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Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.

Lokhorst, Henk M; Plesner, Torben; Laubach, Jacob P; Nahi, Hareth; Gimsing, Peter; Hansson, Markus LU ; Minnema, Monique C; Lassen, Ulrik; Krejcik, Jakub and Palumbo, Antonio, et al. (2015) In New England Journal of Medicine 373(13). p.1207-1219
Abstract
Background Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. Methods In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. Results No maximum tolerated dose was identified in part 1.... (More)
Background Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. Methods In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. Results No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. Conclusions Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288 .). (Less)
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New England Journal of Medicine
volume
373
issue
13
pages
1207 - 1219
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Massachusetts Medical Society
external identifiers
  • pmid:26308596
  • wos:000361635200006
  • scopus:84942436321
ISSN
0028-4793
DOI
10.1056/NEJMoa1506348
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English
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4dcc0105-0723-46ba-b407-9440ff8dbf8a (old id 7834399)
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http://www.ncbi.nlm.nih.gov/pubmed/26308596?dopt=Abstract
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2015-09-07 20:44:37
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@article{4dcc0105-0723-46ba-b407-9440ff8dbf8a,
  abstract     = {Background Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. Methods In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. Results No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. Conclusions Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288 .).},
  author       = {Lokhorst, Henk M and Plesner, Torben and Laubach, Jacob P and Nahi, Hareth and Gimsing, Peter and Hansson, Markus and Minnema, Monique C and Lassen, Ulrik and Krejcik, Jakub and Palumbo, Antonio and van de Donk, Niels W C J and Ahmadi, Tahamtan and Khan, Imran and Uhlar, Clarissa M and Wang, Jianping and Sasser, A Kate and Losic, Nedjad and Lisby, Steen and Basse, Linda and Brun, Nikolai and Richardson, Paul G},
  issn         = {0028-4793},
  language     = {eng},
  number       = {13},
  pages        = {1207--1219},
  publisher    = {Massachusetts Medical Society},
  series       = {New England Journal of Medicine},
  title        = {Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.},
  url          = {http://dx.doi.org/10.1056/NEJMoa1506348},
  volume       = {373},
  year         = {2015},
}