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Lenalidomide maintenance therapy delayed recurrences significantly when given to patients newly diagnosed with multiple myeloma in a trio of clinical trials that reported much-anticipated outcomes May 9 in the New England Journal of Medicine.
Only one trial showed a gain in overall survival, however, and the prospect of lenalidomide (Revlimid) maintenance becoming a standard of care remains uncertain despite the substantial benefit clearly demonstrated in these multicenter, double-blind, placebo-controlled phase III studies.
Notably, investigators reported that prolonged administration of lenalidomide was associated with an increased incidence of second cancers in patients who had undergone stem cell transplantation. This led the Food and Drug Administration to add a warning to the drug’s label on May 7 after a yearlong analysis of early data from the trials.
In addition, a bevy of new drugs, both approved and in the pipeline, has changed the course of multiple myeloma from one with a short life expectancy to that of a chronic disease, with most patients embarking on second-line therapies after experiencing recurrences within 3 years of initial treatment.
"It remains to be determined whether the incorporation of other new agents with lenalidomide will further increase the time to disease progression and overall survival," Dr. Philip L. McCarthy and his coauthors wrote at the conclusion of their report on the one trial that showed a benefit in overall survival.
Two trials compared maintenance lenalidomide with placebo in patients who achieved stable disease or better after stem cell transplantation. The third trial focused on an older group of patients that was not eligible for transplantation. All were stopped early after achieving their goals.
Crossover Did Not Erase Benefit
The Cancer and Leukemia Group B (CALGB) trial reported by Dr. McCarthy, of the Roswell Park Cancer Institute in Buffalo, N.Y., and his associates randomized 460 patients up to 70 years of age after stem cell transplantation. Patients in the lenalidomide arm started at 10 mg daily, and doses ranged from 5 to 15 mg until disease progression.
When the study was unblinded in December 2009, disease progression or death had occurred in 44% of the placebo group, but only 20% of patients on lenalidomide maintenance (hazard ratio, 0.37; P less than .001). Investigators reported that median time to progression was nearly twice as long with lenalidomide – 39 months vs. 21 months (P less than .001). At that point the study’s primary end point – time to progression – had been met, and 86 of 128 eligible patients in the placebo group began to receive lenalidomide maintenance.
Despite this crossover, lenalidomide maintenance continued to demonstrate a significant advantage at a median follow-up as of Oct. 31, 2011. By then, investigators reported, only 37% of the lenalidomide group had disease progression or death, compared with 58% of the placebo group (HR, 0.48). Median time to progression reached 46 months in the lenalidomide group vs. 27 months in the placebo arm (P less than .001), according to the new report.
The 3-year rate of freedom from progression or death was higher with lenalidomide maintenance (66% vs. 39%), as was the overall survival rate (88% vs. 80%, HR 0.62) (N. Engl. J. Med. 2012;366:1770-81).
Younger Group in IFM Trial
Dr. Michel Attal of Hôpital Purpan in Toulouse, France, and his colleagues from the Intergroupe Francophone du Myélome (IFM) conducted a similar trial in a population of 614 patients under age 65 whose disease had not progressed after stem cell transplantation. All patients received two 28-day cycles of consolidation treatment with lenalidomide (25 mg daily on days 121) followed by maintenance with placebo or lenalidomide (10 mg daily for 3 months, after which the dose could be increased to 15 mg if tolerated) until disease progression.
At the time the study was unblinded at a median follow-up of 30 months in July 2010, median progression-free survival was nearly twice as long with lenalidomide maintenance – 41 months, compared with 23 months with a placebo (HR, 0.50; P less than .001). Overall survival was similar between the groups, and neither group had reached median overall survival.
By October 2011, median follow-up from time of randomization had reached 45 months, and the probability of surviving without progression 4 years after randomization was still about double with lenalidomide: 43% vs. 22% (HR, 0.50; P less than .001).
The overall survival rate was still similar, however, at 73% with lenalidomide and 75% with placebo. These survival rates are high, the authors noted, and longer follow-up may show an advantage for lenalidomide maintenance.
"Together with the findings reported by McCarthy et al., our data support the use of lenalidomide maintenance therapy after high-dose chemotherapy and autologous hematopoietic stem-cell transplantation in patients with myeloma, but the impressive benefits must be weighed against the increased risks," said Dr. Attal and his coauthors (N. Engl. J. Med. 2012;366:1782-91).
