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Daratumumab: A First-in-Class Agent with an Expanding Role in the Treatment of Multiple Myeloma

Patrick McBride, PharmD
Pharmacist
Dana-Farber Cancer Institute
Boston, MA

Multiple myeloma is a plasma-cell dyscrasia that results in the overproduction of clonal malignant plasma cells.1 These plasma cells can be detected in the bone marrow, blood, and urine, and their accumulation can lead to bone marrow and organ dysfunction in affected patients. Although the disease remains incurable, recent therapeutic advances have improved outcomes and allowed patients to live longer.

Daratumumab is a first-in-class immunoglobulin 1 kappa human monoclonal antibody that targets the CD38 antigen on the exterior of myeloma cells.2 Daratumumab induces cancer cell death through several mechanisms, including complement-dependent cytotoxicity, antibody-dependent cell-mediated toxicity, apoptosis through Fc-mediated cross-linking, and modulation of CD38 enzyme activity.2,3 The U.S. Food and Drug Administration (FDA) originally approved daratumumab as monotherapy for the treatment of patients with multiple myeloma (MM) who have received at least three prior therapies, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double-refractory to PI and an IMiD. Daratumumab has also received additional FDA indications as combination therapy with lenalidomide or bortezomib and dexamethasone in MM patients who have received at least one prior line of therapy and with pomalidomide and dexamethasone in MM patients who have received at least two prior therapies, including lenalidomide and a PI. Most recently, it gained approval to be used in combination with bortezomib, melphalan, and prednisone in patients with newly diagnosed disease who are ineligible for transplant. The approved dosing schedule for daratumumab combination and monotherapy can be found in (Table 1-see PDF).

Clinical Trials

The initial approval of daratumumab was based on the results of the 2016 SIRIUS trial, an open-label phase 2 study that examined the use of the drug as a single agent in patients who had previously received at least three lines of therapy (including PIs and IMiDs).4 Patients were randomly assigned to one of two dose levels (8 mg/kg or 16 mg/kg). Among the patients who received the 16 mg/kg dose (n = 108), the overall response rate (ORR) was 29.2%, with a median duration of response of 7.4 months. The median progression-free survival (PFS) was 3.7 months, and 64.8% of patients were alive at 1 year. Fatigue (40%) and anemia (33%) were the most commonly reported adverse effects.

Combination with PIs
Subsequent trials have examined the use of daratumumab in combination with other agents active in myeloma. In 2016, Palumbo and colleagues conducted a phase 3 trial (CASTOR) in which patients (N = 498) with relapsed or refractory disease were randomly assigned to receive bortezomib (1.3 mg/m2) and dexamethasone (20 mg) either with or without daratumumab (16 mg/kg).5 The primary end point of PFS was prolonged in the daratumumab arm compared to the control arm at the median follow-up period of 7.4 months (not reached vs. 7.2 months). The ORR was also improved in the daratumumab cohort versus the control group (82.9% vs. 63.2%, p < .001). The most prevalent grade 3–4 adverse effects in the daratumumab and control groups were hematologic (thrombocytopenia: 45.3% vs. 32.9%; anemia: 14.4% vs. 16%; neutropenia: 12.8% vs. 4.2%), and rates of grade 3–4 infection were similar between the two cohorts (21.4% vs. 19%).

In a more recent 2018 phase 3 study by Mateos and colleagues,transplant-ineligible treatment-naive patients (N = 706) received bortezomib, melphalan, and prednisone with or without daratumumab.6 At the interim analysis cutoff (18 months), both the PFS rate and ORR were improved in the daratumumab group versus the control group (PFS at 18 months: 71.6% vs. 50.2%; ORR: 90.9% vs. 73.9%). Grade 3–4 adverse effects in the daratumumab arm were again mainly hematologic (neutropenia: 39.9%; thrombocytopenia: 34.3%; anemia: 15.9%) but also included diarrhea (2.6%) and peripheral sensory neuropathy (1.4%). The rate of grade 3–4 infections in the daratumumab and control groups were 23.1% and 14.1%, respectively.

