Adis evaluation of daratumumab monotherapy in patients with relapsed and refractory multiple myeloma

First targeted therapy for multiple myeloma

Induces an overall response in about 30 % of patients

Response is rapid and durable

Response improves with continued treatment in some patients

Survival benefit is conferred to patients with stable disease or better

Generally well tolerated

Infusion-related reactions are common with the first infusion, but are manageable

What is the rationale for using daratumumab in multiple myeloma?

Multiple myeloma, a malignant neoplasm of plasma cells, is characterized by the uncontrolled production of monoclonal plasma cells in the bone marrow, followed by the production of non-functional intact immunoglobulins or immunoglobulin chains [1, 2]. Multiple myeloma accounts for ≈10–15 % of all haematological neoplasms and ≈1 % of all cancers worldwide [1, 2]. The incidence increases with age, with ≈98 % of patients being diagnosed during or after the fourth decade of life [1, 2]. Most patients present with bone pain, fatigue and anaemia, with other common findings including osteolytic skeletal lesions (80 % of patients), elevated serum creatinine levels (20 %) and hypercalcaemia (15 %) [1].

The survival of patients with multiple myeloma has improved over the past 15 years with the introduction of proteasome inhibitors (e.g. bortezomib) and immunomodulatory drugs (e.g. thalidomide and lenalidomide) [3, 4]. However, the disease remains incurable, and once patients relapse and become refractory to a proteasome inhibitor and an immunomodulatory agent, the prognosis is poor (median overall survival ≈8–9 months) [5, 6]. Therefore, new treatment strategies are needed, and one focus of research has been on targeted therapies [7].

Daratumumab is the first targeted therapy to become available for use in multiple myeloma. It is approved in several regions, including the USA [8] and EU [9]. This article focuses on its use as monotherapy in the EU.

How does daratumumab work?

Daratumumab (Darzalex™) is a first-in-class, human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that targets and binds to the CD38 epitope, which is highly expressed on the surface of myeloma cells, as well as to a lesser extent on other haematological cells and possibly non-haematological cells [9]. The drug binds to CD38 with high affinity where it causes on-tumour activity via several immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and antibody-dependent cell-mediated cytotoxicity, as well as inducing direct apoptosis via cross-linking [10–13] (Fig. 1).

Fig. 1
figure 1

Mechanisms of action of daratumumab

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In addition, daratumumab works through immunomodulatory mechanisms, which are thought to adjust the immune response, including modulation of the tumour microenvironment, depletion of immunosuppressive cell populations and inducing an increase in cytotoxic and helper T cells [14] (Fig. 1). The direct on-tumour actions of daratumumab may provide rationale for the rapid response observed in some patients following treatment, and the immunomodulatory mechanisms may explain the sustained responses [12, 14]. Thus, daratumumab appears to provide a multifaceted approach to promoting myeloma cell death by combining the direct on-tumour activity of traditional antibody therapy with a systemic immunomodulatory role.

How should daratumumab monotherapy be used?

Daratumumab monotherapy via intravenous infusion is indicated for the treatment of adults with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy [9]. Table 1 provides a summary of the administration and use of daratumumab in the EU [9]. Consult local prescribing information for further details.

Table 1 Prescribing summary of intravenous daratumumab (Darzalex™) in the treatment of multiple myeloma in the EU [9]
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What is the clinical efficacy of daratumumab monotherapy?

The efficacy of intravenous daratumumab 16 mg/kg in the treatment of relapsed and refractory multiple myeloma was demonstrated in two open-label, multicentre trials (SIRIUS [15] and GEN501 [16]) and an updated pooled analysis of data from both trials [17]. In the phase 2 SIRIUS trial, eligible patients had been treated previously with ≥3 lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or had disease that was double refractory to the most recently received proteasome inhibitor and immunomodulatory drug [15]. In the phase 1/2 GEN501 trial, eligible patients were refractory to ≥2 prior lines of therapy [16]. The primary endpoint in the SIRIUS trial was the overall response rate (ORR) as determined by an independent review committee [15], whereas the GEN501 trial was primarily designed to evaluate safety [16]. Response evaluation was based on International Myeloma Working Group response criteria [18].

Patients enrolled in the daratumumab 16 mg/kg dosage arms of the SIRIUS (n = 106) [15] and GEN501 (n = 42) [16] trials had previously received a median of five and four lines of therapy, respectively, including bortezomib, carfilzomib, lenalidomide, pomalidomide and thalidomide. The proportion of patients who were refractory to both proteasome inhibitors and immunomodulatory drugs was 95 % in the SIRIUS trial and 64 % in the GEN501 trial. Autologous stem cell transplantation had been performed in 80 and 76 % of patients, respectively. In both trials, patients were premedicated with corticosteroids, paracetamol (acetaminophen) and antihistamines, and corticosteroids were given on each of the two days following each daratumumab infusion [15, 16]. The median time since initial diagnosis was 4.8 years in the SIRIUS trial [15] and 6 years in the GEN501 trial [16]. The median number of daratumumab cycles administered in the SIRIUS trial was 4.0 (range 1–16), and the median duration of first, second and subsequent infusions was 7.0, 4.2 and 3.4 h [15].

