Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

Henk M Lokhorst; Torben Plesner; Jacob P Laubach; Hareth Nahi; Peter Gimsing; Markus Hansson; Monique C Minnema; Ulrik Lassen; Jakub Krejcik; Antonio Palumbo; Niels W C J van de Donk; Tahamtan Ahmadi; Imran Khan; Clarissa M Uhlar; Jianping Wang; A Kate Sasser; Nedjad Losic; Steen Lisby; Linda Basse; Nikolai Brun; Paul G Richardson

doi:10.1056/nejmoa1506348

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

Henk M Lokhorst, Torben Plesner, Jacob P Laubach, Hareth Nahi, Peter Gimsing, Markus Hansson, Monique C Minnema, Ulrik Lassen, Jakub Krejcik, Antonio Palumbo, Niels W C J van de Donk, Tahamtan Ahmadi, Imran Khan, Clarissa M Uhlar, Jianping Wang, A Kate Sasser, Nedjad Losic, Steen Lisby, Linda Basse, Nikolai BrunPaul G Richardson

Institut for Klinisk Medicin

645 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	New England Journal of Medicine
Vol/bind	373
Udgave nummer	13
Sider (fra-til)	1207-19
Antal sider	13
ISSN	0028-4793
DOI	https://doi.org/10.1056/nejmoa1506348
Status	Udgivet - 24 sep. 2015

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10.1056/nejmoa1506348

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Lokhorst, H. M., Plesner, T., Laubach, J. P., Nahi, H., Gimsing, P., Hansson, M., Minnema, M. C., Lassen, U., Krejcik, J., Palumbo, A., van de Donk, N. W. C. J., Ahmadi, T., Khan, I., Uhlar, C. M., Wang, J., Sasser, A. K., Losic, N., Lisby, S., Basse, L., ... Richardson, P. G. (2015). Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. New England Journal of Medicine, 373(13), 1207-19. https://doi.org/10.1056/nejmoa1506348

Lokhorst, HM, Plesner, T, Laubach, JP, Nahi, H, Gimsing, P, Hansson, M, Minnema, MC, Lassen, U, Krejcik, J, Palumbo, A, van de Donk, NWCJ, Ahmadi, T, Khan, I, Uhlar, CM, Wang, J, Sasser, AK, Losic, N, Lisby, S, Basse, L, Brun, N & Richardson, PG 2015, 'Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma', New England Journal of Medicine, bind 373, nr. 13, s. 1207-19. https://doi.org/10.1056/nejmoa1506348

@article{762e81f89f0e438b9f06dad7dcc18489,

title = "Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma",

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.",

keywords = "Adult, Aged, Antibodies, Monoclonal, Antigens, CD38, Antineoplastic Agents, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Female, Humans, Male, Middle Aged, Multiple Myeloma, Pneumonia, Thrombocytopenia",

author = "Lokhorst, {Henk M} and Torben Plesner and Laubach, {Jacob P} and Hareth Nahi and Peter Gimsing and Markus Hansson and Minnema, {Monique C} and Ulrik Lassen and Jakub Krejcik and Antonio Palumbo and {van de Donk}, {Niels W C J} and Tahamtan Ahmadi and Imran Khan and Uhlar, {Clarissa M} and Jianping Wang and Sasser, {A Kate} and Nedjad Losic and Steen Lisby and Linda Basse and Nikolai Brun and Richardson, {Paul G}",

year = "2015",

month = sep,

day = "24",

doi = "10.1056/nejmoa1506348",

language = "English",

volume = "373",

pages = "1207--19",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "13",

}

TY - JOUR

T1 - Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

AU - Lokhorst, Henk M

AU - Plesner, Torben

AU - Laubach, Jacob P

AU - Nahi, Hareth

AU - Gimsing, Peter

AU - Hansson, Markus

AU - Minnema, Monique C

AU - Lassen, Ulrik

AU - Krejcik, Jakub

AU - Palumbo, Antonio

AU - van de Donk, Niels W C J

AU - Ahmadi, Tahamtan

AU - Khan, Imran

AU - Uhlar, Clarissa M

AU - Wang, Jianping

AU - Sasser, A Kate

AU - Losic, Nedjad

AU - Lisby, Steen

AU - Basse, Linda

AU - Brun, Nikolai

AU - Richardson, Paul G

PY - 2015/9/24

Y1 - 2015/9/24

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Antibodies, Monoclonal

KW - Antigens, CD38

KW - Antineoplastic Agents

KW - Disease-Free Survival

KW - Dose-Response Relationship, Drug

KW - Drug Resistance, Neoplasm

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Multiple Myeloma

KW - Pneumonia

KW - Thrombocytopenia

U2 - 10.1056/nejmoa1506348

DO - 10.1056/nejmoa1506348

M3 - Journal article

C2 - 26308596

SN - 0028-4793

VL - 373

SP - 1207

EP - 1219

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 13

ER -

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

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