CHICAGO—Maintenance therapy may help to transform myeloma and lymphoma into chronic diseases, with long-term treatment keeping patients in remission by preventing relapses, researchers report.
In a prospective Phase III randomized, placebo-controlled trial, maintenance therapy with lenalidomide more than halved the risk of recurrence in patients with multiple myeloma, French researchers said in a study presented at the ASCO Annual Meeting and that was one of six studies selected for discussion at a teleconference two weeks earlier.
In contrast to its chemical cousin thalidomide, lenalidomide was well tolerated, said Michel Attal, PhD, Professor of Hematology at Purpan Hospital in Toulouse. “These results are very promising. Lenalidomide is “probably the first effective maintenance therapy in myeloma.”
In a second study, maintenance therapy with rituximab halved the risk of relapse in patients with advanced follicular lymphoma who responded to induction treatment.
Those results were reported by Gilles Salles, MD, PhD, Professor of Hematology at Université de Lyon.
The new lenalidomide results come from an interim analysis of data from a Phase III study conducted by the Intergroupe Francophone du Myélome. The study was designed to determine whether lenalidomide could prevent relapse after autologous stem-cell transplantation in patients younger than 65 with nonprogressive disease.
After stem cell transplantation, 614 patients underwent high-dose chemotherapy induction, mostly with a combination of vincristine, doxorubicin, and dexamethasone or with bortezomib plus dexamethasone. Patients were enrolled between July 2006 and September 2008.
Patients were then stratified according to response to transplant, beta-2 microglobulin, and chromosome 13 deletions, and given two months of oral lenalidomide consolidation therapy at 25 mg a day orally, for 21 days a month.
Patients were then randomized to placebo or lenalidomide (10 to 15 mg a day) until relapse occurred.
By three-year follow-up, 143 of the 307 patients in the placebo arm had disease progression or had died, compared with 77 of the 307 patients in the lenalidomide arm.
The three-year progression-free survival rate was 68% in the lenalidomide arm, compared with 35% for placebo.
This corresponds to a 54% reduction in the risk of progression in the lenalidomide arm, Dr. Attal said.
The median progression-free survival time was 24 months in the placebo arm but has not been reached in the lenalidomide arm. The drug was well tolerated, with a low discontinuation rate because of adverse effects and no cases of Grade 3 or 4 neuropathy.
Overall Survival Still to Be Determined
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Whether lenalinomide maintenance therapy will improve overall survival rates remains to be seen, he said. At 24 months, the survival curves are similar: 88% for lenalinomide and 80% for placebo. Still, he said, “I would be surprised not to see an improvement in survival over the long term because of the dramatic effect on progression-free survival.
“I have been doing clinical trials in multiple myeloma for 25 years now, but I have never seen such a large effect on progression-free survival. I have seen smaller effects, and all of these have converted in time to survival benefits,” Dr. Attal said.
A final analysis of these data is due out in December, he said.
The study had support from the Programme Hospitalier de Recherche Clinique. Dr. Attal reported financial links with Celgene and Janssen-Ortho.
Rituximab is an anti-CD20 monoclonal antibody that has been shown to improve outcomes in patients with follicular lymphoma when used in combination, Dr. Salles said.
Follicular lymphoma, the second most common lymphoma subtype, usually remains incurable despite “efficient therapy” with rituximab and chemotherapy, he said. The median life expectancy is 12 to 15 years, with patients suffering several recurrences during that period.
However previous studies suggest that rituximab maintenance may increase the length of periods of remission in patients with previously untreated or relapsed follicular lymphoma, Dr. Salles said.
To test that idea, the large international Primary Rituximab and Maintenance (PRIMA) trial, funded by rituximab manufacturer Roche, enrolled 1,217 patients with untreated follicular lymphoma and a high tumor burden.
The aim of the study was to assess whether two-year maintenance treatment with rituximab after induction immunochemotherapy is able to improve the progression-free survival times of untreated follicular lymphoma patients in need of first-line therapy.
Patients who responded to the induction therapy were randomly assigned to receive rituximab maintenance (375 mg/m2 intravenously every eight weeks for two years) or to be followed with observation alone for the same length of time.
An interim analysis at a median follow-up of 25 months showed a significant improvement in progression-free survival rates in the rituximab group.
A total of 18% of the 505 patients in the rituximab group had disease progression, compared with 34% of the 513 patients in the observation group, corresponding to a significant, 50% reduced risk of relapse with rituximab treatment, Dr. Salles said.
Subgroup analyses showed that benefits persisted regardless of age, severity of disease, or type of chemotherapy regimen, he said.
Maintenance therapy was also associated with a significant, 39% reduction in the risk of starting a new round of lymphoma treatment.
Rituximab maintenance therapy was generally well tolerated, he reported. Grade three and four adverse events occurred in 23% of patients in the rituximab arm versus 16% in the observation arm. Grade two or higher infections were also more common in the rituximab arm: 37% versus 22% in the observation arm.
But “very few” patients stopped the trial because of adverse effects—one in the observation arm and 10 in the rituximab arm.
Quality of life scores were similar in both arms, he added.
Roche is using the data to apply for extended approval for the use of rituximab maintenance in patients with follicular lymphoma in both the US and Europe, he said.
“Maintenance therapy with lenalidomide can improve quality of life in patients with myeloma by delaying the need for more intensive therapy to treat a relapse,” Dr. Attal concluded.
ASCO 2009-2010 President Douglas W. Blayney, MD, Professor of Internal Medicine at the University of Michigan Medical School and Medical Director of the University's Comprehensive Cancer Center, commented that “myeloma is now one of those diseases that is moving into the chronic disease category,” with maintenance therapy keeping the disease in remission.
Similarly, rituximab maintenance treatment “significantly improves outcomes” and should be considered “a standard of care” in first-line follicular lymphoma, Dr. Salles said
Dr. Blayney said that in the US, a lot of oncologists are already using rituximab maintenance treatment—“based on surmise and some earlier evidence that is helpful.”
“Maintenance therapy seems to be coming back not only in hematologic but perhaps lung cancer,” he told OT.
ASCO 2010-2011 President George W. Sledge Jr., MD, the Ballvé Professor of Oncology at Indiana University School of Medicine, called the rituximab study “strikingly positive and truly important.”
The findings suggest that “lymphoma, like many human cancers, is a chronic disease…and increasingly is likely to require chronic therapy to maintain the disease in remission.”
As with lenalidomide for multiple myeloma, a big question is whether the improvement in progression-free survival rates seen with rituximab will translate into an overall survival benefit, Dr. Sedge said.
“Still, this is fascinating—a few years ago, we would never have thought of myeloma or lymphoma as chronic diseases.”
© 2010 Lippincott Williams & Wilkins, Inc.