Monotherapy with daratumumab 16 mg/kg was effective in the treatment of relapsed or refractory multiple myeloma, with an ORR of 29.2 % in the SIRIUS trial [15] and 36.0 % in the GEN501 trial [16] (Table 2). Results of the pooled analysis demonstrated that almost one-third of patients achieved a response and >80% achieved stable disease or better with daratumumab [17] (Table 2).

Table 2 Efficacy of intravenous daratumumab 16 mg/kg in open-label trials in patients with relapsed and refractory multiple myeloma
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Daratumumab was associated with a rapid response, with median times to first response of 1.0 [15] and 0.9 [16] months. Responses were observed across all prespecified subgroups irrespective of the number or types of previous therapy or the refractory status [15, 16]. For example, in the SIRIUS trial, 30 of 101 (29.7 %) patients who were refractory to both proteasome inhibitors and immunomodulatory drugs achieved a response [15].

In the updated pooled analysis, the median duration of response across both trials was 7.6 months [17]. Among 46 responders in both trials, the degree of response improved with continued treatment in 14 (22 %) patients. For example, among 10 patients who achieved an initial partial response, seven went on to achieve a very good partial response, one achieved a complete response and two achieved a stringent complete response [17].

After a median follow-up of 20.7 months in the updated pooled analysis, median progression-free survival for the combined overall patient population was 4.0 months and the overall 12-month progression-free survival rate was 21.6 % [17]. The median overall survival was 20.1 months, and a clear overall survival benefit with daratumumab was not restricted to patients with a partial response or better, but extended to those with stable disease or better. Among patients who achieved a minimal response or stable disease, the median overall survival was 18.5 months compared with 3.7 months in patients with progressive disease or who were not evaluable [17].

What is the tolerability profile of daratumumab monotherapy?

Intravenous daratumumab monotherapy was generally well tolerated in clinical trials in patients with relapsed and refractory multiple myeloma [15, 16]. Across both trials, only six (4.1 %) patients discontinued treatment as a result of adverse events [17]. The most frequent (occurring in ≥20 % of patients) treatment-emergent adverse events to occur across both trials are summarized in Fig. 2.

Fig. 2
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Incidence and severity of most frequent (≥20 %) treatment-emergent adverse events associated with intravenous daratumumab 16 mg/kg monotherapy in 148 patients with relapsed and refractory multiple myeloma [17]. URTI upper respiratory tract infection

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Infusion-related reactions occurred in 48 % of patients across both trials, but did not necessitate treatment discontinuation in any patients [17]. Among infusion-related reactions that occurred in ≥5 % of patients, respiratory conditions featured most commonly, including nasal congestion, cough, allergic rhinitis, throat irritation and dyspnoea [17]. Nausea and chills were the only nonrespiratory infusion-related reactions that occurred in ≥5 % of patients. Five infusion-related reactions with a severity of ≥Grade 3 occurred in four (2.7 %) patients (two patients with bronchospasm, and one patient each with dyspnoea, hypoxia and hypertension). Among patients who experienced an infusion-related reaction, most (95.8 %) occurred with the first infusion, and were substantially less common with the second (7.0 %) and subsequent (7.0 %) infusions (some patients experienced more than one infusion-related reaction) [17].

Patients experiencing infusion-related reactions were safely managed with pre- and post-infusion medications [17] (Table 1). Across both clinical trials, twelve (8.1 %) patients required treatment with granulocyte colony-stimulating factor [17]. Transfusions (199 in total) were administered in 46 (31.1 %) patients; 44 received red blood cells and 14 received platelets. As daratumumab binds to CD38 on the surface of red blood cells, there is a theoretical risk of haemolysis. However, no adverse events relating to haemolysis were reported in clinical trials [17].

The median time to an infusion-related reaction, based on a review of clinical trials reported in the European Medicines Agency’s summary of product characteristics, was 1.5 (range 0.2–9.3) h [9].

What is the current clinical positioning of daratumumab?

Daratumumab monotherapy provides an option for the treatment of patients with relapsed and refractory multiple myeloma, irrespective of how many lines of previous treatment they had received or their refractory status. In clinical trials, a response was achieved by ≈30 % of patients. Patients who responded to daratumumab had a rapid (within ≈1 month) and durable (median 7.6 months) response, with some patients continuing to improve with continued treatment. Median overall survival was 20.1 months, and a clear overall survival benefit was evident in the 83 % of patients who achieved stable disease or better. Daratumumab was generally well tolerated and, although infusion-related reactions occurred during the first infusion in a substantial proportion of patients, they were manageable and did not lead to treatment discontinuation. Precautions should be followed to reduce the risk of infusion-related reactions and other potential adverse effects and drug–test interactions (Table 1).

Research is continuing into the use of daratumumab as part of combination therapy regimens. According to preliminary results from the randomized phase 3 CASTOR [19] and POLLUX [20] trials in patients with relapsed or refractory multiple myeloma, treatment with daratumumab + standard of care (bortezomib + dexamethasone in CASTOR [19], and lenalidomide + dexamethasone in POLLUX [20]) reduced the risk of disease progression or death by >60 % relative to treatment with standard of care alone.