Sandra P. Susanibar-Adaniya

Diffuse large B cell lymphoma (DLBCL), the most common type of Non-Hodgkin lymphoma (NHL), comprises a heterogeneous group of diseases with different biology, clinical presentations, and response to treatment. R-CHOP remains the mainstay of therapy and can achieve long-term disease control in nearly 90% of patients presenting with limited-stage and in up to 60% of those presenting with advanced stages. Advances on the understanding of the genetic landscape and molecular features of DLBCL have identified high-risk subsets with poor outcomes to chemo-immunotherapy that are actively being studied in clinical trials. Novel therapies could potentially improve outcomes for patients with high-risk disease. Studies evaluating risk-adapted therapy based on classification by cell of origin (COO) and molecular features are ongoing. Developments in the fields of immunotherapy, mostly with adoptive T-cell therapy, have significantly improved the outcomes of patients with relapsed refractory disease. In this review, we will summarize the recent data and discuss ongoing efforts to improve DLBCL treatment in the frontline and relapsed refractory settings.

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)-negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment. SIGNIFICANCE: CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy. This article is highlighted in the In This Issue feature, p. 101.

Light chain deposition disease (LCDD) is characterized by monotypic immunoglobulin depositions which will eventually lead to loss of organ function if left untreated. While the kidney is almost always affected, the presence and degree of LCDD in other organs vary. Ten to thirty percent of LCDD patients have underlying Multiple Myeloma (MM), yet outcome and prognostic markers in this particular patient group are still lacking. Here, we analyzed 69 patients with MM and biopsy proven LCDD and report on renal and extra-renal involvement and its impact on prognosis as well as renal response depending on hematologic response. Coexisting light chain diseases such as AL amyloid and cast nephropathy were found in 30% of patients; those with LCDD and concurrent amyloid tended to have shorter survival. Cardiac involvement by LCDD was seen in one-third of our patients and was associated with shorter overall survival; such patients also had a significantly higher risk of treatment-related mortality (TRM) after stem cell transplant (SCT) compared to LCDD patients without cardiac involvement. This study highlights that MM patients with LCDD present with different clinical features compared to previously reported LCDD cohorts. Rapid initiation of treatment is necessary to prevent progressive renal disease and worse outcome. Coexisting light chain diseases and cardiac involvement are more common than previously reported and confer worse clinical outcome, emphasizing the need for careful patient careful patient evaluation and treatment selection.

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.