Stem Cell Transplant With Melphalan Still Preferred in Myeloma

Veronica Hackethal, MD

September 04, 2014

Stem cell transplantation with melphalan is still the preferred treatment for younger patients with multiple myeloma, even in the era of new therapies for the disease, according to a phase 3 trial.

The results were published in the September 4 issue of the New England Journal of Medicine.

The past decade has seen tremendous advances in the treatment of myeloma, centered around 2 classes of drugs — proteasome inhibitors like bortezomib and carfilzomib, and immunomodulatory drugs like thalidomide and lenalidomide, explained Jacalyn Rosenblatt, MD, hematologist and assistant professor of medicine at Beth Israel Deaconess Medical Center in Boston.

The improved outcomes with these new drugs has raised the question of whether they preclude the need for transplantation, which has been considered the treatment gold standard for myeloma in patients younger than 65 years, Dr. Rosenblatt told Medscape Medical News.

"This study demonstrates that induction therapy with lenalidomide and dexamethasone followed by autologous transplantation results in improved progression-free survival and overall survival, compared with consolidation with melphalan, prednisone, and lenalidomide. This supports the benefit of high-dose melphalan with autologous stem cell rescue, even in the era of novel agents," said Dr. Rosenblatt, who is coauthor of an accompanying editorial.

In patients younger than 35, "a sequential approach that also includes consolidation with transplantation and maintenance seems to be the preferable therapeutic strategy," said study researcher Antonio Palumbo, MD, chief of the myeloma unit at the University of Torino in Italy. "Consolidation with transplantation significantly improved both progression-free and overall survival."

"This sequential approach should be used at diagnosis, not delayed until relapse, as is currently done in several centers," Dr. Palumbo told Medscape Medical News.

The study addresses another question about the treatment of multiple myeloma — namely, whether to use maintenance therapy after transplantation.

"Maintenance therapy with lenalidomide (Revlimid) further improved progression-free survival," Dr. Palumbo reported.

Previous studies have had mixed results, Dr. Rosenblatt noted. In an American study, maintenance lenalidomide administered until progression was associated with better progression-free and overall survival than no maintenance (N Engl J Med. 2012;366:1770-1781). In contrast, a French study showed that maintenance lenalidomide improved progression-free survival, but had no impact on overall survival (N Engl J Med. 2012;366:1782-1791).

The study by Dr. Palumbo's team "demonstrated that lenalidomide maintenance following either high-dose or standard-dose consolidation resulted in improved rates of complete response and progression-free survival, but did not improve overall survival," Dr. Rosenblatt pointed out.

However, the study did not address the role of proteasome inhibitors, and whether incorporating them into induction and maintenance therapy affects the role of transplantation. An ongoing international trial, led by the French Intergroupe Francophone du Myoleme and a group from the Dana-Farber Cancer Institute in Boston, is addressing this issue.

"The overarching message is that we now have newer drugs and novel agents. Thinking about how to incorporate them into the care of myeloma patients is important," Dr. Rosenblatt emphasized. This study and one published in the same issue (N Engl J Med. 2014;371:906-917) "are starting to address these critical issues."

Phase 3 Trial Results

In their open-label phase 3 trial, Dr. Palumbo and colleagues evaluated patients younger than 65 who had newly diagnosed multiple melanoma and were eligible for transplantation. From November 2007 and July 2009, the researchers randomized participants at 62 centers in Italy and Israel to high-dose melphalan plus stem cell transplantation (n = 141) or to consolidation therapy with a combination of melphalan, prednisone, and lenalidomide (MPR) (n = 132).

After consolidation therapy, participants were randomized to maintenance therapy (67 after high-dose melphalan and 59 after MPR) or to no maintenance therapy (68 after high-dose melphalan and 57 after MPR).

All participants received induction therapy with lenalidomide and dexamethasone. The researchers did not monitor quality of life or minimal residual disease, and the maintenance phase lacked a placebo group.

Median follow-up was 51.2 months.

Median progression-free survival was significantly better with high-dose melphalan plus stem cell transplantation than with MPR (43.0 vs 22.4 months; hazard ratio [HR] for progression or death, 0.44; 95% confidence interval [CI], 0.32 - 0.61; P < .001), as was 4-year overall survival (81.6% vs 65.3%; HR for death, 0.55; 95% CI, 0.32 - 0.93; P = .02).

In addition, progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance therapy (41.9 vs 21.6 months; HR for progression or death, 0.47; 95% CI, 0.33 - 0.65; P < .001).

Lenalidomide maintenance delayed relapse by about 2 years, the researchers note, compared with no maintenance. However, for 3-year overall survival, there was no significant difference between lenalidomide maintenance and no maintenance (88.0% vs 79.2%; HR for death, 0.64; 95% CI, 0.36 - 1.15; P = .14).

However, there was significantly more toxicity with high-dose melphalan plus stem cell transplantation than with MPR.

Table. Adverse Events

Event Melphalan + Transplantation, % MPR, % P Value
Grade 3/4 neutropenia 94.3 51.5 <.001
Thrombocytopenia 93.6 8.3 <.001
Gastrointestinal problems 18.4 0.0 <.001
Infections 16.3 0.8 <.001
Systemic events 12.8 1.5 <.001


In addition, there was significantly more neutropenia with lenalidomide maintenance than with no maintenance (23.3% vs 0.0%; P < .001), and more adverse dermatologic effects (4.3% vs 0.0%; P = .03).

The 1 death that occurred during the induction phase was due to arrhythmia. Overall, 6.8% of participants discontinued treatment because of adverse events and 14.0% discontinued for other reasons.

"In conclusion, we found that consolidation therapy with high-dose melphalan, as compared with MPR, improved both progression-free survival and overall survival, although at the cost of increased toxicity," the researchers write. "Our findings confirm that high-dose melphalan remains the more effective therapeutic option in patients with newly diagnosed multiple myeloma."

"Maintenance therapy with lenalidomide, as compared with no maintenance therapy, significantly reduced the risk of disease progression," they add.

The study was sponsored by Fondazione Neoplasie Sange Onlus and by a grant from Celgene. Dr. Palumbo and some of his coauthors report financial relationships with Amgen, Array BioPharma, Bristol-Myers Squibb, Celgene, Genmab, Janssen-Cilag, Millennium, Onyx, Novartis, Merck, Sharp & Dohme, BioLine Rx, CureTech, Medison, Neopharm Israel, Sigma Tau, Johnson & Johnson, and/or sanofi-aventis, as detailed in the publication. Dr. Rosenblatt reports receiving grant support from Millennium.

N Engl J Med. 2014; 371:895-905, 961-962. Abstract, Editorial


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