This protocol has been superseded as it is the consensus of the eviQ Haematology Reference Committee that subcutaneous daratumumab is the more commonly used route of administration of daratumumab. ID 4084 Multiple myeloma daratumumab subcutaneous is the preferred regimen.
The evidence supporting this protocol is provided by a combined analysis of two phase 1/2 open-label studies (GEN501 and SIRIUS studies) involving 148 patients with relapsed and/or refractory multiple myeloma (MM), who were treated with daratumumab monotherapy.r
GEN501 was an open label, multicentre, phase I/2, dose escalation and dose expansion study that included patients with at least 2 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). SIRIUS was an open-label multicentre phase II study that included patients with MM with at least 3 prior lines of therapy (including PI and IMiD) or who were double refractory to PI and IMiD. For the combined analysis, data from all patients who received daratumumab 16 mg/kg in GEN501 part 2 and SIRIUS were included.
Between March 2008 and December 2015, 148 patients received daratumumab, 16 mg/kg IV, per week for 8 weeks, every 2 weeks for 16 weeks, then once every 4 weeks until disease progression.
The primary end point for the combined analysis was overall response rate (ORR) and secondary end points were duration of response, progression free survival and overall survival.
Daratumumab monotherapy demonstrated rapid, deep and durable responses with a median OS that was better than what was expected for this particular group of heavily pretreated patients and a clinical survival benefit that extended to patients with responses that were <PR (ie. stable disease and minor responses).
A search of the literature found limited evidence to support the use of daratumumab for the treatment of multiple myeloma. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the trials analysed by Usmani et al.rr
Source
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Study & Year Published
|
Supports Use
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Is the dose and regimen consistent with the protocol?
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Comments
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Phase II trials
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Usmani et al, 2016rr
|
Yes
|
Yes
|
|
Guidelines
|
Date published/revised
|
Supports Use
|
Is the dose and regimen consistent with the protocol?
|
Comments
|
NCCN
|
October 2017
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Yes
|
N/A
|
-
|
BCCA
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N/A
|
N/A
|
N/A
|
-
|
CCO |
October 2017 |
Yes |
Yes |
- |
MSAG |
March 2017 |
Yes |
N/A |
- |
Efficacy
In the combined analysis of the SIRIUS and GEN501 studies, after a median follow up of 20.7 months, the median OS was 20.1 months (95% CI 7.4 months to NE). This is favourable compared to the expected median OS of 7.9 months in real-world data of patients who have had at least 3 prior lines of therapy including an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI), or patients who are double refractory to an IMiD and a PI,r as was the case for the majority of patients in the SIRIUS and GEN501 studies. Thirty-one percent of patients achieved at least a partial response (PR), of which 43% achieved at least a very good partial response (VGPR). The rate of CR or better was 4.7%. Importantly, a survival benefit was seen (med OS 18.5 months) even patients who achieved <PR (ie stable disease or minor responses).
Table 1: Summary of responses in the combined daratumumab 16 mg/kg group.
© Blood 2016
Figure 1: PFS in the combined daratumumab 16 mg/kg group. At a median follow-up of 20.7 months, the median PFS of patients in (A) the combined data set and (B) stratified by response category are shown.
© Blood 2016
Figure 2: OS in the combined daratumumab 16 mg/kg group. The median OS of patients in (A) the combined data set and (B) stratified by response category are shown.
© Blood 2016
The final results of the pooled analysis was presented as ASH 2017, with median follow-up of patients of approximately 3 years. Median overall survival (OS) was 20.5 months (95% CI 16.6-28.1), and the 3-year OS was 36.5% (95% CI 28.4-44.6). Amongst responders, the median duration of response was 8.0 months (95% CI 6.5-14.7). 19.6% of responders remained progression-free at 3 years.r
No quality of life (QoL) data was collected in these phase I/II studies. In general, treatment was very well tolerated.
Toxicity
The most common treatment related adverse events (AEs) are summarised in table 1. Infusion related reactions (IRRs) occurred in 48% of patients, the majority of which were grade 1 and 2, the symptoms of which mainly included nasal congestions, cough, allergic rhinitis, throat irritability and dyspnoea. Ninety-six percent of IRRs occurred in the first infusion, with decreasing incidence in subsequent infusions (7% during the second, and 7% during subsequent infusions). IRRs were safety managed with pre (+/- post) medications including antihistamines, corticosteroids and paracetamol.
Thirty-one percent of patients required blood transfusions. As CD38 is weakly expressed on red blood cells (RBCs), daratumumab is known to weakly bind to RBCs and interferes with the indirect antiglobulin tests in pretransfusion immunohaematology testing. While no direct AEs related to blood transfusion reaction were reported in these studies, as a result pretransfusion intereference by daratumumab, it is recommended that all patients have extended red cell phenotyping prior to the first dose of daratumumab (or genotyping at any time) to allow dispensing of extended phenotype matched blood if daratumumab interference in pretransfusion testing cannot be resolved by recommended methods.r Communications to blood transfusion laboratory is important to enable this. Patients should be encouraged to carry an alert card indicating their daratumumab treatment, extended red cell phenotype and presence of any known red cell alloantibodies for at least 6 months after the last dose of daratumumab.
Table 1: Overall treatment emergent adverse events.
© Blood 2016