Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial

Sagar Lonial, Brendan M. Weiss, Saad Z. Usmani, Seema Singhal, Ajai Chari, Nizar J. Bahlis, Andrew Belch, Amrita Krishnan, Robert A. Vescio, Maria Victoria Mateos, Amitabha Mazumder, Robert Z. Orlowski, Heather J. Sutherland, Joan Bladé, Emma Scott, Albert Oriol, Jesus Berdeja, Mecide Gharibo, Don A. Stevens, Richard LeblancMichael Sebag, Natalie Callander, Andrzej Jakubowiak, Darrell White, Javier De La Rubia, Paul G. Richardson, Steen Lisby, Huaibao Feng, Clarissa M. Uhlar, Imran Khan, Tahamtan Ahmadi, Peter M. Voorhees

Research output: Contribution to journalArticle

352 Citations (Scopus)

Abstract

Background New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. Methods In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. Findings The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29·2%, 95% CI 20·8-38·9) - three (2·8%, 0·6-8·0) had a stringent CR, ten (9·4%, 4·6-16·7) had a very good PR, and 18 (17·0%, 10·4-25·5) had a PR. The median time to first response was 1·0 month (range 0·9-5·6). Median duration of response was 7·4 months (95% CI 5·5-not estimable) and progression-free survival was 3·7 months (95% CI 2·8-4·6). The 12-month overall survival was 64·8% (95% CI 51·2-75·5) and, at a subsequent cutoff, median overall survival was 17·5 months (95% CI 13·7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. Interpretation Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. Funding Janssen Research & Development.

Original languageEnglish (US)
Pages (from-to)1551-1560
Number of pages10
JournalThe Lancet
Volume387
Issue number10027
DOIs
StatePublished - Apr 9 2016

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Multiple Myeloma
Proteasome Inhibitors
Therapeutics
daratumumab
Pharmaceutical Preparations
Survival
Stem Cell Transplantation
Random Allocation
Drug-Related Side Effects and Adverse Reactions
Spain
Disease-Free Survival
Canada
Fatigue
Anemia
Appointments and Schedules
Monoclonal Antibodies

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lonial, S., Weiss, B. M., Usmani, S. Z., Singhal, S., Chari, A., Bahlis, N. J., ... Voorhees, P. M. (2016). Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial. The Lancet, 387(10027), 1551-1560. https://doi.org/10.1016/S0140-6736(15)01120-4

Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS) : An open-label, randomised, phase 2 trial. / Lonial, Sagar; Weiss, Brendan M.; Usmani, Saad Z.; Singhal, Seema; Chari, Ajai; Bahlis, Nizar J.; Belch, Andrew; Krishnan, Amrita; Vescio, Robert A.; Mateos, Maria Victoria; Mazumder, Amitabha; Orlowski, Robert Z.; Sutherland, Heather J.; Bladé, Joan; Scott, Emma; Oriol, Albert; Berdeja, Jesus; Gharibo, Mecide; Stevens, Don A.; Leblanc, Richard; Sebag, Michael; Callander, Natalie; Jakubowiak, Andrzej; White, Darrell; De La Rubia, Javier; Richardson, Paul G.; Lisby, Steen; Feng, Huaibao; Uhlar, Clarissa M.; Khan, Imran; Ahmadi, Tahamtan; Voorhees, Peter M.

In: The Lancet, Vol. 387, No. 10027, 09.04.2016, p. 1551-1560.