Older Patients Ineligible for Transplant
Dr. Antonio Palumbo of the University of Turin, Italy, and his coinvestigators from the Multiple Myeloma-015 (MM-015) trial also explored continuous lenalidomide, but in a population of 459 patients aged 65 years and older who were not eligible for stem cell transplantation.
Patients were randomized to three groups: One group received induction therapy with melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR-R); the second received MPR followed by placebo maintenance; and the third received only melphalan and prednisone (MP) followed by placebo. Investigators reported that about two-thirds of patients completed their induction regimens.
Median progression-free survival, the primary end point, was significantly longer in the group that received lenalidomide maintenance (31 months) than in the groups that received MPR with placebo (14 months) or MP without any lenalidomide in the induction and maintenance phases (13 months).
In a landmark analysis that looked at progression-free survival from the start of maintenance therapy, the median reached 26 months with lenalidomide vs. 7 months with placebo, with a hazard ratio of 0.34 for MPR-R vs. MPR (P less than .001).
Greater benefit was seen in patients 65-75 years of age, with median progression-free survival of 31 months with MPR-R, 15 months with MPR, and 12 months with MP. In patients over age 75, the medians were 19 months, 12 months, and 15 months, respectively.
Median overall survival at 3 years was not significantly different, reaching 70% with MPR-R, 62% with MPR, and 66% with MP.
"Altogether, these results confirm the benefits of maintenance therapy with respect to progression-free survival. The influence on overall survival remains unclear," concluded Dr. Palumbo and his coauthors (N. Engl. J. Med. 2012;366:1759-69).
Secondary Malignancies
In all three studies lenalidomide was associated with higher rates of secondary primary cancers.
• The rate was 8% in the lenalidomide group vs. 3% in the placebo group in the CALGB study.
• The IFM investigators calculated the incidence as 3.1 per 100 patient-years in their lenalidomide group vs. 1.2 per 100 patient-years with placebo (P = .002).
• In the MM-015 study, the 3-year rate was 7% with MPR-R, 7% with MPR, and 3% with MP. The increased risk was "mainly confined to acute myeloid leukemia or myelodysplastic syndromes, and is observed when lenalidomide is given with or after melphalan," the investigators wrote.
Other Adverse Events
Hematologic toxicity dominated the adverse event reports from all three studies.
• In the CALBG trial, grade 3 and 4 hematologic side effects were significantly more common with lenalidomide maintenance, as were grade 3 nonhematologic events. The most pronounced was neutropenia in 45% of the lenalidomide group vs. 15% of the placebo group (P less than .001).
• The IFM investigators also reported that grade 3 or 4 hematologic events were more frequent with lenalidomide than with placebo (58% vs. 23%, P less than .001), as were thromboembolic events (6% vs. 2%, P = .01).
• Similarly, the MM-015 group found that the most frequent adverse events were hematologic, with grade 4 neutropenia occurring in 35% of patients given lenalidomide. Nonhematologic events, including deep vein thrombosis, occurred at low rates, however, according to Dr. Palumbo and his coauthors. "Lenalidomide maintenance was associated with little evidence of cumulative toxic effects," they said.
How the safety profiles will influence adoption of lenalidomide maintenance is uncertain. "A major concern during maintenance therapy is toxicity that limits long-term use and the ability to receive future treatment after disease progression or that results in life-threatening disorders," noted Dr. McCarthy and his coauthors.
The National Cancer Institute supported the CALGB trial. Celgene, maker of lenalidomide, provided support for the IFM and MM-015 studies. The IFM trial also received support from the Programme Hospitalier de Recherche Clinique and the Swiss Group for Clinical Cancer Research (SAKK). Disclosure forms filed by individual investigators are posted at http://www.nejm.org.
Though the studies provide compelling evidence that lenalidomide maintenance can improve progression-free survival, they also raise critical questions for Dr. Ashraf Z. Badros. In an accompanying editorial, he listed the following issues:
• "First, is progression-free survival the appropriate primary end point in maintenance trials?"
That all patients with myeloma will receive lenalidomide is "a given," he noted. The studies do not address how early use of lenalidomide maintenance compares with its use at relapse in improving overall survival. Nor do they determine whether prolonged exposure could "select a refractory clone" that would result in shortened overall survival after relapse. "Is delayed progression beneficial to patients in and of itself?" he asked (N. Engl. J. Med. 2012;366:1836-38).
