Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma

a randomised, double-blind, phase 3 trial

Sarah A. Holstein, Sin Ho Jung, Paul G. Richardson, Craig C. Hofmeister, David D. Hurd, Hani Hassoun, Sergio Giralt, Edward A. Stadtmauer, Daniel J. Weisdorf, Ravi Vij, Jan S. Moreb, Natalie S. Callander, Koen van Besien, Teresa G. Gentile, Luis Isola, Richard Maziarz, Asad Bashey, Heather Landau, Thomas Martin, Muzaffar H. Qazilbash & 18 others Cesar Rodriguez, Brian McClune, Robert L. Schlossman, Scott E. Smith, Vera Hars, Kouros Owzar, Chen Jiang, Molly Boyd, Chelsea Schultz, Marcia Wilson, Parameswaran Hari, Marcelo C. Pasquini, Mary M. Horowitz, Thomas C. Shea, Steven M. Devine, Charles Linker, Kenneth C. Anderson, Philip L. McCarthy

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months. Methods Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated β2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up. Findings Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6–103·1). The median time to progression was 57·3 months (95% CI 44·2–73·3) for the lenalidomide group and 28·9 months (23·0–36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46–0·71; p<0·0001). The most common grade 3–4 adverse events were neutropenia (116 [50%] patients in the lenalidomide group and 41 [18%] patients in the placebo group) and thrombocytopenia (34 [15%] patients in the lenalidomide group and 12 [5%] patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup. Interpretation Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care. Funding The National Cancer Institute.

Original languageEnglish (US)
Pages (from-to)e431-e442
JournalThe Lancet Haematology
Volume4
Issue number9
DOIs
StatePublished - Sep 1 2017

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Stem Cell Transplantation
Multiple Myeloma
Placebos
Second Primary Neoplasms
Random Allocation
Intention to Treat Analysis
Capsules
lenalidomide
Therapeutics
Neoplasms
Thalidomide
National Cancer Institute (U.S.)
Standard of Care
Survival Analysis
Neutropenia
Thrombocytopenia
Disease Progression
Cause of Death

ASJC Scopus subject areas

  • Hematology

Cite this

Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma : a randomised, double-blind, phase 3 trial. / Holstein, Sarah A.; Jung, Sin Ho; Richardson, Paul G.; Hofmeister, Craig C.; Hurd, David D.; Hassoun, Hani; Giralt, Sergio; Stadtmauer, Edward A.; Weisdorf, Daniel J.; Vij, Ravi; Moreb, Jan S.; Callander, Natalie S.; van Besien, Koen; Gentile, Teresa G.; Isola, Luis; Maziarz, Richard; Bashey, Asad; Landau, Heather; Martin, Thomas; Qazilbash, Muzaffar H.; Rodriguez, Cesar; McClune, Brian; Schlossman, Robert L.; Smith, Scott E.; Hars, Vera; Owzar, Kouros; Jiang, Chen; Boyd, Molly; Schultz, Chelsea; Wilson, Marcia; Hari, Parameswaran; Pasquini, Marcelo C.; Horowitz, Mary M.; Shea, Thomas C.; Devine, Steven M.; Linker, Charles; Anderson, Kenneth C.; McCarthy, Philip L.

In: The Lancet Haematology, Vol. 4, No. 9, 01.09.2017, p. e431-e442.

