Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

H. M. Lokhorst, T. Plesner, J. P. Laubach, H. Nahi, P. Gimsing, M. Hansson, M. C. Minnema, U. Lassen, Jakub Krejcik, A. Palumbo, Nwcj van de Donk, T. Ahmadi, I. Khan, C. M. Uhlar, J. Wang, A. K. Sasser, N. Losic, S. Lisby, L. Basse, N. Brun & 1 andre P. G. Richardson

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

BACKGROUND Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1 kappa 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.)
OriginalsprogEngelsk
TidsskriftThe New England Journal of Medicine
Vol/bind373
Udgave nummer13
Sider (fra-til)1207-1219
ISSN0028-4793
DOI
StatusUdgivet - 2015

Emneord

  • MONOCLONAL-ANTIBODY ANTITUMOR-ACTIVITY MULTICENTER BORTEZOMIB ELOTUZUMAB SAR650984 THERAPIES SURVIVAL PROTEIN CELLS

Citer dette

Lokhorst, H. M., Plesner, T., Laubach, J. P., Nahi, H., Gimsing, P., Hansson, M., ... Richardson, P. G. (2015). Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. The New England Journal of Medicine, 373(13), 1207-1219. https://doi.org/10.1056/NEJMoa1506348
Lokhorst, H. M. ; Plesner, T. ; Laubach, J. P. ; Nahi, H. ; Gimsing, P. ; Hansson, M. ; Minnema, M. C. ; Lassen, U. ; Krejcik, Jakub ; Palumbo, A. ; van de Donk, Nwcj ; Ahmadi, T. ; Khan, I. ; Uhlar, C. M. ; Wang, J. ; Sasser, A. K. ; Losic, N. ; Lisby, S. ; Basse, L. ; Brun, N. ; Richardson, P. G. / Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. I: The New England Journal of Medicine. 2015 ; Bind 373, Nr. 13. s. 1207-1219.
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title = "Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma",
abstract = "BACKGROUND Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1 kappa 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.)",
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author = "Lokhorst, {H. M.} and T. Plesner and Laubach, {J. P.} and H. Nahi and P. Gimsing and M. Hansson and Minnema, {M. C.} and U. Lassen and Jakub Krejcik and A. Palumbo and {van de Donk}, Nwcj and T. Ahmadi and I. Khan and Uhlar, {C. M.} and J. Wang and Sasser, {A. K.} and N. Losic and S. Lisby and L. Basse and N. Brun and Richardson, {P. G.}",
note = "Janssen Research and Development; Genmab 6 26308596",
year = "2015",
doi = "10.1056/NEJMoa1506348",
language = "English",
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pages = "1207--1219",
journal = "The New England Journal of Medicine",
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Lokhorst, HM, Plesner, T, Laubach, JP, Nahi, H, Gimsing, P, Hansson, M, Minnema, MC, Lassen, U, Krejcik, J, Palumbo, A, van de Donk, N, 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', The New England Journal of Medicine, bind 373, nr. 13, s. 1207-1219. https://doi.org/10.1056/NEJMoa1506348

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. / Lokhorst, H. M.; Plesner, T.; Laubach, J. P.; Nahi, H.; Gimsing, P.; Hansson, M.; Minnema, M. C.; Lassen, U.; Krejcik, Jakub; Palumbo, A.; van de Donk, Nwcj; Ahmadi, T.; Khan, I.; Uhlar, C. M.; Wang, J.; Sasser, A. K.; Losic, N.; Lisby, S.; Basse, L.; Brun, N.; Richardson, P. G.

I: The New England Journal of Medicine, Bind 373, Nr. 13, 2015, s. 1207-1219.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

AU - Lokhorst, H. M.

AU - Plesner, T.

AU - Laubach, J. P.

AU - Nahi, H.

AU - Gimsing, P.

AU - Hansson, M.

AU - Minnema, M. C.

AU - Lassen, U.

AU - Krejcik, Jakub

AU - Palumbo, A.

AU - van de Donk, Nwcj

AU - Ahmadi, T.

AU - Khan, I.

AU - Uhlar, C. M.

AU - Wang, J.

AU - Sasser, A. K.

AU - Losic, N.

AU - Lisby, S.

AU - Basse, L.

AU - Brun, N.

AU - Richardson, P. G.

N1 - Janssen Research and Development; Genmab 6 26308596

PY - 2015

Y1 - 2015

N2 - BACKGROUND Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1 kappa 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.)

AB - BACKGROUND Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1 kappa 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.)

KW - MONOCLONAL-ANTIBODY ANTITUMOR-ACTIVITY MULTICENTER BORTEZOMIB ELOTUZUMAB SAR650984 THERAPIES SURVIVAL PROTEIN CELLS

U2 - 10.1056/NEJMoa1506348

DO - 10.1056/NEJMoa1506348

M3 - Journal article

VL - 373

SP - 1207

EP - 1219

JO - The New England Journal of Medicine

JF - The New England Journal of Medicine

SN - 0028-4793

IS - 13

ER -