• "Second, is lenalidomide maintenance therapy safe?"
Though secondary cancers are a known risk in myeloma, the incidence seen in the trials was surprising. "Unfortunately the way in which lenalidomide increases this risk could not be explained solely by longer survival, and is currently under investigation," said Dr. Badros.
• "A third concern involves the duration and cost of maintenance therapy."
Optimal duration is not established, according to Dr. Badros. "Lenalidomide costs $447.62 per 10-mg tablet (or $163,381 per year for the average patient), as listed on the manufacturer’s website. This total does not account for the costs of laboratory monitoring, physician visits, and management of side effects. Is it cost-effective?" he wrote.
"Whether these data establish a new standard of care for myeloma may be debatable," Dr. Badros concluded, citing newer investigational therapies currently in clinical trials. "As myeloma evolves from an ‘incurable’ cancer to a chronic disease, physicians are faced with the task of maximizing available treatments not only to improve survival but also to maintain their patients’ quality of life."
Dr. Ashraf Z. Badros is a professor of medicine at the University of Maryland in Baltimore. He disclosed receiving grants from seven drug companies as the principal investigator in clinical trials in myeloma. He also disclosed payment for writing a review of maintenance therapy in myeloma for a symposium sponsored by Millennium Pharmaceuticals.
Though the studies provide compelling evidence that lenalidomide maintenance can improve progression-free survival, they also raise critical questions for Dr. Ashraf Z. Badros. In an accompanying editorial, he listed the following issues:
• "First, is progression-free survival the appropriate primary end point in maintenance trials?"
That all patients with myeloma will receive lenalidomide is "a given," he noted. The studies do not address how early use of lenalidomide maintenance compares with its use at relapse in improving overall survival. Nor do they determine whether prolonged exposure could "select a refractory clone" that would result in shortened overall survival after relapse. "Is delayed progression beneficial to patients in and of itself?" he asked (N. Engl. J. Med. 2012;366:1836-38).
• "Second, is lenalidomide maintenance therapy safe?"
Though secondary cancers are a known risk in myeloma, the incidence seen in the trials was surprising. "Unfortunately the way in which lenalidomide increases this risk could not be explained solely by longer survival, and is currently under investigation," said Dr. Badros.
• "A third concern involves the duration and cost of maintenance therapy."
Optimal duration is not established, according to Dr. Badros. "Lenalidomide costs $447.62 per 10-mg tablet (or $163,381 per year for the average patient), as listed on the manufacturer’s website. This total does not account for the costs of laboratory monitoring, physician visits, and management of side effects. Is it cost-effective?" he wrote.
"Whether these data establish a new standard of care for myeloma may be debatable," Dr. Badros concluded, citing newer investigational therapies currently in clinical trials. "As myeloma evolves from an ‘incurable’ cancer to a chronic disease, physicians are faced with the task of maximizing available treatments not only to improve survival but also to maintain their patients’ quality of life."
Dr. Ashraf Z. Badros is a professor of medicine at the University of Maryland in Baltimore. He disclosed receiving grants from seven drug companies as the principal investigator in clinical trials in myeloma. He also disclosed payment for writing a review of maintenance therapy in myeloma for a symposium sponsored by Millennium Pharmaceuticals.
Though the studies provide compelling evidence that lenalidomide maintenance can improve progression-free survival, they also raise critical questions for Dr. Ashraf Z. Badros. In an accompanying editorial, he listed the following issues:
• "First, is progression-free survival the appropriate primary end point in maintenance trials?"
That all patients with myeloma will receive lenalidomide is "a given," he noted. The studies do not address how early use of lenalidomide maintenance compares with its use at relapse in improving overall survival. Nor do they determine whether prolonged exposure could "select a refractory clone" that would result in shortened overall survival after relapse. "Is delayed progression beneficial to patients in and of itself?" he asked (N. Engl. J. Med. 2012;366:1836-38).
• "Second, is lenalidomide maintenance therapy safe?"
Though secondary cancers are a known risk in myeloma, the incidence seen in the trials was surprising. "Unfortunately the way in which lenalidomide increases this risk could not be explained solely by longer survival, and is currently under investigation," said Dr. Badros.
