A natural head start to MRD negativity in multiple myeloma Free

In this issue of Blood, Korst and colleagues leverage large patient cohorts and single-cell technologies to illuminate how the composition of natural killer (NK) cells in bone marrow (BM) impacts clinical outcomes of daratumumab-based regimens in newly diagnosed multiple myeloma (MM).¹ 

MM is a cancer of plasma cells in the bone marrow and is associated with a progressive decline in overall immune function and decreased immunosurveillance. Currently, there is momentum to improve combination regimens for the treatment of patients with MM, especially focused on optimal integration of immunotherapy, the efficacy of which depends upon overall immune function. Frontline CD38-targeting immunotherapy (daratumumab)-based triplet and quadruplet standard-of-care regimens have demonstrated improved survival outcomes in newly diagnosed multiple myeloma (NDMM).^2-4 Thus, identifying immune biomarkers predictive of response to immunotherapies in patients with MM, especially to daratumumab in the newly diagnosed phase, could be high impact to inform treatment regimens.

NK cells are innate cytotoxic lymphocytes that play pivotal roles in cancer immunosurveillance. They also play integral roles in many anti-MM therapies, including monoclonal antibodies, proteasome inhibitors, and immunomodulatory drugs, and are in development as effectors for multispecifics and chimeric antigen therapy–based biotechnologies. NK cells provide direct and indirect anti-MM immunity through killing mechanisms like antibody-dependent cellular cytotoxicity and cytokine production. Notably, several recent studies have discovered how the abundance or specific profiles of NK cells in patients with NDMM⁵ or relapsed or refractory MM correlate with response to daratumumab-based regimens.^6,7 Korst et al builds upon this foundation by assessing function of NK cells in NDMM, and utilizing patient samples from multiple phases of the double-randomized CASSIOPEIA trial to link NK-cell states to achievement of MRD negativity.

In their study, Korst et al provide 2 single-cell, high-parameter immune-profiling atlases of NK cells in patients with MM. First, a single-cell RNA-seq data set of BM-derived NK cells generated from 19 patients with NDMM and 5 healthy controls is presented. Differential gene expression clarified 7 major NK cell clusters as largely “cytotoxic” or “cytokine-producing.” These clusters were delineated by FCGR3A (CD16, a key mediator on NK cells for cytotoxic activity), type of granzyme (B/K), and level of NCAM1 (CD56). Cytotoxic NK cells were the most common type in healthy individuals and many patients with NDMM. However, there was a striking stepwise pattern across NDMM patients with increasing abundance of cytokine-producing/low-cytotoxicity cells, referred to as “skewed” composition.

Next, to understand whether NK-cell subtypes were conserved across patients with normal and skewed composition, the authors investigated whether each cluster’s transcriptional program and predicted interactions with MM tumor were maintained. Indeed, similar patterns were present, suggesting that patients exhibiting a skewed NK composition at diagnosis had the lowest cytotoxic potential. To validate these observations functionally and in the context of therapeutic antibodies, the authors cocultured NK cells with daratumumab-labeled MM cell lines or a positive control to induce activation. NK cells from patients with a skewed composition showed compromised cytotoxicity and cytokine production, specifically in response to daratumumab but not the positive control. It remains to be determined why this defect occurs specifically in response to daratumumab. Thus, studies into NK crosstalk with the tumor or its microenvironment could be fruitful.

The authors also explored the clinical implications of NK cell composition within patients enrolled in the CASSIOPEIA trial, which was a 2-part randomized trial to test the addition of daratumumab to induction and consolidation (bortezomib-thalidomide-dexamethasone, VTd), and maintenance phases of treatment for patients with NDMM.³ Using baseline BM and blood from over 100 patients, they profiled the NK compartment using flow cytometry to determine whether subtypes correlated with the clinical outcome of minimal residual disease (MRD) status 100 days post–autologous stem cell transplant, which is the strongest prognostic factor for progression-free survival and overall survival (see figure). The authors found that patients treated with daratumumab-VTd (D-VTd) who achieved MRD negativity had more CD16⁺ BM NK cells at baseline. In multivariate analysis to consider clinical variables, CD16⁺, and DNAM1⁺ BM NK cells were independently associated with MRD negativity. It is of interest that this immune correlate was found in BM but not in the blood. The authors speculated that BM-infiltrating NK cells are more likely to impact clinical outcomes as this is the site of immune responses and interactions with the tumor. Furthermore, although MRD negativity is supported as an early end point in clinical trials, additional studies are needed to identify the impact of NK cell composition on survival outcomes.

Next, the authors investigated whether NK-cell compositions fluctuate in transient or permanent patterns in response to daratumumab, which may have a clinical impact on subsequent NK cell–dependent therapies. They confirmed that, during D-VTd treatment, the number of CD16⁺ cytotoxic NK cells decreased, presumably by fratricide, whereas “cytokine-producing” subtypes became more abundant. Importantly, they observed recovery of the cytotoxic CD16⁺ subset by evaluating blood from patients randomized to D-VTd followed by observation (in contrast to daratumumab maintenance).

This robust study by Korst and colleagues addresses clinically relevant and timely questions pertaining to using NK composition as an immune biomarker for potentially predicting responses to anti-MM therapies that rely on NK cytotoxicity, like daratumumab. It also raises additional pertinent questions. Given the recent landmark study that dissected the tumor intrinsic factors contributing to MM immune evasion of NK cell–mediated killing,⁸ how much of those mechanisms are involved in resistance to daratumumab-containing regimens? Given that MM predominantly affects the older population, to what extent does innate immunosenescence and aging⁹ contribute to the efficacy of monoclonal antibodies? May the compositional changes identified here be more broadly informative to other regimens containing anti-CD38 monoclonal antibodies and allow for improved stratification of patients based on immune components?

Conflict-of-interest disclosure: E.W.M. declares no competing financial interests.