Combination with IMiDs
In the 2016 phase 3 POLLUX trial, patients (N = 569) who had received at least one previous line of therapy were randomly assigned to receive lenalidomide and dexamethasone with or without daratumumab.7 Patients in the daratumumab group experienced a significantly higher overall response rate compared to the control group (92.9% vs. 76.4%; p < .001) and improved PFS at 12 months (83.2% vs. 60.15%). Common grade 3–4 adverse effects in the daratumumab and control groups were again hematologic (neutropenia: 51.9% vs. 37%; thrombocytopenia: 12.7% vs. 13.5%; anemia: 12.4% vs. 19.6%), with grade 3–4 infection marginally increased in the daratumumab group (28.3% vs. 22.8%).

Daratumumab has also been studied in combination with the IMiD pomalidomide. In a 2017 study conducted by Chari and colleagues, patients with relapsed or refractory MM who had received at least two previous lines of therapy were treated with daratumumab (16 mg/kg), pomalidomide (4 mg), and dexamethasone (40 mg).8 At a median follow-up of 13.1 months, the estimated PFS was 8.8 months, with a 12-month survival rate of 66%. As seen in previous studies, common adverse effects were hematologic, although the incidence of grade 3–4 neutropenia was particularly pronounced (78% of patients). Upper respiratory tract infections and pneumonia occurred in 28% and 10% of patients, respectively. The incidence of grade 3–4 infection (32%) was comparable to previous studies that examined the use of pomalidomide and dexamethasone alone.

Safety

Although daratumumab is generally well tolerated, it is associated with a high incidence of infusion-related reactions (IRRs) (27.7%–56%; grade 3–4: 2%–9%).2-8 The vast majority of IRRs (88%–98.2%) occur during the first infusion.2,5,9 The manufacturer recommends both pre- and postmedications for daratumumab, including steroids, antipyretics, and antihistamines, with or without other supplementary agents (Table 2-see PDF). Prescribing information also suggests using bronchodilators and inhaled corticosteroids for at least the first four infusions in patients with a history of chronic obstructive pulmonary disease to prevent an IRR.1 In addition, the first dose is delivered in a larger dilution volume (1,000 ml) and at a slower rate of infusion to mitigate IRRs.

A limited number of studies have examined the utility of additional premedications beyond the prescribing information recommendations. In a 2016 multicenter open-label early-access study, a cohort of patients received recommended premedications plus montelukast (10 mg by mouth at least 30 minutes prior to daratumumab) at the investigator’s discretion.10 Infusion reactions with the first daratumumab infusion were reduced in patients who received montelukast compared to those who did not (38.0% vs. 58.5%). The infusion time for daratumumab was also 0.9 hours shorter in patients who received montelukast. Institutional practice may dictate the administration of supplemental premedications like montelukast for at least the first 1–2 daratumumab infusions.

Daratumumab is associated with decreased hematologic parameters, including thrombocytopenia, anemia, and neutropenia as outlined in the studies above. Infection is also common, most notably upper respiratory tract infection (any grade: 21.6%–31%; grade 3–4: 0.7%–2.0%) and pneumonia (any grade: 10%–15.3%; grade 3–4: 9%–11.3%).3,6-8 Other common nonhematologic adverse effects include fatigue, nausea, diarrhea, back pain, muscle spasms, pyrexia, dyspnea, peripheral edema, and peripheral sensory neuropathy.

Interference with Laboratory Testing

M-Protein Monitoring
An integral laboratory marker used in the diagnosis and monitoring of disease burden in MM is the monoclonal immunoglobulin protein (M protein).11 This M protein is secreted by malignant plasma cells and can be detected in the blood and urine. It can be quantified using both serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE), processes that are able to separate and measure the specific protein.

Monoclonal antibodies, including daratumumab, are detectable on SPE and IFE and therefore can interfere with these monitoring assays.11 The therapeutic antibody and monoclonal protein migrate closely on electrophoresis and are difficult to differentiate on analysis. Certain clonal protein subtypes (immunoglobulin G [IgG] kappa and kappa light chain MM) are harder to distinguish from daratumumab than others.12 Measurement of daratumumab on the assays can be misinterpreted as an elevated M protein and can lead to an inaccurate response assessment. Strategies to mitigate M-protein monitoring interference are available; one is the use of a daratumumab-specific immunofixation electrophoresis reflex assay (DIRA).11,12 DIRAs use antidaratumumab antibodies, which form a complex with daratumumab and alter its migration on IFE. By specifically shifting daratumumab on the assay, the M spike can be quantified with greater accuracy. Clinicians should be aware of this assay interference and take appropriate steps to ensure that treatment response is being measured appropriately.