• "A third concern involves the duration and cost of maintenance therapy."
Optimal duration is not established, according to Dr. Badros. "Lenalidomide costs $447.62 per 10-mg tablet (or $163,381 per year for the average patient), as listed on the manufacturer’s website. This total does not account for the costs of laboratory monitoring, physician visits, and management of side effects. Is it cost-effective?" he wrote.
"Whether these data establish a new standard of care for myeloma may be debatable," Dr. Badros concluded, citing newer investigational therapies currently in clinical trials. "As myeloma evolves from an ‘incurable’ cancer to a chronic disease, physicians are faced with the task of maximizing available treatments not only to improve survival but also to maintain their patients’ quality of life."
Dr. Ashraf Z. Badros is a professor of medicine at the University of Maryland in Baltimore. He disclosed receiving grants from seven drug companies as the principal investigator in clinical trials in myeloma. He also disclosed payment for writing a review of maintenance therapy in myeloma for a symposium sponsored by Millennium Pharmaceuticals.
Lenalidomide maintenance therapy delayed recurrences significantly when given to patients newly diagnosed with multiple myeloma in a trio of clinical trials that reported much-anticipated outcomes May 9 in the New England Journal of Medicine.
Only one trial showed a gain in overall survival, however, and the prospect of lenalidomide (Revlimid) maintenance becoming a standard of care remains uncertain despite the substantial benefit clearly demonstrated in these multicenter, double-blind, placebo-controlled phase III studies.
Notably, investigators reported that prolonged administration of lenalidomide was associated with an increased incidence of second cancers in patients who had undergone stem cell transplantation. This led the Food and Drug Administration to add a warning to the drug’s label on May 7 after a yearlong analysis of early data from the trials.
In addition, a bevy of new drugs, both approved and in the pipeline, has changed the course of multiple myeloma from one with a short life expectancy to that of a chronic disease, with most patients embarking on second-line therapies after experiencing recurrences within 3 years of initial treatment.
"It remains to be determined whether the incorporation of other new agents with lenalidomide will further increase the time to disease progression and overall survival," Dr. Philip L. McCarthy and his coauthors wrote at the conclusion of their report on the one trial that showed a benefit in overall survival.
Two trials compared maintenance lenalidomide with placebo in patients who achieved stable disease or better after stem cell transplantation. The third trial focused on an older group of patients that was not eligible for transplantation. All were stopped early after achieving their goals.
Crossover Did Not Erase Benefit
The Cancer and Leukemia Group B (CALGB) trial reported by Dr. McCarthy, of the Roswell Park Cancer Institute in Buffalo, N.Y., and his associates randomized 460 patients up to 70 years of age after stem cell transplantation. Patients in the lenalidomide arm started at 10 mg daily, and doses ranged from 5 to 15 mg until disease progression.
When the study was unblinded in December 2009, disease progression or death had occurred in 44% of the placebo group, but only 20% of patients on lenalidomide maintenance (hazard ratio, 0.37; P less than .001). Investigators reported that median time to progression was nearly twice as long with lenalidomide – 39 months vs. 21 months (P less than .001). At that point the study’s primary end point – time to progression – had been met, and 86 of 128 eligible patients in the placebo group began to receive lenalidomide maintenance.
Despite this crossover, lenalidomide maintenance continued to demonstrate a significant advantage at a median follow-up as of Oct. 31, 2011. By then, investigators reported, only 37% of the lenalidomide group had disease progression or death, compared with 58% of the placebo group (HR, 0.48). Median time to progression reached 46 months in the lenalidomide group vs. 27 months in the placebo arm (P less than .001), according to the new report.
The 3-year rate of freedom from progression or death was higher with lenalidomide maintenance (66% vs. 39%), as was the overall survival rate (88% vs. 80%, HR 0.62) (N. Engl. J. Med. 2012;366:1770-81).
Younger Group in IFM Trial
Dr. Michel Attal of Hôpital Purpan in Toulouse, France, and his colleagues from the Intergroupe Francophone du Myélome (IFM) conducted a similar trial in a population of 614 patients under age 65 whose disease had not progressed after stem cell transplantation. All patients received two 28-day cycles of consolidation treatment with lenalidomide (25 mg daily on days 121) followed by maintenance with placebo or lenalidomide (10 mg daily for 3 months, after which the dose could be increased to 15 mg if tolerated) until disease progression.
