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High-dose melphalan plus HSCT extends PFS, OS in newly diagnosed multiple myeloma
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ORLANDO, Fla. — High-dose melphalan with autologous hematopoietic stem cell transplantation significantly prolonged PFS and OS compared with cyclophosphamide, lenalidomide and dexamethasone among patients with newly diagnosed multiple myeloma, according to phase 3 study results presented at the ASH Annual Meeting and Exposition.
These outcomes persisted regardless of maintenance therapy, as lenalidomide (Revlimid, Celgene) and prednisone maintenance did not significantly improve PFS compared with lenalidomide alone, results showed.
High-dose melphalan (Alkeran, GlaxoSmithKline) plus autologous hematopoietic stem cell transplantation (HSCT) serves as the standard treatment approach for patients with newly diagnosed, transplant-eligible multiple myeloma.
“However, a second trial enrolling young adult patients showed superiority of high-dose chemotherapy in comparison with a transplant,” Francesca Gay, MD, of the myeloma unit at University of Turin in Italy, said during a presentation. “Prednisone and lenalidomide have been also combined and evaluated in comparison with prednisone alone and have shown improvement in PFS. However, there have been conflicting results with OS.”
Gay and colleagues evaluated consolidation with high-dose melphalan plus autologous HSCT vs. treatment with cyclophosphamide, lenalidomide and dexamethasone (CRD). Researchers compared maintenance with lenalidomide and prednisone vs. with lenalidomide alone.
The analysis included data from 389 patients aged 65 years or younger with newly diagnosed multiple myeloma. The researchers randomly assigned patients to consolidation with melphalan (200 mg/m2) followed by autologous HSCT, or CRD (300 mg/m2 cyclophosphamide on days 1, 8 and 15; 40 mg dexamethasone on days 1, 8, 15 and 22; 25 mg lenalidomide on days 1-21). Researchers assigned patients to maintenance with lenalidomide (10 mg on days 1-21) and prednisone (50 mg every other day) or lenalidomide alone.
PFS served as the primary endpoint.
Median follow-up was 54.5 months.
Melphalan consolidation conferred a significantly prolonged median PFS compared with CRD (43.3 months vs. 28.6 months; HR = 0.4; P < .001). Further, more patients assigned melphalan achieved 4-year OS (86% vs. 73%; HR = 0.42; P = .004).
However, patients who received lenalidomide and prednisone maintenance vs. lenalidomide alone did not demonstrate statistically significant differences in median PFS (37.5 months vs. 28.5 months; HR = 0.84) and rate of 3-year OS (83% vs. 88%; HR = 1.53)
Patients assigned melphalan experienced higher rates of grade 3 to grade 4 hematologic toxicity (84% vs. 26%; P < .001), gastrointestinal toxicity (20% vs. 5%; P < .001) and infections (19% vs. 6%; P = .002). However, no significant differences in adverse events occurred between the maintenance therapy cohorts.
The most frequent grade 3 to grade 4 hematologic adverse events included neutropenia, infections, systemic adverse events and vascular adverse events.
Among patients assigned lenalidomide and prednisone maintenance, 9% required lenalidomide dose reductions and 36% required prednisone dose reductions (median time to dose reduction = 4 months). Five percent of patients discontinued treatment due to toxicity, whereas 3% ceased treatment after developing a second primary malignancy.
In the lenalidomide arm, 21% of patients required a dose reduction. Eight percent ceased treatment due to toxicity, with 2% developing a second primary malignancy.
The median duration of lenalidomide treatment was comparable between the two arms.
“Our trial confirmed the role of high-dose melphalan plus transplant in conferring superior PFS and OS,” Gay said. “Transplantation should remain the standard of care for young adult patients with newly diagnosed multiple myeloma.” – by Cameron Kelsall
Reference:
Gay F, et al. Abstract 392. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: Gay reports honoraria from Celgene and Janssen-Cilag, as well as advisory board memberships with Celgene and Sanofi. Please see the full abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Noopur Raje, MD
These studies presented at the ASH Annual Meeting are interesting because they evaluate the role of transplantation in the context of new agents for multiple myeloma. The study by Gay and colleagues included patients who received cyclophosphamide, lenalidomide (Revlimid, Celgene) and dexamethasone as the initial treatment for myeloma, followed by an autologous transplant and subsequent maintenance treatment. What the researchers showed very nicely in this dataset is that transplant — even in the context of new drugs — does tend to improve PFS. In this particular study, there also was an OS advantage. This demonstrates that transplant still seems to have a role.Attal and colleagues of the Intergroupe Francophone du Myélome and Dana-Farber Cancer Institute (IFM-DFCI) study also presented data at ASH, mostly from the French dataset of 700 patients. Patients also received new drugs — lenalidomide, bortezomib (Velcade; Millennium Pharmaceuticals, Takeda Oncology) and dexamethasone — and were subsequently randomly assigned to undergo immediate transplant or were stem-cell collected for transplant at the time of relapse. The French data have shown so far that PFS appears in favor of somebody who undergoes immediate transplant. Unlike the study from Gay and colleagues, however, it did not demonstrate an OS advantage, and the OS curves are completely overlapping.
The DFCI part of the study is ongoing and awaiting completion, with nearly 500 patients accrued. There are a few differences between the French and DFCI parts of the study, in that the maintenance schedules are different, and the way we think about these studies is either transplant upfront vs. transplant at the time of relapse and whether the incorporation of maintenance makes a difference. Given the data did not demonstrate an OS benefit, we still continue to maintain that we should evaluate this question of transplant vs. no transplant in the context of new drugs.
What is nice about these studies, specifically the IFM-DFCI study, is the fact that data on minimal residual disease (MRD) status are being incorporated. Whether you get a transplant or the new drugs, researchers have seen MRD negativity in patients, and those who acquire the MRD-negative status tend to do better than others. Obviously, we have to wait on the full dataset to make formal conclusions.
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