Blood Typing and Transfusion Medicine
As stated previously, daratumumab is a human IgG monoclonal antibody that binds to CD38 receptors on malignant plasma cells; however, CD38 receptors are located on the surface of other cells, including red blood cells (RBCs) and platelets.13 Daratumumab is therefore able to bind to RBCs and conceal the existence of antibodies in a patient’s plasma. This binding can cause a false-positive result in blood compatibility testing (direct and indirect antiglobulin test), making it difficult to detect clinically relevant RBC antibodies in an assay. Because multiple myeloma patients frequently require RBC transfusions, this issue is particularly relevant.

Patients should complete baseline blood compatibility testing before initiating daratumumab therapy. If this testing is not an option, certain strategies can be used to overcome daratumumab antibody interference. Chemical denaturation of cell surface CD38 disulfide bonds using dithiothreitol (DTT) or trypsin is one such method.14 These reducing agents cleave CD38 from the cell surface of RBCs, preventing the binding of daratumumab and a subsequent false positive antiglobulin test. It should be noted that DTT can also degrade other blood antigens, most notably Kell antigens, and therefore patients should be given K-negative RBC units.13 Daratumumab-positive blood samples can also be treated with soluble CD38, or anti-DARA idiotype antibodies, which bind and neutralize drug molecules. Although both denaturation and neutralization have been proven effective in preventing panreactivity, cost of the assay and availability of reagents may factor into a clinician’s decision on which method to use.13,14 It is also important to consider that daratumumab can interfere with RBC antibody screening for up to 6 months after the last daratumumab infusion.13

Conclusion

Daratumumab is a first-in-class anti-CD38 monoclonal antibody that can be used as monotherapy or in combination with PIs, IMiDs, alkylating agents, and corticosteroids for the treatment of MM. Although it is generally well tolerated, the medication has been associated with decreased blood counts, and patients should be monitored closely for infection (specifically upper respiratory tract infections and pneumonia). Infusion reactions may occur, especially during the first two infusions, and patients should follow an appropriate pre- and postmedication regimen according to the package insert and institutional standards. Daratumumab has the unique ability to interfere with laboratory testing, including M-protein monitoring and blood typing. It is important for clinicians to note this interaction, both during therapy and after its completion, and take appropriate steps to ensure that laboratory values are accurately interpreted. Daratumumab is one of the more recent therapeutic advances in the treatment of MM that is allowing patients to achieve improved outcomes.

References

  1. Palumbo A, Anderson K. Multiple myeloma. NEJM. 2011;364:1046-1060.
  2. Darzalex (daratumumab) [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2015.
  3. Usmani S, Weiss B, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016;128(1):37-44.
  4. Lonial S, Weiss B, Usmani S, et al. Daratumumab monotherapy in patients with treatment refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial. The Lancet. 2016;387:1551-1560.
  5. Palumbo A, Chan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. NEJM. 2016;375(8):754-766.
  6. Mateos MV, Dimopoulos M, Suzuki K, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. NEJM. 2018;378(6):518-528.
  7. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. NEJM. 2016;375(14):1319-1331.
  8. Chari A, Suvannasanka A, Fay JW et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130(8):974-981
  9. Voorhees P, Weiss B, Usmani S, et al. Management of infusion-related reactions following daratumumab monotherapy in patients with at least 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). Blood. 2015;126:1829.
  10. Chari A, Mark T, Krishan A, et al. Use of montelukast to reduce infusion reactions in an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma. American Society of Hematology. December 2016. Session 653. Myeloma therapy, excluding transplantation: Poster I.
  11. McCudden C, Axel A, Slaets D, et al. Monitoring multiple myeloma patients treated with daratumumab: Teasing out monoclonal antibody interference. Clin Chem Lab Med. 2016;54(6):1095-1104.
  12. Caillon H, Irimia A, Simon J, et al. Overcoming the interference of daratumumab with immunofixation electrophoresis (IFE) using an industry-developed DIRA test: Hydrashift 2/4 Daratumumab. Blood. 2016;128(22):2063.
  13. Brilhante D, Chabert T, Brites A, et al. Management of daratumumab interference in Portuguese blood transfusion medicine: A literature review about unmet needs and challenges. Int J Blood Transfus Immunohematol. 2018;8:1-7.
  14. Chapuy C, Nicholson R, Aguad M, et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion. 2015;55(6):1545-1554.
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