Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

Torben Plesner; Hendrik-Tobias Arkenau; Peter Gimsing; Jakub Krejcik; Charlotte Lemech; Monique C Minnema; Ulrik Niels Lassen; Jacob P Laubach; Antonio Palumbo; Steen Lisby; Linda Basse; Jianping Wang; A Kate Sasser; Mary E Guckert; Carla de Boer; Nushmia Z Khokhar; Howard Yeh; Pamela L Clemens; Tahamtan Ahmadi; Henk M Lokhorst; Paul G Richardson

doi:10.1182/blood-2016-07-726729

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

Torben Plesner, Hendrik-Tobias Arkenau, Peter Gimsing, Jakub Krejcik, Charlotte Lemech, Monique C Minnema, Ulrik Niels Lassen, Jacob P Laubach, Antonio Palumbo, Steen Lisby, Linda Basse, Jianping Wang, A Kate Sasser, Mary E Guckert, Carla de Boer, Nushmia Z Khokhar, Howard Yeh, Pamela L Clemens, Tahamtan Ahmadi, Henk M LokhorstPaul G Richardson

Department of Clinical Medicine

75 Citations (Scopus)

Abstract

Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years,with amedian of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumabmonotherapy. This trial was registered atwww.clinicaltrials.gov as #NCT01615029.

Original language	English
Journal	Blood
Volume	128
Issue number	14
Pages (from-to)	1821-1828
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2016-07-726729
Publication status	Published - 6 Oct 2016

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Plesner, T., Arkenau, H-T., Gimsing, P., Krejcik, J., Lemech, C., Minnema, M. C., Lassen, U. N., Laubach, J. P., Palumbo, A., Lisby, S., Basse, L., Wang, J., Sasser, A. K., Guckert, M. E., de Boer, C., Khokhar, N. Z., Yeh, H., Clemens, P. L., Ahmadi, T., ... Richardson, P. G. (2016). Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood, 128(14), 1821-1828. https://doi.org/10.1182/blood-2016-07-726729

Plesner, T, Arkenau, H-T, Gimsing, P, Krejcik, J, Lemech, C, Minnema, MC, Lassen, UN, Laubach, JP, Palumbo, A, Lisby, S, Basse, L, Wang, J, Sasser, AK, Guckert, ME, de Boer, C, Khokhar, NZ, Yeh, H, Clemens, PL, Ahmadi, T, Lokhorst, HM & Richardson, PG 2016, 'Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma', Blood, vol. 128, no. 14, pp. 1821-1828. https://doi.org/10.1182/blood-2016-07-726729

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title = "Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma",

abstract = "Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years,with amedian of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumabmonotherapy. This trial was registered atwww.clinicaltrials.gov as #NCT01615029.",

author = "Torben Plesner and Hendrik-Tobias Arkenau and Peter Gimsing and Jakub Krejcik and Charlotte Lemech and Minnema, {Monique C} and Lassen, {Ulrik Niels} and Laubach, {Jacob P} and Antonio Palumbo and Steen Lisby and Linda Basse and Jianping Wang and Sasser, {A Kate} and Guckert, {Mary E} and {de Boer}, Carla and Khokhar, {Nushmia Z} and Howard Yeh and Clemens, {Pamela L} and Tahamtan Ahmadi and Lokhorst, {Henk M} and Richardson, {Paul G}",

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T1 - Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

AU - Plesner, Torben

AU - Arkenau, Hendrik-Tobias

AU - Gimsing, Peter

AU - Krejcik, Jakub

AU - Lemech, Charlotte

AU - Minnema, Monique C

AU - Lassen, Ulrik Niels

AU - Laubach, Jacob P

AU - Palumbo, Antonio

AU - Lisby, Steen

AU - Basse, Linda

AU - Wang, Jianping

AU - Sasser, A Kate

AU - Guckert, Mary E

AU - de Boer, Carla

AU - Khokhar, Nushmia Z

AU - Yeh, Howard

AU - Clemens, Pamela L

AU - Ahmadi, Tahamtan

AU - Lokhorst, Henk M

AU - Richardson, Paul G

PY - 2016/10/6

Y1 - 2016/10/6

N2 - Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years,with amedian of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumabmonotherapy. This trial was registered atwww.clinicaltrials.gov as #NCT01615029.

AB - Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years,with amedian of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumabmonotherapy. This trial was registered atwww.clinicaltrials.gov as #NCT01615029.

U2 - 10.1182/blood-2016-07-726729

DO - 10.1182/blood-2016-07-726729

M3 - Journal article

C2 - 27531679

SN - 0006-4971

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SP - 1821

EP - 1828

JO - Blood

JF - Blood

IS - 14

ER -

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

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