Spotlight: Cancer Drug Licensed from Danish Antibody Developer Continues to Reap Benefits for Janssen
By Nashrah Ahmad, Ph.D. Candidate &
Rajaneesh K. Gopinath, Ph.D.
As the second most common blood cancer in the United States, multiple myeloma has proved to be a huge burden to society. While existing treatments for this cancer type are effective in reducing cancer growth, it soon becomes refractory and continues to grow. Daratumumab, an anti-CD38 monoclonal antibody, has demonstrated remarkable response in patients with relapsed myeloma. In 2015, it was first approved by the US Food and Drug Administration (FDA) for treating patients with relapsed refractory multiple myeloma (RRMM) and those with newly diagnosed multiple myeloma (MM) who are ineligible for stem cell transplant .
Developed by Danish biotech, Genmab, and later licensed to Janssen Pharmaceuticals, daratumumab (DARZALEX®) has shown substantial clinical efficacy and rapid and durable response in patients with RRMM who relapse after initial therapy or are refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) . Daratumumab partners well with other antimyeloma agents such as IMiDs (e.g., bortezomib) and PIs (e.g., lenalidomide), and has also demonstrated the best single-agent response rates among the currently available drugs in the antimyeloma armamentarium [1,2]
In August 2020, Daratumumab notched its eighth approval as a combinatorial therapy with Kyprolis® (carfilzomib) and dexamethasone (DKd) for the treatment of adult patients with relapsed/refractory multiple myeloma who have received one to three previous lines of therapy. We, therefore, delved into the merits of daratumumab as a combo therapy.
Immunomodulatory Mechanism of Action of Daratumumab
An important therapeutic target in myeloma is CD38, a transmembrane glycoprotein whose expression in MM cells is higher than that in normal myeloid and lymphoid cells . Daratumumab is the first FDA-approved anti-CD38 monoclonal antibody. It can kill MM cells via multiple mechanisms of action that comprise antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), induction of apoptosis, and inhibition of CD38 enzymatic activity .
Daratumumab targets the myeloma cells expressing CD38, and since CD38 is also expressed on non-plasma cells, analysis of its effects on CD38 positive non-plasma immune cells is critical. Krejcik et al. evaluated the immunomodulatory effects of daratumumab by assessing the proliferation, clonality, and activation of T cells in patients with RRMM on daratumumab monotherapy .
Peripheral blood and bone marrow were isolated from the patients for immune profiling and functional assessments of immune cells. In myeloma, CD38 positive immunosuppressive cells such as myeloid-derived suppressor cells (MDSC), T regulatory (Treg) cells, B regulatory (Breg) cells contribute to immune dysfunction and promote tumor growth, angiogenesis, and progression of the disease. It was found that daratumumab treatment led to the depletion of CD38 positive MDSC, Treg, and Breg cells.
Elimination of these CD38 positive immunosuppressive cells led to a concomitant increase in positive immune effectors cells, thereby resulting in antimyeloma activity . Additionally, an increase in the number of memory T cells, cytotoxic T cells, and T helper cells was observed. Based on these results, Krejcik et al. proposed an additional mechanism of action for daratumumab, according to which it enhances antimyeloma activity by depleting CD38 expressing immunosuppressive cells and stimulating effector functions of T cells .
Clinical Efficacy and Safety of Daratumumab-Based Combination Therapies
In addition to demonstrating antimyeloma activity in monotherapy, daratumumab also demonstrated high efficacy when used in triple combination therapy. In a Phase 3 clinical trial, 498 patients with RRMM were randomly divided into two cohorts: the first cohort received daratumumab, bortezomib, and dexamethasone combination therapy while the other received bortezomib and dexamethasone alone 
The use of daratumumab in combination with bortezomib and dexamethasone resulted in significantly higher survival rates than those obtained with bortezomib and dexamethasone combination regimen (60.7% vs. 26.9%)  The overall response rate was higher in the daratumumab, bortezomib, and dexamethasone combination cohort than in the bortezomib and dexamethasone cohort (82.9% vs. 63.2%, P<0.001).
The most common adverse effects associated with daratumumab are infusion-related reactions (IRRs). IRRs are most common during the first infusion and are predominantly grade 1 or 2; they most commonly affect the upper respiratory tract and are accompanied by cough, wheezing, allergic rhinitis, and nausea. Adverse effects of grade 3-4 usually include anemia, thrombocytopenia, and neutropenia. There was a higher incidence of IRRs, thrombocytopenia, and neutropenia in the daratumumab, bortezomib, and dexamethasone regimen cohort as compared to the control group.
In another Phase 3 clinical trial, 569 patients with MM were randomly divided into two groups: one group received the daratumumab, lenalidomide, and dexamethasone combination therapy while the control group received lenalidomide and dexamethasone alone . The use of daratumumab with lenalidomide and dexamethasone in patients with MM resulted in more prolonged survival than the use of lenalidomide and dexamethasone combination therapy. The overall response was significantly higher in the daratumumab triple combination therapy than in the control group (43.1% vs. 19.2%, P<0.001). Though, the rate of IRRs and neutropenia was higher in the daratumumab, lenalidomide, and dexamethasone as compared to the control group.
The recent approval is based on a Phase 3 trial (CANDOR study), which is the first to compare daratumumab, carfilzomib, and dexamethasone triple combo (DKd) versus carfilzomib and dexamethasone (Kd) combo in patients with relapsed/refractory multiple myeloma. The study met its primary endpoint of PFS after a median follow-up of 16.9 months and 16.3 months for the DKd and Kd arms, respectively. The median PFS had not been reached in the DKd arm and was 15.8 months in the Kd arm (Hazard Ratio=0.63; 95 percent confidence interval, 0.46- 0.85; P=0.0014), representing a 37 percent reduction in the risk of disease progression or death for patients treated with DKd versus Kd .
In summary, daratumumab has revolutionized the treatment outcome and prognostic expectations in patients with relapsed myeloma, and its antimyeloma activity can be attributed to its multi-faceted mechanism of action. The addition of daratumumab, to either bortezomib, carfilzomib, or lenalidomide combination regimen, significantly increased the efficacy of the treatment regimen and resulted in prolonged survival in patients with RRMM. However, the incidence of IRRs and other adverse events such as thrombocytopenia and neutropenia was higher in the daratumumab group as compared to the control group.
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