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In younger adults with multiple myeloma, a three-drug combination plus a transplant of their own blood-forming stem cells can hold the disease in check longer than in patients who receive the drug trio alone, but with no difference in overall survival, a major clinical trial co-led by investigators at Dana-Farber Cancer Institute, Boston, indicates. The findings suggest outcomes for patients who receive a transplant early or late in their treatment are equivalent, so patients can potentially choose when to undergo the procedure during the course of their disease.

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The phase III trial, a trans-Atlantic collaboration between researchers at Dana-Farber and the Intergroupe Francophone Myelome (IFM) in France, supports the role of stem-cell transplants in treating adults with myeloma-a role that had come to be questioned as combinations of novel drugs proved highly effective in a wide array of patients with the disease-the researchers noted (N Engl J Med 2017;376:1311-1320). The results of the trial, dubbed IFM/DFCI 2009, also address the proper timing of novel drug and transplant treatment for myeloma patients.


"Over the past decade, drugs that modulate the immune system and agents known as proteasome inhibitors have shown a great deal of promise in patients with multiple myeloma, when used in combination with chemotherapy," said Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research at Dana-Farber's Jerome Lipper Center for Multiple Myeloma, a leader of the new study. "This led us to propose that these combinations could be used selectively with established modalities such as transplant for patients with newly diagnosed myeloma, and this in turn raised questions about where and how transplant should be fit into the therapeutic paradigm. Our trial sought to comprehensively address these issues in a prospective fashion, and provide a foundation for future studies as the next generation of agents, such as monoclonal antibodies, impact the field."


Three-Drug Treatment

The study involved 700 adult patients being treated for myeloma at 69 centers in France, Belgium, and Switzerland, and utilized a three-drug combination dubbed RVD: lenalidomide, which activates the immune system, kills tumor cells, and chokes off their blood supply; bortezomib, which impedes myeloma cells' ability to break down proteins; and dexamethasone, a corticosteroid. This combination was developed by scientists and clinicians at Dana-Farber, and is now the most widely used upfront combination therapy for myeloma in the U.S.


Participants were randomly divided into two equal-sized groups. Both received three initial cycles of RVD. One group then received five more cycles of the drug combination. The other received high-dose chemotherapy followed by an autologous stem-cell transplant (which utilized their own stem cells) and two additional cycles of RVD. Patients in both groups then received lenalidomide as maintenance therapy for 1 year.


The median time before patients' disease began to worsen was significantly longer for those who underwent a transplant early-50 months versus 36 months. The percentage of patients who had a complete response-whose cancer diminished to undetectable levels-was also higher in the transplant group: 59 percent versus 48 percent.


Most importantly, however, the overall survival rate-the percentage of patients still living-4 years after treatment didn't differ much between the transplant and RVD-only groups-at 81 percent and 82 percent, respectively.


Furthermore, patients in the transplant group had significantly higher rates of high-grade neutropenia, gastrointestinal disorders, and infections, as well as longer-term toxicities, such as secondary leukemia, which, although rare, was more frequent in patients undergoing early transplant.


The benefits of stem-cell transplantation plus RVD "must therefore be weighed against the increased risk of toxic effects associated with high-dose chemotherapy plus transplantation," the study authors wrote, "especially since we found that later transplantation might be as effective as early transplantation in securing long-term survival."


Additional Studies

The ongoing parallel U.S. study of the IFM/DFCI 2009 project (the so-called DETERMINATION trial), which is now almost fully enrolled with 720 patients, complements this work by evaluating the impact of maintenance until progression, versus 1 year as was assessed in the French protocol. Results from this trial, which is led by the Dana-Farber team, are expected within the next 1-2 years.


In conjunction with both studies is a highly innovative correlative science effort led by the Dana-Farber team and their IFM partners, under the direction of Dana-Farber's Nikhil Munshi, MD, and Herve Avet-Loiseau, MD, of Institut Universitaire du Cancer de Toulouse-Oncopole. Data from this project are also anticipated within the next 2-3 years, and should further enhance clinicians' ability to optimally tailor therapy for their patients and improve outcome.