Elsevier

The Lancet

Volume 387, Issue 10027, 9–15 April 2016, Pages 1551-1560
The Lancet

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

https://doi.org/10.1016/S0140-6736(15)01120-4Get rights and content

Summary

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.

Introduction

Multiple myeloma is a malignant plasma cell disorder that is characterised by bone, renal, haematological, and infectious complications due to accumulation of clonal plasma cells in the bone marrow and pathogenic antibody production.1 Although survival has improved substantially with new drug classes (eg, proteasome inhibitors and immunomodulatory drugs), along with autologous stem cell transplantation, most patients will die from refractory disease.2, 3 Outcomes for patients who are resistant to proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory drugs (lenalidomide, thalidomide, and pomalidomide) are especially poor. Before the availability of carfilzomib and pomalidomide, median expected overall survival in these patients was 9 months.4 Additional treatment can be complicated by cytopenias, secondary to poor haematological reserves, and comorbidities such as renal insufficiency. Therefore, effective treatments that target novel pathways with little toxicity and favourable tolerability are needed. Monoclonal antibodies are a novel class of agents in myeloma, targeting cell surface markers, such as SLAMF7 (CS-1) and CD38, with few off-target effects.5

Research in context

Evidence before this study

We searched PubMed on July 29, 2015, with no date restriction using the keywords “progression risk”, “overall survival”, “multiple myeloma”, “relapsed”, and “refractory”. From the 45 articles identified, the evidence indicates that despite the introduction of new agents that have prolonged survival, multiple myeloma remains incurable because most patients relapse or become refractory to available treatments. Daratumumab, a human monoclonal antibody that binds CD38-expressing malignant cells, gained US Food and Drug Administration breakthrough therapy designation based on phase 1 data from a first-in-human study in patients with multiple myeloma who relapsed or were refractory to at least two previous therapies. The first-in-human study was expanded and we concurrently initiated our study to further investigate the selected dose schedule.

Added value of this study

The current study is the largest study so far of the single-agent activity of daratumumab 16 mg/kg in heavily pretreated patients with multiple myeloma who were refractory to both a proteasome inhibitor and an immunomodulatory drug. The overall response rate was 29% and responses were rapid, deep, and durable. Efficacy was consistent in subgroups based on previous therapy and patients' characteristics, including age and renal function. Side-effects of daratumumab were clinically manageable, and no patient discontinued treatment because of drug-related adverse events. These data are in accord with results from the expansion of the first-in-human study in which the overall response rate was 36% in patients given daratumumab 16 mg/kg monotherapy.

Implications of all the available evidence

As a result of this study, daratumumab was the first monoclonal antibody approved by the US Food and Drug Administration for the treatment of refractory myeloma. Daratumumab is indicated for patients who have received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who are double refractory to a proteasome inhibitor and an immunomodulatory drug. Based on its efficacy, with rapid, deep, and durable responses, and its favourable safety profile, further activity in combination regimens is being investigated.

Daratumumab is a first-in-class, human IgG1 monoclonal antibody that binds CD38-expressing malignant cells with high affinity and induces tumour cell death through diverse mechanisms of action, which include complement-dependent cytotoxicity,6, 7 antibody-dependent cell-mediated cytotoxicity,6, 7 antibody-dependent cellular phagocytosis,7, 8 and induction of apoptosis.7, 9 In a first-in-human phase 1/2 study of daratumumab monotherapy (0·005–24 mg/kg) in patients with relapsed or relapsed and refractory multiple myeloma, a maximum tolerated dose was not achieved.10 In an expansion cohort of this study, the overall response rate (ORR) was 36% with daratumumab 16 mg/kg.10

In the current phase 2 study, we assessed daratumumab in patients with multiple myeloma and an unmet medical need—specifically, those who were refractory to their most recent treatment regimen after receiving at least three previous lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or whose disease was refractory to both the most recent proteasome inhibitors and immunomodulatory drugs they had received, irrespective of the number of previous lines of treatment.

Section snippets

Study design and participants

This two-part, open-label, multicentre, phase 2 study started on Sept 30, 2013, at 26 sites in Canada, Spain, and the USA, and is ongoing. Inclusion criteria for patients included age at least 18 years old, documented secretory multiple myeloma, and evidence of disease progression on or within 60 days of the last dose of the most recent previous treatment regimen, based on the International Myeloma Working Group criteria.11, 12 Eligible patients had responded to at least one previous treatment

Results

124 patients received at least one dose of daratumumab (18 received 8 mg/kg, 106 received 16 mg/kg; figure 1). The clinical cutoff date for primary analysis was Jan 9, 2015, 7·7 months after the last patient had received the first dose. At the first interim analysis, the daratumumab 8 mg/kg group did not meet the criteria for expansion because of an ORR of 11·1% (95% CI 1·4–34·7). Baseline characteristics of this group are presented in the appendix. Concurrent pharmacokinetic analyses of the 8

Discussion

Daratumumab monotherapy showed substantial clinical activity, with an ORR of 29%, and was well tolerated in patients with multiple myeloma who had been heavily treated; most patients were double refractory to bortezomib and lenalidomide, and many were refractory to pomalidomide or carfilzomib. Resistance to any previous therapy had no effect on the activity of daratumumab, lending support to a novel mechanism of action, but these findings need to be confirmed in larger studies. Similar response

References (25)

  • SK Kumar et al.

    Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study

    Leukemia

    (2012)
  • J Kuroda et al.

    Elotuzumab and daratumumab: emerging new monoclonal antibodies for multiple myeloma

    Expert Rev Anticancer Ther

    (2013)
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