Almost all patients with multiple myeloma (MM) who respond to initial therapy will relapse, while some patients do not respond to initial treatment (refractory). This is a brief review of three seminal studies from 2016 that established foundation for daratumumab-based combination therapy regimens in MM. These studies have shown that daratumumab, an IgG1 monoclonal antibody targeting CD38, has broad immunomodulatory effects and superior efficacy and safety in treating relapsed and refractory MM.
The antitumor effects of daratumumab are multifaceted, involving both direct and indirect mechanisms. Myeloma cells express high levels of CD38, and can be directly eliminated by daratumumab-mediated pathways such as cytotoxicity and apoptosis1,2.
However, this direct mechanism does not explain all effects of daratumumab on MM. The study by Krejcik et al reported that daratumumab targets CD38+ immunosuppressive cells and rescues antitumor immune response through an indirect immunomodulatory mechanism3. Moreover, two multi-center, randomized, open-label phase III studies, namely CASTOR and POLLUX, showed that daratumumab-based combination regimens (DVd and DRd) have provided significant improvement of disease control and survival with excellent safety profiles44,5.
Immunomodulatory Function of Daratumumab
Krejcik et al focused on the 148 patients with relapsed/refractory MM who were undergoing daratumumab monotherapy in two phase I/II studies (GEN501 and SIRIUS)3. Peripheral blood (PB) and bone marrow (BM) mononuclear cells were collected from patients pre- and post-daratumumab treatment in order to evaluate in vivo effect of the drug.
Daratumumab treatment led to reduction of CD38+ immunosuppressive cells. Specifically, the regulatory T-cells (Tregs), regulatory B-cells (Bregs) and interleukin-10 produced by Bregs were reduced at one week of daratumumab treatment and the effect persisted throughout the course of treatment. Although myeloid-derived suppressor cells (MDSCs) were not readily detectable from PB, G-MDSCs generated using a coculture model demonstrated similar sensitivity to daratumumab.
As would be expected from reduction in immunosuppressive cells, daratumumab triggered expansion and activation of T cell populations. CD3+ total T cells, CD4+ helper T cells, CD8+ cytotoxic T-cell, and HLA-DR+ CD8+ effector memory T cells all expanded in both PB and BM. CD8+/CD4+ and CD8+/Tregs ratios in both PD and BM also increased significantly, suggesting a shift toward positive regulation of T-cell immunity. T-cell clonality and IFN-γ production in response to viral antigens also increased, consistent with improved functionality of T-cells. Notably, the effects of daratumumab on PB and BM cells have been associated with clinical response in patients. For instance, the increase of T-cell counts and clonality correlated with positive clinical response in patients, suggesting an improved immunity induced by daratumumab. This study thus uncovered a mechanism underlying the efficacy of daratumumab in treating relapsed and refractory MM.
Clinical Efficacy of Daratumumab-based Combination Therapies
In CASTOR and POLLUX studies, 498 and 569 with relapsed or refractory MM were recruited, respectively. In CASTOR study, patients were treated with bortezomib and dexamethasone alone (control group) or in combination with daratumumab (DVd regimen group)4. In POLLUX study, patients were treated with either lenalidomide and dexamethasone alone (control group) or in combination with daratumumab (DRd regimen group)5. Both daratumumab-containing regimens showed significantly higher efficacy than the corresponding control group (Table 1). Overall, the DVd and DRd regimens led to 61% and 63% lower risk of disease progression or death than the control group, respectively. Moreover, in POLLUX study, the minimal residual disease status was examined in relapsed and refractory MM for the first time. Patients in the DRd group had significantly higher rate of below-threshold results for minimal residual disease compared with the control group (22.4% vs. 4.6%) (at threshold of 1 tumor cell per 105 white cells by next-generation sequencing). This is remarkable as minimal residual disease status has been associated with clinical outcomes and used as surrogate for estimating disease control and survival.
Safety and tolerability of Daratumumab-based Combination Therapies
Daratumumab has excellent safety and tolerability profiles. Infusion-related reactions associated with daratumumab were reported in 45.3% of the patients inDVd group and 47.7% in DRd group, which usually occurred during the first infusion and can be controlled by premedication. In both CASTOR and POLLUX studies, the daratumumab group showed higher incidence of several adverse effects than the control group, including neutropenia, thrombocytopenia and non-hematologic adverse effects. In each study the daratumumab group had similar percentage of patients who discontinued treatment due to adverse effects compared to the control group.
It is worth noting that daratumumab can interfere with certain assays. It binds to CD38 on red blood cells and thus interferes with blood-compatibility labtest. However, no transfusion incidents have been reported in daratumumab-treated patients. Daratumumab also interferes with the serum immunofixation assay used for evaluation of response to treatment. A modified immunofixation assay has been developed to avoid such interference.
CASTOR and POLLUX phase III studies have reported superior efficacy of daratumumab-based combination therapies, even though long-term survival data were not available when these two studies were published in 2016. Immunosuppression and immune evasion contribute to relapse and refractory MM. Daratumumab reversed the immunosuppression, stimulated T-cell expansion, and rescued antitumor immunity (Figure 1). These broad immunomodulatory effects also appeared to be long-lasting, which could further benefits patients with relapsed MM. Future studies are needed in order to identify downstream pathways targeted by antitumor immunity rescued by daratumumab.
Table 1.Efficacy of daratumumab-based combination regimens#.
|CASTOR||61%||60.7% vs. 26.9%(P<0.05)||82.9% vs. 63.2%(P<0.001)||59.2% vs. 29.1% (P<0.001)||19.2% vs. 9.0% (P=0.001)||0.39(95% CI 0.28-0.35, P<0.001)|
|POLLUX||63%||83.2%vs. 60.1%(P<0.05)||92.9%vs. 76.4%(P<0.001)||75.8%vs. 44.2%, (P<0.001)||43.1%vs. 19.2% (P<0.001)||0.37(95%CI 0.27-0.52, P<0.001)|
# ↓Risk: reduced risk for progression or death; PFS:progression free survival (at 12 month); ORR: overall response rate; VGPR: very good partial response or better; CR: complete response or better; HR: hazard ratio (DVd or DRd vs. control).
1. OverdijkMB, Verploegen S, Bögels M, et al. Antibody-mediated phagocytosis contributesto the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs 2015;7(2):311–21.
2. de Weers M, Tai Y-T, van der Veer MS, etal. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol2011;186(3):1840–8.
3. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 2016;128(3):384–94.
4. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. New England Journal of Medicine 2016;375(8):754–66.
5. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. New England Journal of Medicine 2016;375(14):1319–31.
I received my MD from PUMC in Beijing China and my Ph.D. in Biochemistry from Stony Brook University on Long Island. Over the years, I have worked in the fields of genetic research and clinical medicine in different parts of the US, including PA, MO, CT, FL, NY and MI. My research has been published in multiple scientific journals. Currently I live in Ann Arbor, MI with my husband and our children and Mango the orange tabby. I love hiking, running, baking, cooking and biking.