Daratumumab Offers New Hope for Patients with Multiple Myeloma

Multiple myeloma (MM) is a malignancy characterized by the proliferation of monoclonal plasma cells within the bone marrow, which may result in hypercalcemia, renal dysfunction, anemia, and lytic bone lesions.¹ Historically, therapies for patients with MM included high-dose dexamethasone, alkylating agents, and autologous stem cell transplantation. In the late 1990s, a new era in myeloma treatment began with the introduction of the immunomodulatory drug (IMiD) thalidomide, followed by subsequent development of the proteasome inhibitors bortezomib and carfilzomib, and the next-generation IMiDs lenalidomide and pomalidomide.

The treatment landscape of myeloma continues to evolve, with recent regulatory approvals of the histone deacetylase inhibitor panobinostat and the monoclonal antibodies (mAbs) daratumumab and elotuzumab. Notably, daratumumab, an anti-CD38 mAb, was granted accelerated approval in 2015 by the FDA, based on the results of 2 clinical trials that showed it to be highly efficacious, with overall response rates (ORRs) of 29.2%² and 36%³ when used as monotherapy at a dose of 16 mg/kg. This article will discuss the mechanisms of action of daratumumab, clinical trial data pertaining to its safety and efficacy, and practical considerations for nurses who care for patients being treated with this agent.

Mechanisms of Action

Preclinical studies have shown that daratumumab has significant potential in eliminating myeloma cells through targeted destruction via a variety of pathways. CD38 is a transmembrane glycoprotein that affects cell growth and survival. It is not only expressed on lymphoid cells, myeloid cells, and nonhematopoietic tissue, but also is highly expressed on the surface of myeloma cells.¹ Daratumumab is a human immunoglobulin G (IgG) kappa mAb that binds to CD38, resulting in complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, apoptosis, and direct inhibition of CD38 enzyme activities.³ Preclinical studies demonstrated the efficacy of daratumumab as monotherapy or in combination with bortezomib or lenalidomide in murine models, providing the rationale for its transition to clinical use.⁴

Clinical Trial Data

The phase 1/2 GEN 501 clinical trials evaluated daratumumab as monotherapy in patients who were refractory to ≥2 prior lines of therapy. In part 1 of the study (the dose-escalation phase), 33% of patients who received doses between 4 and 24 mg/kg achieved a partial response, whereas in part 2 (the dose-expansion phase), the ORR was approximately 36% for patients receiving the 16-mg/kg dose. Ultimately, the 16-mg/kg dose of daratumumab was found to produce a greater ORR than the 8-mg/kg dose, with a median time to response of 0.9 months.³ Patients who had received 2 to 3 previous lines of therapy had a higher response rate (56%) than did more heavily pretreated patients (23%). Median duration of response was 6.9 months in the 8-mg/kg cohort but had not been reached in the 16-mg/kg cohort.³

The most common adverse events (AEs) experienced in the 16-mg/kg cohort included infusion-related reactions (71%), fatigue (40%), allergic rhinitis (24%), nasopharyngitis (24%), cough (21%), diarrhea (21%), upper respiratory infection (17%), pyrexia (17%), and dyspnea (14%). Most AEs were self-limiting, with spontaneous resolution. In this study, patients who received the 16-mg/kg dose experienced grade 3/4 AEs at a lower rate (26%) than those who received the 8-mg/kg dose (53%). These events included pneumonia (11.9%), thrombocytopenia (9.5%), neutropenia (4.8%), leukopenia (4.8%), anemia (4.8%), and hyperglycemia (4.8%).³

Based on data from this trial, the phase 2 SIRIUS trial of daratumumab monotherapy in patients with refractory MM was conducted, which showed an ORR of 29.2% in the 16-mg/kg dose cohort.² The most common AEs of any grade in this trial included fatigue (40%), anemia (33%), nausea (29%), thrombocytopenia (26%), neutropenia (23%), back pain (23%), and cough (21%). Grade 3 or 4 treatment-emergent AEs occurred in approximately 23% of patients and included anemia (24%), thrombocytopenia (19%), neutropenia (12%), fatigue (3%), and back pain (3%).²

Daratumumab was then studied in combination with proteasome inhibitors and an IMiD after preclinical data indicated synergy between lenalidomide and bortezomib. Two phase 3 clinical trials were designed to evaluate daratumumab in combination with bortezomib/dexamethasone as well as in combination with lenalidomide/dexamethasone.

In the phase 3 CASTOR trial, patients were randomized to daratumu­mab/bortezomib/dexamethasone (daratumumab arm) or to bortezomib/dexamethasone (control arm).⁵ The ORR was higher in the daratumumab arm compared with the control group (82.9% vs 63.2%; P <.001). In addition, in the subgroup of patients who had received 1 previous line of therapy, progression-free survival (PFS) was also higher in the daratumumab arm versus control (77.5% vs 29.4% at 12 months; P <.001). This trend was similar for patients who had received 2 or 3 previous lines of therapy, with a median PFS of 9.3 months in the daratumumab arm versus 6.5 months in the control arm.

