June 13, 2011 (London, United Kingdom) — Contrary to expectation, progression-free survival in patients with multiple myeloma is longer in patients who receive high-dose melphalan (Alkeran, GlaxoSmithKline) and undergo autologous stem cell transplantation (ASCT) than in those treated with the novel agent lenalidomide (Revlimid, Celgene) plus conventional chemotherapy (melphalan plus prednisone).
Results of the randomized phase 3 trial were presented here at the 16th Congress of the European Hematology Association (EHA) by Antonio Palumbo, MD, from the Division of Hematology, University of Torino, in Italy.
"The complete response rate is similar between the 2 groups, but the expectation that we would see a similar progression-free survival was not evident. In fact, in our study, progression-free survival was superior in patients who received high-dose melphalan plus ASCT," Dr. Palumbo told Medscape Medical News.
All 402 of the patients in the study received induction therapy consisting of four 28-day cycles of lenalidomide (25 mg on days 1 to 21) and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22), followed by 1 of the 2 comparator groups. Half the patients received six 28-day cycles of melphalan (0.18 mg/kg on days 1 to 4), prednisone (2 mg/kg on days 1 to 4), and lenalidomide (10 mg on days 1 to 21) (the conventional group); the other half received tandem melphalan 200 mg/m2 with ASCT.
Complete Response Rates Similar But Progression-Free Survival Differs
More complete response rates were seen in the group that received melphalan plus ASCT than in the conventional group, but this difference was not statistically significant (25% vs 20%; P = .49). However, surprisingly, progression-free survival at 24 months was significantly greater in the group that received melphalan plus ASCT than in the conventional group (73% vs 54%; P = .0004).
This is the first report to show a progression-free survival advantage for high-dose melphalan plus ASCT over combinations that included novel agents, Dr. Palumbo pointed out.
"It seems that the idea is gaining ground that a more intensive approach to therapy offers an advantage in the most sensitive disease, rather than in high-risk disease," he added.
In terms of overall survival, there was no statistically significant difference between the group that received melphalan plus ASCT and the conventional group (90% vs 87%; P = 0.21), but follow-up continues.
Patients were randomized for a second time to investigate the efficacy and safety of maintenance therapy, but these results are not available because of an insufficient follow-up period so far.
More Toxicity With Melphalan Plus ASCT
As expected, toxicity was much higher with high-dose melphalan plus ASCT than with conventional therapy, including grade 3/4 neutropenia (89% vs 55%; P < .001), grade 3/4 infections (17% vs 0%; P < .001), and grade 3/4 gastrointestinal toxicity (21% vs 0%; P < .001). The incidence of second tumors was the same in both groups (0.005%), but the incidence of deep vein thrombosis was lower with melphalan plus ASCT (1.13% vs 2.44%; P = .43).
"As far as second cancers are concerned, there have been no cases of cancer after 2 years of follow-up," Dr. Palumbo explained.
Anton Hagenbeek, MD, PhD, from University Medical Center Utrecht, the Netherlands, who was not involved with the study, found the results impressive, despite the increased toxicity with high-dose melphalan. "It shows that the quality of the remission was better in the double transplant arm. These results mean the tumor-load reduction with high-dose melphalan is much more effective. Hence, the quality of remission is better because it takes longer for the residual myeloma cells to return to levels that show symptoms of disease," he told Medscape Medical News.
Dr. Palumbo's presentation stimulated discussion about the importance of dose optimization to limit toxicities. He noted that improved progression-free survival comes at the price of increased toxicities, and that this challenge will only intensify as the patient population becomes older.
"Myeloma is a disease of the aging population. There's an increasing frequency and prevalence due to our population's increasing age. There's a major need to improve treatment and schedule because we are creating too much toxicity," he added.
Commenting on the this issue, Robin Foà MD, from the Department of Cellular Biotechnologies and Hematology, University of Rome "La Sapienza," in Italy, who is president of the EHA, said that different hematological malignancies — such as chronic lymphocytic leukemia, myeloma, and myelodysplastic syndromes — are dramatically increasing because people are living longer, and that these diseases have a greater incidence in the elderly. "We are going to see a burst of patients with hematological malignancies, as well as anemia, so optimizing the management of these patients at a time of high costs is important."
Dr. Foà also noted that the definition of an elderly patient should be based on performance status, not age. "While a growing number of elderly patients are indeed fit and can undergo more aggressive treatments, a substantial proportion of patients may have comorbidities and be eligible for milder therapeutic approaches. In Europe, the management of the elderly is becoming a largely unmet medical need."
Responding to Dr. Foà, Dr. Palumbo said that during drug development, dose-limiting toxicity is measured at the age of 50. "This becomes the standard dose for the whole population, which is a major issue because the aging population will not be able to tolerate these drugs."
Also commenting specifically on the results of Dr. Palumbo's study, Pieter Sonneveld, MD, from the Department of Hematology, Erasmus MC University Hospital, Rotterdam, the Netherlands said: "The first results of this trial indicate that high-dose therapy with autologous bone marrow transplantation is still the backbone of myeloma treatment. Novel drugs may be utilized to augment the effect of this treatment, rather than replacing it."