Research output: Contribution to journalArticle

Lonial, S, Weiss, BM, Usmani, SZ, Singhal, S, Chari, A, Bahlis, NJ, Belch, A, Krishnan, A, Vescio, RA, Mateos, MV, Mazumder, A, Orlowski, RZ, Sutherland, HJ, Bladé, J, Scott, E, Oriol, A, Berdeja, J, Gharibo, M, Stevens, DA, Leblanc, R, Sebag, M, Callander, N, Jakubowiak, A, White, D, De La Rubia, J, Richardson, PG, Lisby, S, Feng, H, Uhlar, CM, Khan, I, Ahmadi, T & Voorhees, PM 2016, 'Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial', The Lancet, vol. 387, no. 10027, pp. 1551-1560. https://doi.org/10.1016/S0140-6736(15)01120-4
Lonial, Sagar ; Weiss, Brendan M. ; Usmani, Saad Z. ; Singhal, Seema ; Chari, Ajai ; Bahlis, Nizar J. ; Belch, Andrew ; Krishnan, Amrita ; Vescio, Robert A. ; Mateos, Maria Victoria ; Mazumder, Amitabha ; Orlowski, Robert Z. ; Sutherland, Heather J. ; Bladé, Joan ; Scott, Emma ; Oriol, Albert ; Berdeja, Jesus ; Gharibo, Mecide ; Stevens, Don A. ; Leblanc, Richard ; Sebag, Michael ; Callander, Natalie ; Jakubowiak, Andrzej ; White, Darrell ; De La Rubia, Javier ; Richardson, Paul G. ; Lisby, Steen ; Feng, Huaibao ; Uhlar, Clarissa M. ; Khan, Imran ; Ahmadi, Tahamtan ; Voorhees, Peter M. / Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS) : An open-label, randomised, phase 2 trial. In: The Lancet. 2016 ; Vol. 387, No. 10027. pp. 1551-1560.
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abstract = "Background New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. Methods In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. Findings The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80{\%}) patients had previously received autologous stem cell transplantation, 101 (95{\%}) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97{\%}) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29·2{\%}, 95{\%} CI 20·8-38·9) - three (2·8{\%}, 0·6-8·0) had a stringent CR, ten (9·4{\%}, 4·6-16·7) had a very good PR, and 18 (17·0{\%}, 10·4-25·5) had a PR. The median time to first response was 1·0 month (range 0·9-5·6). Median duration of response was 7·4 months (95{\%} CI 5·5-not estimable) and progression-free survival was 3·7 months (95{\%} CI 2·8-4·6). The 12-month overall survival was 64·8{\%} (95{\%} CI 51·2-75·5) and, at a subsequent cutoff, median overall survival was 17·5 months (95{\%} CI 13·7-not estimable). Daratumumab was well tolerated; fatigue (42 [40{\%}] patients) and anaemia (35 [33{\%}]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. Interpretation Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. Funding Janssen Research & Development.",
author = "Sagar Lonial and Weiss, {Brendan M.} and Usmani, {Saad Z.} and Seema Singhal and Ajai Chari and Bahlis, {Nizar J.} and Andrew Belch and Amrita Krishnan and Vescio, {Robert A.} and Mateos, {Maria Victoria} and Amitabha Mazumder and Orlowski, {Robert Z.} and Sutherland, {Heather J.} and Joan Blad{\'e} and Emma Scott and Albert Oriol and Jesus Berdeja and Mecide Gharibo and Stevens, {Don A.} and Richard Leblanc and Michael Sebag and Natalie Callander and Andrzej Jakubowiak and Darrell White and {De La Rubia}, Javier and Richardson, {Paul G.} and Steen Lisby and Huaibao Feng and Uhlar, {Clarissa M.} and Imran Khan and Tahamtan Ahmadi and Voorhees, {Peter M.}",
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TY - JOUR

T1 - Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS)

T2 - An open-label, randomised, phase 2 trial

AU - Lonial, Sagar

AU - Weiss, Brendan M.

AU - Usmani, Saad Z.

AU - Singhal, Seema

AU - Chari, Ajai

AU - Bahlis, Nizar J.

AU - Belch, Andrew

AU - Krishnan, Amrita

AU - Vescio, Robert A.

AU - Mateos, Maria Victoria

AU - Mazumder, Amitabha

AU - Orlowski, Robert Z.

AU - Sutherland, Heather J.

AU - Bladé, Joan

AU - Scott, Emma

AU - Oriol, Albert

AU - Berdeja, Jesus

AU - Gharibo, Mecide

AU - Stevens, Don A.

AU - Leblanc, Richard

AU - Sebag, Michael

AU - Callander, Natalie

AU - Jakubowiak, Andrzej

AU - White, Darrell

AU - De La Rubia, Javier

AU - Richardson, Paul G.

AU - Lisby, Steen

AU - Feng, Huaibao

AU - Uhlar, Clarissa M.

AU - Khan, Imran

AU - Ahmadi, Tahamtan

AU - Voorhees, Peter M.

PY - 2016/4/9

Y1 - 2016/4/9

N2 - Background New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. Methods In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. Findings The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29·2%, 95% CI 20·8-38·9) - three (2·8%, 0·6-8·0) had a stringent CR, ten (9·4%, 4·6-16·7) had a very good PR, and 18 (17·0%, 10·4-25·5) had a PR. The median time to first response was 1·0 month (range 0·9-5·6). Median duration of response was 7·4 months (95% CI 5·5-not estimable) and progression-free survival was 3·7 months (95% CI 2·8-4·6). The 12-month overall survival was 64·8% (95% CI 51·2-75·5) and, at a subsequent cutoff, median overall survival was 17·5 months (95% CI 13·7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. Interpretation Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. Funding Janssen Research & Development.

AB - Background New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. Methods In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. Findings The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29·2%, 95% CI 20·8-38·9) - three (2·8%, 0·6-8·0) had a stringent CR, ten (9·4%, 4·6-16·7) had a very good PR, and 18 (17·0%, 10·4-25·5) had a PR. The median time to first response was 1·0 month (range 0·9-5·6). Median duration of response was 7·4 months (95% CI 5·5-not estimable) and progression-free survival was 3·7 months (95% CI 2·8-4·6). The 12-month overall survival was 64·8% (95% CI 51·2-75·5) and, at a subsequent cutoff, median overall survival was 17·5 months (95% CI 13·7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. Interpretation Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. Funding Janssen Research & Development.

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