At the time the study was unblinded at a median follow-up of 30 months in July 2010, median progression-free survival was nearly twice as long with lenalidomide maintenance – 41 months, compared with 23 months with a placebo (HR, 0.50; P less than .001). Overall survival was similar between the groups, and neither group had reached median overall survival.
By October 2011, median follow-up from time of randomization had reached 45 months, and the probability of surviving without progression 4 years after randomization was still about double with lenalidomide: 43% vs. 22% (HR, 0.50; P less than .001).
The overall survival rate was still similar, however, at 73% with lenalidomide and 75% with placebo. These survival rates are high, the authors noted, and longer follow-up may show an advantage for lenalidomide maintenance.
"Together with the findings reported by McCarthy et al., our data support the use of lenalidomide maintenance therapy after high-dose chemotherapy and autologous hematopoietic stem-cell transplantation in patients with myeloma, but the impressive benefits must be weighed against the increased risks," said Dr. Attal and his coauthors (N. Engl. J. Med. 2012;366:1782-91).
Older Patients Ineligible for Transplant
Dr. Antonio Palumbo of the University of Turin, Italy, and his coinvestigators from the Multiple Myeloma-015 (MM-015) trial also explored continuous lenalidomide, but in a population of 459 patients aged 65 years and older who were not eligible for stem cell transplantation.
Patients were randomized to three groups: One group received induction therapy with melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR-R); the second received MPR followed by placebo maintenance; and the third received only melphalan and prednisone (MP) followed by placebo. Investigators reported that about two-thirds of patients completed their induction regimens.
Median progression-free survival, the primary end point, was significantly longer in the group that received lenalidomide maintenance (31 months) than in the groups that received MPR with placebo (14 months) or MP without any lenalidomide in the induction and maintenance phases (13 months).
In a landmark analysis that looked at progression-free survival from the start of maintenance therapy, the median reached 26 months with lenalidomide vs. 7 months with placebo, with a hazard ratio of 0.34 for MPR-R vs. MPR (P less than .001).
Greater benefit was seen in patients 65-75 years of age, with median progression-free survival of 31 months with MPR-R, 15 months with MPR, and 12 months with MP. In patients over age 75, the medians were 19 months, 12 months, and 15 months, respectively.
Median overall survival at 3 years was not significantly different, reaching 70% with MPR-R, 62% with MPR, and 66% with MP.
"Altogether, these results confirm the benefits of maintenance therapy with respect to progression-free survival. The influence on overall survival remains unclear," concluded Dr. Palumbo and his coauthors (N. Engl. J. Med. 2012;366:1759-69).
Secondary Malignancies
In all three studies lenalidomide was associated with higher rates of secondary primary cancers.
• The rate was 8% in the lenalidomide group vs. 3% in the placebo group in the CALGB study.
• The IFM investigators calculated the incidence as 3.1 per 100 patient-years in their lenalidomide group vs. 1.2 per 100 patient-years with placebo (P = .002).
• In the MM-015 study, the 3-year rate was 7% with MPR-R, 7% with MPR, and 3% with MP. The increased risk was "mainly confined to acute myeloid leukemia or myelodysplastic syndromes, and is observed when lenalidomide is given with or after melphalan," the investigators wrote.
Other Adverse Events
Hematologic toxicity dominated the adverse event reports from all three studies.
• In the CALBG trial, grade 3 and 4 hematologic side effects were significantly more common with lenalidomide maintenance, as were grade 3 nonhematologic events. The most pronounced was neutropenia in 45% of the lenalidomide group vs. 15% of the placebo group (P less than .001).
• The IFM investigators also reported that grade 3 or 4 hematologic events were more frequent with lenalidomide than with placebo (58% vs. 23%, P less than .001), as were thromboembolic events (6% vs. 2%, P = .01).
• Similarly, the MM-015 group found that the most frequent adverse events were hematologic, with grade 4 neutropenia occurring in 35% of patients given lenalidomide. Nonhematologic events, including deep vein thrombosis, occurred at low rates, however, according to Dr. Palumbo and his coauthors. "Lenalidomide maintenance was associated with little evidence of cumulative toxic effects," they said.
