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The addition of subcutaneous daratumumab to bortezomib, lenalidomide, and dexamethasone therapy and to lenalidomide maintenance therapy had a significant benefit on progression-free survival among patients with multiple myeloma.

Daratumumab was associated with impressive antitumor responses, including complete and very good partial responses, in heavily pretreated patients with myeloma. Infusion reactions were the main adverse effect. Current therapies, including proteasome inhibitors and immunomodulatory agents, have improved outcomes substantially in patients with multiple myeloma. 1 Unfortunately, the majority of these patients have a relapse and have limited treatment options after exposure to these classes of agents. 2 , 3 Patients with disease that is refractory to both proteasome inhibitors and immunomodulatory drugs have poor prognoses; the estimated median overall survival is 9 months, and the estimated event-free survival is 5 months at best. 2 , 3 CD38 is a 45-kD, type II transmembrane glycoprotein that associates with cell-surface receptors in lipid rafts, regulates cytoplasmic Ca 2+ flux, and mediates signal transduction in lymphoid . . .

Chimeric antigen receptors (CARs) can effectively redirect cytotoxic T cells toward highly expressed surface antigens on tumor cells. The low expression of several tumor-associated antigens (TAAs) on normal tissues, however, hinders their safe targeting by CAR T cells due to on-target/off-tumor effects. Using the multiple myeloma (MM)-associated CD38 antigen as a model system, here, we present a rational approach for effective and tumor-selective targeting of such TAAs. Using “light-chain exchange” technology, we combined the heavy chains of two high-affinity CD38 antibodies with 176 germline light chains and generated ∼124 new antibodies with 10- to >1,000-fold lower affinities to CD38. After categorizing them into three distinct affinity classes, we incorporated the single-chain variable fragments of eight antibodies from each class into new CARs. T cells carrying these CD38-CARs were extensively evaluated for their on-tumor/off-tumor cytotoxicity as well as CD38-dependent proliferation and cytokine production. We identified CD38-CAR T cells of ∼1,000- fold reduced affinity, which optimally proliferated, produced Th1-like cytokines, and effectively lysed CD382+ MM cells, but spared CD38+ healthy hematopoietic cells in vitro and in vivo. Thus, this systematic approach is highly suitable for the generation of optimal CARs for effective and selective targeting of TAAs. Drent et al. used the light-chain exchange method to identify CD38-CAR T cells of reduced affinity, which effectively lysed multiple myeloma cells but spared healthy hematopoietic cells, in vitro and in vivo. This paper proposes a rational strategy for the selective targeting of tumor-associated antigens by CAR T cells.

CD38-targeted antibody, daratumumab, is approved for the treatment of multiple myeloma (MM). Phase 1/2 studies GEN501/SIRIUS revealed a novel immunomodulatory mechanism of action (MOA) of daratumumab that enhanced the immune response, reducing natural killer (NK) cells without affecting efficacy or safety. We further evaluated daratumumab’s effects on immune cells in whole blood samples of relapsed/refractory MM patients from both treatment arms of the phase 3 POLLUX study (lenalidomide/dexamethasone [Rd] or daratumumab plus Rd [D-Rd]) at baseline (D-Rd, 40; Rd, 45) and after 2 months on treatment (D-Rd, 31; Rd, 33) using cytometry by time-of-flight. We confirmed previous reports of NK cell reduction with D-Rd. Persisting NK cells were phenotypically distinct, with increased expression of HLA-DR, CD69, CD127, and CD27. The proportion of T cells increased preferentially in deep responders to D-Rd, with a higher proportion of CD8 + versus CD4 + T cells. The expansion of CD8 + T cells correlated with clonality, indicating generation of adaptive immune response with D-Rd. D-Rd resulted in a higher proportion of effector memory T cells versus Rd. D-Rd reduced immunosuppressive CD38 + regulatory T cells. This study confirms daratumumab’s immunomodulatory MOA in combination with immunomodulatory drugs and provides further insight into immune cell changes and activation status following daratumumab-based therapy.