Research output: Contribution to journalArticle

Holstein, SA, Jung, SH, Richardson, PG, Hofmeister, CC, Hurd, DD, Hassoun, H, Giralt, S, Stadtmauer, EA, Weisdorf, DJ, Vij, R, Moreb, JS, Callander, NS, van Besien, K, Gentile, TG, Isola, L, Maziarz, R, Bashey, A, Landau, H, Martin, T, Qazilbash, MH, Rodriguez, C, McClune, B, Schlossman, RL, Smith, SE, Hars, V, Owzar, K, Jiang, C, Boyd, M, Schultz, C, Wilson, M, Hari, P, Pasquini, MC, Horowitz, MM, Shea, TC, Devine, SM, Linker, C, Anderson, KC & McCarthy, PL 2017, 'Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial', The Lancet Haematology, vol. 4, no. 9, pp. e431-e442. https://doi.org/10.1016/S2352-3026(17)30140-0
Holstein, Sarah A. ; Jung, Sin Ho ; Richardson, Paul G. ; Hofmeister, Craig C. ; Hurd, David D. ; Hassoun, Hani ; Giralt, Sergio ; Stadtmauer, Edward A. ; Weisdorf, Daniel J. ; Vij, Ravi ; Moreb, Jan S. ; Callander, Natalie S. ; van Besien, Koen ; Gentile, Teresa G. ; Isola, Luis ; Maziarz, Richard ; Bashey, Asad ; Landau, Heather ; Martin, Thomas ; Qazilbash, Muzaffar H. ; Rodriguez, Cesar ; McClune, Brian ; Schlossman, Robert L. ; Smith, Scott E. ; Hars, Vera ; Owzar, Kouros ; Jiang, Chen ; Boyd, Molly ; Schultz, Chelsea ; Wilson, Marcia ; Hari, Parameswaran ; Pasquini, Marcelo C. ; Horowitz, Mary M. ; Shea, Thomas C. ; Devine, Steven M. ; Linker, Charles ; Anderson, Kenneth C. ; McCarthy, Philip L. / Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma : a randomised, double-blind, phase 3 trial. In: The Lancet Haematology. 2017 ; Vol. 4, No. 9. pp. e431-e442.
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abstract = "Background In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months. Methods Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated β2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up. Findings Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67{\%}) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6–103·1). The median time to progression was 57·3 months (95{\%} CI 44·2–73·3) for the lenalidomide group and 28·9 months (23·0–36·3) for the placebo group (hazard ratio 0·57, 95{\%} CI 0·46–0·71; p<0·0001). The most common grade 3–4 adverse events were neutropenia (116 [50{\%}] patients in the lenalidomide group and 41 [18{\%}] patients in the placebo group) and thrombocytopenia (34 [15{\%}] patients in the lenalidomide group and 12 [5{\%}] patients in the placebo group). 18 (8{\%}) haematological and 14 (6{\%}) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1{\%}) haematological and nine (4{\%}) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup. Interpretation Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care. Funding The National Cancer Institute.",
author = "Holstein, {Sarah A.} and Jung, {Sin Ho} and Richardson, {Paul G.} and Hofmeister, {Craig C.} and Hurd, {David D.} and Hani Hassoun and Sergio Giralt and Stadtmauer, {Edward A.} and Weisdorf, {Daniel J.} and Ravi Vij and Moreb, {Jan S.} and Callander, {Natalie S.} and {van Besien}, Koen and Gentile, {Teresa G.} and Luis Isola and Richard Maziarz and Asad Bashey and Heather Landau and Thomas Martin and Qazilbash, {Muzaffar H.} and Cesar Rodriguez and Brian McClune and Schlossman, {Robert L.} and Smith, {Scott E.} and Vera Hars and Kouros Owzar and Chen Jiang and Molly Boyd and Chelsea Schultz and Marcia Wilson and Parameswaran Hari and Pasquini, {Marcelo C.} and Horowitz, {Mary M.} and Shea, {Thomas C.} and Devine, {Steven M.} and Charles Linker and Anderson, {Kenneth C.} and McCarthy, {Philip L.}",
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day = "1",
doi = "10.1016/S2352-3026(17)30140-0",
language = "English (US)",
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pages = "e431--e442",
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TY - JOUR

T1 - Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma

T2 - a randomised, double-blind, phase 3 trial

AU - Holstein, Sarah A.

AU - Jung, Sin Ho

AU - Richardson, Paul G.

AU - Hofmeister, Craig C.

AU - Hurd, David D.

AU - Hassoun, Hani

AU - Giralt, Sergio

AU - Stadtmauer, Edward A.

AU - Weisdorf, Daniel J.

AU - Vij, Ravi

AU - Moreb, Jan S.

AU - Callander, Natalie S.

AU - van Besien, Koen

AU - Gentile, Teresa G.

AU - Isola, Luis

AU - Maziarz, Richard

AU - Bashey, Asad

AU - Landau, Heather

AU - Martin, Thomas

AU - Qazilbash, Muzaffar H.

AU - Rodriguez, Cesar

AU - McClune, Brian

AU - Schlossman, Robert L.

AU - Smith, Scott E.

AU - Hars, Vera

AU - Owzar, Kouros

AU - Jiang, Chen

AU - Boyd, Molly

AU - Schultz, Chelsea

AU - Wilson, Marcia

AU - Hari, Parameswaran

AU - Pasquini, Marcelo C.

AU - Horowitz, Mary M.

AU - Shea, Thomas C.

AU - Devine, Steven M.

AU - Linker, Charles

AU - Anderson, Kenneth C.

AU - McCarthy, Philip L.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Background In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months. Methods Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated β2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up. Findings Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6–103·1). The median time to progression was 57·3 months (95% CI 44·2–73·3) for the lenalidomide group and 28·9 months (23·0–36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46–0·71; p<0·0001). The most common grade 3–4 adverse events were neutropenia (116 [50%] patients in the lenalidomide group and 41 [18%] patients in the placebo group) and thrombocytopenia (34 [15%] patients in the lenalidomide group and 12 [5%] patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup. Interpretation Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care. Funding The National Cancer Institute.

AB - Background In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months. Methods Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated β2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up. Findings Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6–103·1). The median time to progression was 57·3 months (95% CI 44·2–73·3) for the lenalidomide group and 28·9 months (23·0–36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46–0·71; p<0·0001). The most common grade 3–4 adverse events were neutropenia (116 [50%] patients in the lenalidomide group and 41 [18%] patients in the placebo group) and thrombocytopenia (34 [15%] patients in the lenalidomide group and 12 [5%] patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup. Interpretation Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care. Funding The National Cancer Institute.

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