Dr. Palumbo, Dr. Foà, Dr. Sonneveld, and Dr. Hagenbeek have disclosed no relevant financial relationships.
16th Congress of the European Hematology Association (EHA). Presented June 11, 2011.
Results of the randomized phase 3 trial were presented here at the 16th Congress of the European Hematology Association (EHA) by Antonio Palumbo, MD, from the Division of Hematology, University of Torino, in Italy.
"The complete response rate is similar between the 2 groups, but the expectation that we would see a similar progression-free survival was not evident. In fact, in our study, progression-free survival was superior in patients who received high-dose melphalan plus ASCT," Dr. Palumbo told Medscape Medical News.
All 402 of the patients in the study received induction therapy consisting of four 28-day cycles of lenalidomide (25 mg on days 1 to 21) and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22), followed by 1 of the 2 comparator groups. Half the patients received six 28-day cycles of melphalan (0.18 mg/kg on days 1 to 4), prednisone (2 mg/kg on days 1 to 4), and lenalidomide (10 mg on days 1 to 21) (the conventional group); the other half received tandem melphalan 200 mg/m2 with ASCT.
Complete Response Rates Similar But Progression-Free Survival Differs
More complete response rates were seen in the group that received melphalan plus ASCT than in the conventional group, but this difference was not statistically significant (25% vs 20%; P = .49). However, surprisingly, progression-free survival at 24 months was significantly greater in the group that received melphalan plus ASCT than in the conventional group (73% vs 54%; P = .0004).
This is the first report to show a progression-free survival advantage for high-dose melphalan plus ASCT over combinations that included novel agents, Dr. Palumbo pointed out.
"It seems that the idea is gaining ground that a more intensive approach to therapy offers an advantage in the most sensitive disease, rather than in high-risk disease," he added.
In terms of overall survival, there was no statistically significant difference between the group that received melphalan plus ASCT and the conventional group (90% vs 87%; P = 0.21), but follow-up continues.
Patients were randomized for a second time to investigate the efficacy and safety of maintenance therapy, but these results are not available because of an insufficient follow-up period so far.
More Toxicity With Melphalan Plus ASCT
As expected, toxicity was much higher with high-dose melphalan plus ASCT than with conventional therapy, including grade 3/4 neutropenia (89% vs 55%; P < .001), grade 3/4 infections (17% vs 0%; P < .001), and grade 3/4 gastrointestinal toxicity (21% vs 0%; P < .001). The incidence of second tumors was the same in both groups (0.005%), but the incidence of deep vein thrombosis was lower with melphalan plus ASCT (1.13% vs 2.44%; P = .43).
"As far as second cancers are concerned, there have been no cases of cancer after 2 years of follow-up," Dr. Palumbo explained.
Anton Hagenbeek, MD, PhD, from University Medical Center Utrecht, the Netherlands, who was not involved with the study, found the results impressive, despite the increased toxicity with high-dose melphalan. "It shows that the quality of the remission was better in the double transplant arm. These results mean the tumor-load reduction with high-dose melphalan is much more effective. Hence, the quality of remission is better because it takes longer for the residual myeloma cells to return to levels that show symptoms of disease," he told Medscape Medical News.
Dr. Palumbo's presentation stimulated discussion about the importance of dose optimization to limit toxicities. He noted that improved progression-free survival comes at the price of increased toxicities, and that this challenge will only intensify as the patient population becomes older.
"Myeloma is a disease of the aging population. There's an increasing frequency and prevalence due to our population's increasing age. There's a major need to improve treatment and schedule because we are creating too much toxicity," he added.
Commenting on the this issue, Robin Foà MD, from the Department of Cellular Biotechnologies and Hematology, University of Rome "La Sapienza," in Italy, who is president of the EHA, said that different hematological malignancies — such as chronic lymphocytic leukemia, myeloma, and myelodysplastic syndromes — are dramatically increasing because people are living longer, and that these diseases have a greater incidence in the elderly. "We are going to see a burst of patients with hematological malignancies, as well as anemia, so optimizing the management of these patients at a time of high costs is important."
Dr. Foà also noted that the definition of an elderly patient should be based on performance status, not age. "While a growing number of elderly patients are indeed fit and can undergo more aggressive treatments, a substantial proportion of patients may have comorbidities and be eligible for milder therapeutic approaches. In Europe, the management of the elderly is becoming a largely unmet medical need."
Responding to Dr. Foà, Dr. Palumbo said that during drug development, dose-limiting toxicity is measured at the age of 50. "This becomes the standard dose for the whole population, which is a major issue because the aging population will not be able to tolerate these drugs."
Also commenting specifically on the results of Dr. Palumbo's study, Pieter Sonneveld, MD, from the Department of Hematology, Erasmus MC University Hospital, Rotterdam, the Netherlands said: "The first results of this trial indicate that high-dose therapy with autologous bone marrow transplantation is still the backbone of myeloma treatment. Novel drugs may be utilized to augment the effect of this treatment, rather than replacing it."
Dr. Palumbo, Dr. Foà, Dr. Sonneveld, and Dr. Hagenbeek have disclosed no relevant financial relationships.
16th Congress of the European Hematology Association (EHA). Presented June 11, 2011.
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