Although recent decades have seen continued improvements in survival for patients with multiple myeloma, the disease remains largely incurable, and most patients will experience relapse and/or become refractory to treatment. There thus remains an urgent unmet need for novel treatments, particularly for those patients with relapsed or refractory multiple myeloma. Novel treatment modalities, such as targeted protein degradation, have attracted particular interest due to their ability to expand the range of druggable protein targets in myeloma cells. Iberdomide (CC-220) and mezigdomide (CC-92480) are promising oral CELMoD™ agents currently being evaluated for the treatment of patients with multiple myeloma. Preclinical data from lenalidomide- and pomalidomide-resistant cell lines and mouse models suggest that iberdomide and mezigdomide have the potential to provide therapeutic benefit even in patients who are refractory to lenalidomide and pomalidomide. The optimized specificity, potency, and safety profile of iberdomide and mezigdomide supports their clinical use and aligns with the need for longer durations of a well-tolerated oral CELMoD agent with synergistic combinability with other immune approaches (such as anti-CD38 monoclonal antibodies) and proteasome inhibitors (such as bortezomib and carfilzomib). Although neither iberdomide or mezigdomide has yet received regulatory approval for the treatment of multiple myeloma, based on their mechanism of action and the data available to date, we propose that both drugs may be attractive options for the treatment of patients with relapsed or refractory multiple myeloma; based on their efficacy and safety profiles, iberdomide is likely better suited for use in newly diagnosed, first relapse, or maintenance settings, whereas mezigdomide may also be better suited for use in patients with early relapse or a greater number of prior antimyeloma treatments. Iberdomide and mezigdomide are currently being evaluated for the treatment of patients with multiple myeloma in several trials, and results so far are promising.

T-cell-engaging bispecific antibodies (BsAbs) simultaneously bind to antigens on tumour cells and CD3 subunits on T cells. This simultaneous binding results in the recruitment of T cells to the tumour, followed by T-cell activation and degranulation, and tumour cell elimination. T-cell-engaging BsAbs have shown substantial activity in several haematological malignancies by targeting CD19 in acute lymphoblastic leukaemia, CD20 in B-cell non-Hodgkin lymphoma, and BCMA and GPRC5D in multiple myeloma. Progress with solid tumours has been slower, in part due to the paucity of therapeutic targets with a tumour-specific expression profile, which is needed to limit on-target off-tumour side-effects. Nevertheless, BsAb-mediated recognition of a peptide fragment of gp100 presented by HLA-A2:01 molecules has shown marked activity in patients with unresectable or metastatic uveal melanoma. Cytokine release syndrome is the most frequent toxicity associated with BsAb treatment and is caused by activated T cells secreting proinflammatory cytokines. Understanding of resistance mechanisms has resulted in the development of new T cell-redirecting formats and novel combination strategies, which are expected to further improve depth and duration of response.

Multiple myeloma is the second most common haematological malignancy in high-income countries, and typically starts as asymptomatic precursor conditions—either monoclonal gammopathy of undetermined significance or smouldering multiple myeloma—in which initiating genetic abnormalities, such as hyperdiploidy and translocations involving the immunoglobulin heavy chain, are already present. The introduction of immunomodulatory drugs, proteasome inhibitors, and CD38-targeting antibodies has extended survival, but ultimately the majority of patients will die from their disease, and some from treatment-related complications. Disease progression and subsequent relapses are characterised by subclonal evolution and increasingly resistant disease. Patients with multiple myeloma usually have hypercalcaemia, renal failure, anaemia, or osteolytic bone lesions—and a detailed diagnostic investigation is needed to differentiate between symptomatic multiple myeloma that requires treatment, and precursor states. Risk stratification using both patient-specific (eg, performance status) and disease-specific (eg, presence of high-risk cytogenetic abnormalities) is important for prognosis and to define the best treatment strategy. Current research strategies include the use of minimal residual disease assays to guide therapy, refining immunotherapeutic approaches, and intercepting disease early in smouldering multiple myeloma.

Immunofixation of the peripheral blood showed immunoglobulin M (IgM) κ paraproteinemia of 4.1 g/L with free κ light chain of 10.0 mg/dl and free λ light chain of 26.9 mg/dl, κ/λ ratio of 0.37 and differential free light chain (dFLC) of 16.9 mg/dl. Kidney biopsy was performed and showed subtle enhancement of mesangial areas by light microscopy (Figure 1A), suggestive of depositions, with immunofluorescence demonstrating IgM heavy chain as well as λ light chain deposition (Figure 1C,D). (A): Light microscopy with Jones silver-stained (x40); (B): Electron microscopy; (C): Immunofluorescence with IgM staining; (D): Immunofluorescence with lambda light chain enhancement (Immunofluorescence for kappa, IgG, IgA and complement was negative) Kidney involvement in WM is rare (estimated prevalence 5%) and presents with a wide range of nephropathology.

In this phase 1–2 study involving patients with relapsed or refractory myeloma, a bispecific antibody (teclistamab) that mediates T-cell activation and subsequent lysis of myeloma cells expressing B-cell maturation antigen induced responses in 63% of the patients, including a complete response in nearly 40%.