Despite advances in triplets, HSCT continues to confer benefit in multiple myeloma

Issue: January 25, 2016

ORLANDO, Fla. — Autologous hematopoietic stem cell transplantation should remain a standard of care for younger patients with de novo multiple myeloma, according to phase 3 study results presented at the ASH Annual Meeting and Exposition.

Perspective from Noopur Raje, MD; Paul G. Richardson, MD

Further, treatment with lenalidomide (Revlimid, Celgene), bortezomib (Velcade; Millennium Pharmaceuticals, Takeda Oncology) and dexamethasone plus autologous hematopoietic stem cell transplantation (HSCT), may act as a future reference strategy, according to the researchers.

“The rate of survival after 4 years remains high in both study arms,” Michel Attal, MD, professor at University of Toulouse in France, said during a presentation. “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.”

High-dose chemotherapy, followed by autologous HSCT, currently serves as the standard of care for newly diagnosed younger patients (≤ 65 years) with multiple myeloma. However, the high complete response rate associated with triplet combinations of immunomodulatory drugs, proteasome inhibitors and dexamethasone have led investigators to propose this strategy as an upfront treatment without immediate transplantation, according to study background.

Thus, Attal and colleagues sought to determine whether autologous HSCT was still required for the initial management of younger patients with multiple myeloma.

The researchers conducted a randomized trial comparing conventional-dose treatment, or RVD, to RVD plus autologous HSCT in 700 previously untreated French and Belgian patients (median age, 58 years).

Patients on the RVD arm received eight cycles of lenalidomide, bortezomib and dexamethasone, plus stem cell mobilization after three cycles using high-dose chemotherapy and granulate-colony–stimulating factor. Patients on the transplant arm received three induction cycles of RVD, underwent stem cell collection and HSCT conditioned with melphalan (Alkeran, GlaxoSmithKline), and then received two consolidation cycles of RVD.

Patients in both arms received lenalidomide maintenance (10-15 mg per day) for 1 year. Patients in the RVD arm could undergo HSCT at time of relapse.

PFS served as the primary endpoint.

Median follow-up was 41 months.

At time of reporting, all patients had discontinued treatment (completion of therapy = 66%; disease progression = 16%; adverse events = 10%).

In the transplant arm, 93% of patients underwent HSCT, with five toxic deaths occurring during mobilization or in the actual transplant phase.

HSCT appeared associated with improved PFS (4-year PFS, 47% vs. 35%; P <.001).

The transplant group’s PFS benefit extended across all subgroups, including subgroups based on age, sex, immunoglobulin isotype, International Staging System stage, cytogenetics and response after first three cycles.

Significantly more patients in the transplant arm achieved a complete response (59% vs. 49%; P < .01). However, the high 3-year post-randomization OS rate (88%) remained similar between study groups.

Attal and colleagues further observed a correlation between transplantation and an increased rate of minimal residual disease negativity (80% vs. 65%; P < .001) and improved time to progression (49% vs. 35%; P < .001).

The researchers recorded 41 second primary malignancies in 39 patients (transplant, n = 23; RVD, n = 18).

A parallel U.S. trial using a similar design remains ongoing, according to Attal.

“The design of this trial is absolutely similar to the trial in France, except for the duration in maintenance,” Attal said. “Maintenance therapy was 1 year in the French trial and will be until progression in the U.S. trial. The results of the U.S. trial remain crucial.” – by Cameron Kelsall

Reference:

Attal M, et al. Abstract 391. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Disclosure: Attal reports honoraria from Janssen and an advisory board position with Celgene. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

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.

Noopur Raje, MD

Massachusetts General Hospital Cancer Center

Disclosures: Raje reports advisory board roles with Janssen, Millennium and other pharmaceutical companies.

Perspective

Paul G. Richardson, MD

These data from Attal and our French colleagues in the Intergroupe Francophone du Myélome (as part of our Dana-Farber Cancer Institute collaborative partnership [IFM-DFC]) have examined the role of stem cell transplant and its timing in the treatment of younger, transplant-eligible patients. These patients are candidates for initial therapy with RVD, or lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Takeda/Millennium) and dexamethasone, followed by collection of stem cells with delayed (Arm A) or early transplant (Arm B), followed by RVD consolidation and lenalidomide maintenance in both treatment groups. Zoledronic acid is administered monthly in both arms and high-dose cyclophosphamide plus GCSF is used for mobilization.
In the French study, transplant and consolidation was followed by maintenance for 1 year, which is a key difference to that deployed in the U.S. trial, where lenalidomide treatment is continued in the maintenance phase until progression. The French data, however, are encouraging. They show that there is a significant PFS advantage in favor of early transplant (Arm B), with a median of 8.8 months improvement seen. But importantly, there is no survival difference between the two arms. In fact, 83% of patients in the non-transplant arm (Arm A) are alive at 4 years, compared with 80% of those in the transplant arm (Arm B), which is slightly lower but not significantly so.
These results are the best seen to date in this setting, and suggest that early vs. late transplant remains a very important option for younger patients, and patients can therefore truly have a choice. The role of continuous therapy and, in particular, its effect on achieving minimal residual disease (MRD) negativity, will be important to ascertain. What is also encouraging from the French study is that MRD negativity correlates with better outcome. This provides us with a potentially important tool moving forward to best inform us how to treat our patients. For example, MRD negativity improved with maintenance for 1 year in both arms, and this further suggests continuous treatment may really matter.
In this context, it is now critical for us to complete the U.S. trial, and enrollment to this study continues. We have enrolled over 540 patients, with another 120 to be enrolled within the next year. We hope to answer a key question, both for our patients now and in the future, regarding the role of continuous treatment as part of maintenance, and inform the best position for transplant, in particular in the context of U.S. practice. Specifically, we believe that although transplant clearly is an important treatment option for younger patients, the key premise is that one size does not fit all, and exact timing can be a matter of choice. This trial will hopefully guide us in helping patients make those choices, and further improve outcomes.

Paul G. Richardson, MD

HemOnc Today Editorial Board member

Dana-Farber Cancer Institute

Disclosures: Richardson reports an investigator role on the DFCI portion of the study. He also reports research funding from and advisory roles with Celgene and Millennium.