At the beginning of this year, the first active immunotherapy directed against CD38 in refractory multiple myeloma was approved in Switzerland. The data from the two studies MMY2002 (SIRIUS) and GEN501 are largely responsible for this. They demonstrated that the single agent daratumumab provided a benefit in both survival and response in this population, with an acceptable safety profile.
Daratumumab is a monoclonal antibody that binds to the CD38 protein. CD38 is present in high concentration on the surface of multiple myeloma tumor cells and has various functions such as signal transduction and enzymatic activity. Daratumumab both attacks the cancer cells and triggers the patient’s immune system to fight the myeloma cells. Among other things, daratumumab can cause immune-mediated tumor cell death.
GEN501 – The dose makes the difference
The first study that was pivotal for approval is called GEN501 [1] and was published in 2015. There were two parts, a dose-escalation part in which daratumumab was dosed from 0.005 to 24 mg/kg was given, and a second part, in which 30 subjects were now given the active substance per 8 mg/kg and 42 per 16 mg/kg received (once weekly for eight doses, then twice monthly for eight doses, and finally monthly for up to 24 months). Participants in the study had received a median of four prior therapies, 76% an autologous stem cell transplant. 64% of myelomas were refractory to both proteasome inhibitors and immunomodulatory drugs (IMiD).
Efficacy: The dose of 16 mg/kg proved to be the most appropriate. The overall response was 36% in the 16 mg/kg group, but only 10% in the 8 mg/kg group. Two complete responses were found at the former dosage, also two with a very good partial response and 15 with a partial response. Median progression-free survival here was 5.6 months. After one year, 65% of patients who responded had not experienced progression.
Safety: The most common grade 3 or 4 adverse events in the second part of the study were pneumonia and thrombocytopenia (in at least 5% of patients). In addition, fatigue, allergic rhinitis, and fever were found most frequently. Neutropenia occurred in 12%. Infusion-related reactions were found to be mild: 71% had one, but no patient discontinued treatment because of it.
SIRIUS – here, too, almost one third responds
Second, daratumumab is being studied in the ongoing phase II SIRIUS trial [2]. Participating adults from centers in Canada, Spain, and the United States with multiple myeloma that has either been refractory to proteasome inhibitors and immunomodulatory drugs or has been treated with at least three prior lines of therapy (including the two classes of agents mentioned above). The open-label study again contains two parts, a dose-finding part (intravenous 8 mg/kg or 16 mg/kg) and a treatment part with the previously elicited dose. Primary endpoint is overall response rate.
Efficacy: On median, patients this time had received five prior therapies, including 80% with autologous stem cell transplantation and 95% with refractory myeloma to the latest proteasome inhibitors and immunomodulatory agents. Data from the 106 patients who received daratumumab at the dose of 16 mg/kg in the first and second part of the study showed an overall response of 29.2%. The rate of stringent complete response was 2.8%. Ten subjects (9.4%) had a very good partial response and 17% had a partial response. Median response was 7.4 months, progression-free survival was 3.7 months, and overall survival was 17.5 months (64.8% were alive at one year). Patients responded to therapy after a median of one month.
Safety: fatigue (40%), anemia (33%), and nausea (29%) were most common among side effects. Thrombocytopenia occurred in 25% and neutropenia in 23%. There were no treatment discontinuations due to drug-associated adverse events. The overall tolerability of daratumumab can therefore be assessed as relatively good. The safety profile is clinically controllable.
Expansion of the therapy field
What is clear is that new therapeutic options are urgently desired in extensively pretreated, refractory multiple myeloma. Daratumumab shows pronounced activity with reasonable safety as a single agent and now expands treatment options in Switzerland. Multiple myeloma patients who have received at least three prior lines of therapy (including more than one proteasome inhibitor and IMiD) or who have been double-refractory to more than one proteasome inhibitor and IMiD may benefit.
Further studies with the compound in other malignant and premalignant diseases with CD38 overexpression are ongoing or planned. So it remains exciting.
Literature:
- Lokhorst HM, et al: Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med 2015; 373: 1207-1219.
- Lonial S, et al: Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet 2016; 387: 1551-1560.
InFo ONCOLOGY & HEMATOLOGY 2017; 5(2): 2
