Infectious and immunological sequelae of daratumumab in multiple myeloma (2018)

Daratumumab, an anti-CD38 monoclonal antibody is an important new agent in the therapeutic armamentarium for multiple myeloma (MM). Large clinical trials have demonstrated significant improvements in the outcome of patients with relapsed MM with use of daratumumab (Lokhorst et al, 2015; Dimopoulos et al, 2016; Lonial et al, 2016; Palumbo et al, 2016). In addition, daratumumab is presently being studied in front-line regimens. Investigations into the mechanisms of daratumumab suggest it has pleiotropic effects, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and direct apoptosis by Fc-mediated crosslinking (de Weers et al, 2011). It has also been shown to target normal CD38-expressing cells, including natural killer (NK) cells and immunosuppressive regulatory cells (van de Donk et al, 2018), both populations that can be depleted in the presence of anti-CD38 therapy. It is postulated that daratumumab promotes the expansion of cytotoxic T cells with anti-MM properties (Krejcik et al, 2016). The immunomodulatory effects of daratumumab may be essential to its anti-MM effects and promote sustained responses (Usmani et al, 2018). NK cells play a key role in innate immunity and provide protection against a variety of insults, including viral pathogens. Their depletion in MM patients can be expected to have deleterious immunological effects due to the dismantling of innate immune responses in a population already strained by dysfunctional humoral and cell-mediated immunity. While it has been previously shown that NK cells decline with exposure to daratumumab (Casneuf et al, 2017), the clinical impact of such eradication on the incidence of infection has yet to be elucidated because clinical trials have shown conflicting results. The POLLUX and CASTOR trials showed generally similar rates of grade 3 or 4 infections (28·3% vs. 22·8% and 21·4% vs. 19·0%, respectively) in patients who received daratumumab-containing therapy (Dimopoulos et al, 2016; Palumbo et al, 2016). However, the recent ALCYONE trial, which compared newly diagnosed transplant-ineligible patients treated with bortezomib, melphalan and prednisone either alone (control) or with daratumumab reported that grade 3–4 infections were higher in the daratumumab arm (23·1% vs. 14·7%) (Mateos et al, 2018). We retrospectively reviewed patient records at our institution who received daratumumab-containing therapy for MM between October 2015 and December 2016 to study the occurrence of infections. Patients were divided into four groups based on treatment regimens received: (i) single agent daratumumab with dexamethasone; (ii) daratumumab plus a proteasome inhibitor (PI), immunomodulating drug (IMiD), mitogen-activated protein kinase (MEK) inhibitor or checkpoint inhibitor; (iii) daratumumab with IMiD plus PI +/− checkpoint inhibitor or cyclophosphamide; or (iv) daratumumab with combination chemotherapy. We recorded the incidence of infections and infection-related hospitalisations, nadir absolute counts of lymphocyte populations (T-helper, cytotoxic T cell, and NK cell) and 90-day survival. We employed chi-squared tests for categorical variables and student's t- tests for continuous variables to compare rates of infection and lymphodepletion between different treatment regimens. SPSS software (IBM, Armonk, NY, USA) was used for all statistical analyses. Of 171 patients reviewed, 36·5% encountered infectious complications during therapy (Fig 1A). Leucopenia was prevalent, with both neutrophil and lymphocyte counts correlating with the intensity of the treatment regimen. However, absolute CD56 counts were severely diminished regardless of whether they received single or multi-agent therapy (Fig 1B). Patients who developed an infection had statistically significant lower median nadir absolute neutrophil count (median 0·99 × 109/l, range 0–7·8 × 109/l; P = 0·04), absolute lymphocyte count (median 0·51 × 109/l, range 0–3·56 × 109/l; P < 0·0001) and CD56+ lymphocytes (median 0·024 × 109/l, range 0–0·415 × 109/l; P = 0·001) compared to patients without infection. Viral pathogens accounted for the majority of infections in all groups with the exception of the combination chemotherapy group, where they still accounted for 31% of infections (Fig 1A). Hospitalization occurred in 24% of cases, 51% of which were attributable to an infectious process. The overall 90-day survival for the cohort was 96%. In subjects who did not achieve 90-day survival (n = 12), the cause of death in 66% of cases (n = 8) was related to infections including bacterial endocarditis (n = 1), pneumonia (n = 5), or severe sepsis (n = 2). In a subset of this cohort (n = 53), complete lymphocyte panels were available for serial measurements and analysis throughout the course of treatment with daratumumab-containing therapy. Measurements were obtained as a baseline (pre-treatment) as well as after 8 doses and 16 doses, respectively. After 16 doses, a 67% increase in absolute CD8+ T-cell counts was observed (median CD8+ 0·473–0·79 × 109/l, range 0·044–2·573 × 109/l; P = 0·017), as well as an increase in the CD8/CD4 ratio by 53% (median CD8+/CD4+ 1·27 and 1·95, respectively, range 0·3–12·7; P = 0·12) (Fig 2). We have shown that infections are common in patients treated with daratumumabcontaining therapy for multiple myeloma. Such a high infection rate (36·5% in this cohort) is disconcerting and could be attributable to the depletion of NK cells in a population with already diminished humoral and cellular defences. NK cells play a key role in the defence against viral diseases, which were prominent in our cohort. Of note, marked rates of bacterial infections were also observed. Daratumumab therapy was also associated with a serial rise in CD8+ T-cells, consistent with previous observations that expansion of tumouricidal CD8+ cells is promoted by the anti-CD38 mediated depletion of immunosuppressive regulatory cells. However, functional studies of the CD8+ lymphocyte populations were not performed. It cannot be determined whether the increase in CD8 counts was a daratumumab-mediated effect or a response to infectious complications or increased immunosurveillance. While it is known that immunomodulatory effects of daratumumab play a key role in its efficacy, these effects remain incompletely understood and may potentially predispose patients to infections. Patients should be educated on appropriate precautions and anti-infective measures to prevent complications. The retrospective nature of this study and the fact that some of our patients were more heavily treated than the patients in the aforementioned clinical trials should caution the findings in our study. Nevertheless, both our findings and the clinical trial data suggest that vigilance for, and identification of, clinically relevant infections are warranted when treating patients with daratumumab. The investigation was designed by FVR, JC, MB, AK, AJ, JJ, SA and J Jo. JCR, JJ, AJ, SA and J Jo carried out the data acquisition and statistical analyses. AJ, JJ, SA, J Jo and JC drafted the paper, which was reviewed and modified by all authors. All authors viewed and approved the final version. The authors have no conflicts of interest to disclose.