The hematologic AEs occurring more frequently in the daratumumab arm versus control included thrombocytopenia (58.8% vs 43.9%), neutropenia (17.7% vs 9.3%), and lymphopenia (13.2% vs 3.8%). Nonhematologic events occurring more frequently in the daratumumab arm versus control included peripheral neuropathy (47.3% vs 37.6%), diarrhea (31.7% vs 22.4%), cough (23.9% vs 12.7%), dyspnea (18.5% vs 8.9%), and peripheral edema (16.5% vs 8%).⁵

In the phase 3 POLLUX trial, patients who had received ≥1 previous lines of therapy were randomized to daratumumab/lenalidomide/dexamethasone or lenalidomide/dexamethasone.⁶ The ORR was superior in the daratum­umab arm versus the control arm (92.9% vs 76.4%; P <.001) as was the complete response rate (43.1% vs 19.2%; P <.001). PFS was maintained in the daratumumab arm, regardless of the number of previous lines of therapy, with 12-month PFS of 85.7% compared with 63.2% for the control arm.⁶

AEs were relatively similar between the 2 arms, with the exception of neutropenia (59.4% vs 43.1%), diarrhea (42.8% vs 24.6%), upper respiratory infection (31.8% vs 20.6%), cough (29% vs 12.5%), nasopharyngitis (24% vs 15.3%), and pyrexia (20.1% vs 11%), all of which occurred more frequently in the daratumumab arm. Rates of thromboembolic events were slightly higher in the control arm compared with the daratumumab arm (3.9% vs 1.8%).⁶

Special Considerations

One of the most frequently occurring adverse effects in clinical trials of daratumumab was infusion-related reactions (IRRs), which were observed in 48% of patients.⁷ Approximately 5% of these patients were found to have respiratory symptoms such as cough, nasal congestion, dyspnea, allergic rhinitis, and throat irritation. Patients who exhibited nonrespiratory IRRs reported chills and nausea. It is important to note that, although the percentage of patients experiencing IRRs with the first dose was 95.8%, this percentage dropped to 7% with subsequent infusions.⁷

In the dose-escalation phase (part 1) of the GEN 501 studies, 63% of patients experienced IRRs of any grade, whereas only 6% had grade 3/4 IRRs. Of note, none of the patients studied discontinued treatment because of an IRR. Most IRRs (34%) were related to administration-site conditions or general disorders, such as pyrexia, which accounted for 22% at any grade. Of patients with grade 3/4 IRRs, 3% of those consisted of patients with respiratory, thoracic, and mediastinal disorders, including 3% who experienced bronchospasm.³

In the phase 2 SIRIUS trial, the IRR rates were similar for patients in both the 8- and 16-mg/kg groups. IRRs were predominantly grade 1 or 2 in 42% of patients, whereas other AEs, such as anemia, occurred at a lower rate of approximately 33% at any grade.2 The rate of IRRs of any grade in the phase 3 trial of daratumumab/lenalidomide/dexamethasone was approximately 47.7%, with 92% of those occurring during the first infusion. Most IRRs were grade 1 or 2 with no grade 4 events reported.⁶ The most common symptoms of daratumumab IRRs included cough (8.5%), dyspnea (8.5%), vomiting (5.7%), nausea (4.9%), bronchospasm (4.6%), and chills (4.6%).⁶

In an effort to reduce the risk for IRRs, it is recommended that patients be premedicated with steroids, antipyretics, and antihistamines. The GEN 501 trials (parts 1 and 2) used premedication with dexamethasone 20 mg (or equivalent), acetaminophen 650 to 1000 mg, and diphenhydramine 25 to 50 mg (or equivalent). Because delayed IRRs were initially reported in earlier trials of daratumumab, postinfusion steroids are also recommended for all patients, particularly in the first cycle of treatment. In the dose-escalation phase (part 1) of GEN 501, all patients received 40 mg of methylprednisolone on their first and second days after infusions, which was subsequently reduced to 20 to 25 mg in the dose-expansion phase (part 2).³

Because IRRs may include respiratory symptoms, such as nasopharyngitis and bronchospasm, bronchodilators may be administered prior to infusion (as well as postinfusion) in patients at higher risk for respiratory complications, such as a forced expiratory volume in 1 second (FEV₁) of <80%.⁶ Anecdotal evidence suggests that the use of montelukast may minimize IRRs⁸ and can be administered the day before or the day of infusion. Patients with known chronic obstructive pulmonary disease, moderate or severe persistent asthma within 2 years, or FEV₁ <50% were excluded from clinical trials.

As an anti-CD38–directed mAb, daratumumab binds to CD38 not only on myeloma cells, but also, to a lesser extent, on red blood cells, which may interfere with blood typing and cross-matching. This can result in a false-positive Coombs test, which may persist for up to 6 months from the last infusion of daratumumab.⁹ Therefore, it is important to obtain red blood cell genotyping as well as a type and cross-match before the first infusion of daratumumab. Patients should be provided a wallet card that states that they are currently on daratumumab and a contact phone number for their oncologist to alert other healthcare providers if patients need additional blood.⁸

Because daratumumab is an IgGκ mAb, it may cause interference on serum protein electrophoresis and immunofixation assays, making it difficult to evaluate clinical response, particularly in patients with IgGκ myeloma protein (M-protein) <2 g/L.⁸ It is important to keep this in mind when caring for patients responding to treatment and in those with a residual M-protein, particularly in those with a low peak. The daratumumab-specific immunofixation electrophoresis reflex assay is currently in development to shift the migration of the daratumumab antibody away from the M-protein on immunofixation, so that a true response can be assessed in those patients whose M-protein drops to <2 g/L.¹⁰

Conclusion

Daratumumab is the second mAb to receive FDA approval for the treatment of patients with MM. This agent has been found to be effective as monotherapy and in combination with other therapies, yielding significant improvements in overall PFS rates. It has also proven to be well-tolerated in patients with relapsed and/or refractory disease, with minimal grade 3/4 AEs. IMiDs such as these offer hope to patients and providers that additional effective new therapies can be discovered, which will bring us closer to a cure for the disease.

References
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