How the safety profiles will influence adoption of lenalidomide maintenance is uncertain. "A major concern during maintenance therapy is toxicity that limits long-term use and the ability to receive future treatment after disease progression or that results in life-threatening disorders," noted Dr. McCarthy and his coauthors.
The National Cancer Institute supported the CALGB trial. Celgene, maker of lenalidomide, provided support for the IFM and MM-015 studies. The IFM trial also received support from the Programme Hospitalier de Recherche Clinique and the Swiss Group for Clinical Cancer Research (SAKK). Disclosure forms filed by individual investigators are posted at http://www.nejm.org.
Lenalidomide maintenance therapy delayed recurrences significantly when given to patients newly diagnosed with multiple myeloma in a trio of clinical trials that reported much-anticipated outcomes May 9 in the New England Journal of Medicine.
Only one trial showed a gain in overall survival, however, and the prospect of lenalidomide (Revlimid) maintenance becoming a standard of care remains uncertain despite the substantial benefit clearly demonstrated in these multicenter, double-blind, placebo-controlled phase III studies.
Notably, investigators reported that prolonged administration of lenalidomide was associated with an increased incidence of second cancers in patients who had undergone stem cell transplantation. This led the Food and Drug Administration to add a warning to the drug’s label on May 7 after a yearlong analysis of early data from the trials.
In addition, a bevy of new drugs, both approved and in the pipeline, has changed the course of multiple myeloma from one with a short life expectancy to that of a chronic disease, with most patients embarking on second-line therapies after experiencing recurrences within 3 years of initial treatment.
"It remains to be determined whether the incorporation of other new agents with lenalidomide will further increase the time to disease progression and overall survival," Dr. Philip L. McCarthy and his coauthors wrote at the conclusion of their report on the one trial that showed a benefit in overall survival.
Two trials compared maintenance lenalidomide with placebo in patients who achieved stable disease or better after stem cell transplantation. The third trial focused on an older group of patients that was not eligible for transplantation. All were stopped early after achieving their goals.
Crossover Did Not Erase Benefit
The Cancer and Leukemia Group B (CALGB) trial reported by Dr. McCarthy, of the Roswell Park Cancer Institute in Buffalo, N.Y., and his associates randomized 460 patients up to 70 years of age after stem cell transplantation. Patients in the lenalidomide arm started at 10 mg daily, and doses ranged from 5 to 15 mg until disease progression.
When the study was unblinded in December 2009, disease progression or death had occurred in 44% of the placebo group, but only 20% of patients on lenalidomide maintenance (hazard ratio, 0.37; P less than .001). Investigators reported that median time to progression was nearly twice as long with lenalidomide – 39 months vs. 21 months (P less than .001). At that point the study’s primary end point – time to progression – had been met, and 86 of 128 eligible patients in the placebo group began to receive lenalidomide maintenance.
Despite this crossover, lenalidomide maintenance continued to demonstrate a significant advantage at a median follow-up as of Oct. 31, 2011. By then, investigators reported, only 37% of the lenalidomide group had disease progression or death, compared with 58% of the placebo group (HR, 0.48). Median time to progression reached 46 months in the lenalidomide group vs. 27 months in the placebo arm (P less than .001), according to the new report.
The 3-year rate of freedom from progression or death was higher with lenalidomide maintenance (66% vs. 39%), as was the overall survival rate (88% vs. 80%, HR 0.62) (N. Engl. J. Med. 2012;366:1770-81).
Younger Group in IFM Trial
Dr. Michel Attal of Hôpital Purpan in Toulouse, France, and his colleagues from the Intergroupe Francophone du Myélome (IFM) conducted a similar trial in a population of 614 patients under age 65 whose disease had not progressed after stem cell transplantation. All patients received two 28-day cycles of consolidation treatment with lenalidomide (25 mg daily on days 121) followed by maintenance with placebo or lenalidomide (10 mg daily for 3 months, after which the dose could be increased to 15 mg if tolerated) until disease progression.
At the time the study was unblinded at a median follow-up of 30 months in July 2010, median progression-free survival was nearly twice as long with lenalidomide maintenance – 41 months, compared with 23 months with a placebo (HR, 0.50; P less than .001). Overall survival was similar between the groups, and neither group had reached median overall survival.
By October 2011, median follow-up from time of randomization had reached 45 months, and the probability of surviving without progression 4 years after randomization was still about double with lenalidomide: 43% vs. 22% (HR, 0.50; P less than .001).
