Response to Treatment
Outcome

RVD-Alone Group

(n=350)

RVD Plus Transplantation Group

(n=350)

P Value

Best response during the study

0.02

Complete response

(CR)

169

(48%)

205

(59%)

Very good partial
response (VGPR)

101

(29%)

102

(29%)

PR 70

(20%)

37
(11%)

Stable disease

10

(3%)

6

(2%)

CR 169

(48%)

205

(59%)

0.03

CR or VGPR

270

(77%)

307

(88%)

0.001

MRD not detected during the study*

171/265

(65%)

220/278

(79%)

<0.001

*Represents number of patients with MRD out of the total number of patients with CR or VGPR.

RVD = lenalidomide, bortezomib, and dexamethasone; MRD = minimal residual disease

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