The overall survival rate was still similar, however, at 73% with lenalidomide and 75% with placebo. These survival rates are high, the authors noted, and longer follow-up may show an advantage for lenalidomide maintenance.
"Together with the findings reported by McCarthy et al., our data support the use of lenalidomide maintenance therapy after high-dose chemotherapy and autologous hematopoietic stem-cell transplantation in patients with myeloma, but the impressive benefits must be weighed against the increased risks," said Dr. Attal and his coauthors (N. Engl. J. Med. 2012;366:1782-91).
Older Patients Ineligible for Transplant
Dr. Antonio Palumbo of the University of Turin, Italy, and his coinvestigators from the Multiple Myeloma-015 (MM-015) trial also explored continuous lenalidomide, but in a population of 459 patients aged 65 years and older who were not eligible for stem cell transplantation.
Patients were randomized to three groups: One group received induction therapy with melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR-R); the second received MPR followed by placebo maintenance; and the third received only melphalan and prednisone (MP) followed by placebo. Investigators reported that about two-thirds of patients completed their induction regimens.
Median progression-free survival, the primary end point, was significantly longer in the group that received lenalidomide maintenance (31 months) than in the groups that received MPR with placebo (14 months) or MP without any lenalidomide in the induction and maintenance phases (13 months).
In a landmark analysis that looked at progression-free survival from the start of maintenance therapy, the median reached 26 months with lenalidomide vs. 7 months with placebo, with a hazard ratio of 0.34 for MPR-R vs. MPR (P less than .001).
Greater benefit was seen in patients 65-75 years of age, with median progression-free survival of 31 months with MPR-R, 15 months with MPR, and 12 months with MP. In patients over age 75, the medians were 19 months, 12 months, and 15 months, respectively.
Median overall survival at 3 years was not significantly different, reaching 70% with MPR-R, 62% with MPR, and 66% with MP.
"Altogether, these results confirm the benefits of maintenance therapy with respect to progression-free survival. The influence on overall survival remains unclear," concluded Dr. Palumbo and his coauthors (N. Engl. J. Med. 2012;366:1759-69).
Secondary Malignancies
In all three studies lenalidomide was associated with higher rates of secondary primary cancers.
• The rate was 8% in the lenalidomide group vs. 3% in the placebo group in the CALGB study.
• The IFM investigators calculated the incidence as 3.1 per 100 patient-years in their lenalidomide group vs. 1.2 per 100 patient-years with placebo (P = .002).
• In the MM-015 study, the 3-year rate was 7% with MPR-R, 7% with MPR, and 3% with MP. The increased risk was "mainly confined to acute myeloid leukemia or myelodysplastic syndromes, and is observed when lenalidomide is given with or after melphalan," the investigators wrote.
Other Adverse Events
Hematologic toxicity dominated the adverse event reports from all three studies.
• In the CALBG trial, grade 3 and 4 hematologic side effects were significantly more common with lenalidomide maintenance, as were grade 3 nonhematologic events. The most pronounced was neutropenia in 45% of the lenalidomide group vs. 15% of the placebo group (P less than .001).
• The IFM investigators also reported that grade 3 or 4 hematologic events were more frequent with lenalidomide than with placebo (58% vs. 23%, P less than .001), as were thromboembolic events (6% vs. 2%, P = .01).
• Similarly, the MM-015 group found that the most frequent adverse events were hematologic, with grade 4 neutropenia occurring in 35% of patients given lenalidomide. Nonhematologic events, including deep vein thrombosis, occurred at low rates, however, according to Dr. Palumbo and his coauthors. "Lenalidomide maintenance was associated with little evidence of cumulative toxic effects," they said.
How the safety profiles will influence adoption of lenalidomide maintenance is uncertain. "A major concern during maintenance therapy is toxicity that limits long-term use and the ability to receive future treatment after disease progression or that results in life-threatening disorders," noted Dr. McCarthy and his coauthors.
The National Cancer Institute supported the CALGB trial. Celgene, maker of lenalidomide, provided support for the IFM and MM-015 studies. The IFM trial also received support from the Programme Hospitalier de Recherche Clinique and the Swiss Group for Clinical Cancer Research (SAKK). Disclosure forms filed by individual investigators are posted at http://www.nejm.org.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE