Markus Hansson

In previous analyses of MAIA, daratumumab plus lenalidomide/dexamethasone (D-Rd) significantly improved progression-free survival and overall survival (OS) versus lenalidomide/dexamethasone (Rd) in transplant-ineligible newly diagnosed multiple myeloma (NDMM). We report results on long-term OS and subsequent antimyeloma therapies from the MAIA final analysis. A protocol amendment (July 20, 2021) led to a long-term extension of MAIA, during which patients were followed for OS. A total of 737 patients were randomized to D-Rd ( n = 368) or Rd ( n = 369). At a median follow-up of 89.3 months (range, 0.0–102.2; interquartile range, 85.3–93.0), median OS was 90.3 months (95% confidence interval [CI], 80.8–not estimable [NE]) with D-Rd versus 64.1 months (56.0–70.8) with Rd (hazard ratio [HR], 0.67; 95% CI, 0.55–0.82); estimated 7-year OS rates were 53.1% (95% CI, 47.8–58.2) and 39.3% (34.1–44.5), respectively. Median time to subsequent antimyeloma treatment was not reached (95% CI, 84.1–NE) for D-Rd versus 42.4 months (33.5–50.6) for Rd (HR, 0.51; 95% CI, 0.41–0.63; P < 0.0001). Death due to adverse events occurred in 84 patients (D-Rd, n = 44/364 [12%]; Rd, n = 40/365 [11%]). With >7 years of follow-up, D-Rd demonstrated a new benchmark for median OS (7.5 years) in transplant-ineligible NDMM, further supporting frontline D-Rd use to maximize survival.

B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.

Multiple myeloma (MM) is the second most common hematological malignancy, characterized by a clonal expansion of malignant plasma cells in bone marrow. Monoclonal gammopathy of undetermined significance (MGUS) is the premalignant condition of MM. The tumor microenvironment is thought to influence the progression from premalignant conditions. Myeloid‐derived suppressor cells (MDSCs) are a heterogenous group of different cellular subsets with myeloid origin, characterized by their ability to inhibit T‐cell responses. MDSC are thought to play an important immunoregulatory role in different diseases, and in many cancers their levels seem to correlate with a poor prognosis. There are three different subsets, the neutrophil‐like polymorphonuclear (PMN)‐MDSC, the monocyte‐like (M)‐MDSC, and the immature early (e)MDSC. In this study, we investigate the levels and functions of all MDSC subsets in the bone marrow of both MGUS and MM patients and compare it to blood MDSC. We found that MDSC levels are not increased in neither the blood nor bone marrow of MGUS or MM patients, and they lack strong T‐cell suppressive abilities. Blood PMN‐MDSC seems to have a small inhibitory effect, but mature neutrophils were more suppressive. Interestingly, eMDSC levels were decreased in the blood of MM patients. Our data indicate that MDSC are not key players in the pathogenesis of MM, but that mature neutrophils may be more important as they have a stronger immunoregulatory effect.

Multiple myeloma (MM) is the second most common blood malignancy, with several lines of evidence supporting an inherited genetic component. Here, we sequenced 177 affected individuals from 128 families, and 170 early-onset MM cases diagnosed before 55 years of age. Samples were identified and collected through nationwide efforts in France, Sweden, and Greece. We focused on rare germline protein truncating and likely deleterious missense variants in genes harboring variants in at least two families showing variant-disease segregation, and in additional index (≥2) and/or early-onset (≥2) cases. We identified likely pathogenic variants in ATM (N = 12), ANGPTL6 (N = 5), and FBXW9 (N = 6). Additionally, we detected variants in previously reported MM predisposition genes, including DIS3, EP300, and KDM1A. Our results represent the largest sequencing study on familial and early-onset MM to date, and further illuminate the constitutional genetic basis of MM.

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.

Objectives: Bacterial infections are common and a major cause of morbidity and mortality in multiple myeloma (MM). We have investigated the function of polymorphonuclear leukocyte (PMN), the immune system's first line of defense against bacteria, in peripheral blood (PB) and bone marrow (BM) samples from patients with newly diagnosed MM (NDMM), smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS) and healthy controls.Methods: Phagocytosis and oxidative burst in PMN cells from patients and healthy donors were investigated using PhagoTest and PhagoBurst assay.Results: PMN from NDMM, SMM, and MGUS patients had reduced phagocytosis and oxidative burst ability compared with healthy controls. The dysfunction was most prominent in BM samples from MM, SMM, and MGUS patients. Importantly the reduced phagocytosis in MM patients was restored in patients on lenalidomide therapy. Consistently the ability of Escherichia coli stimulated oxidative burst in BM was reduced for the MM, SMM, and MGUS cohort in contrast to the healthy controls and the patients on lenalidomide treatment.Conclusion: Our results show that MM patients have neutrophil dysfunction that could contribute to susceptibility for bacterial infections and that lenalidomide therapy was associated with restored PMN function.

Scarce data exist on double maintenance in transplant-eligible high-risk (HR) newly diagnosed multiple myeloma (NDMM) patients. This prospective phase 2 study enrolled 120 transplant-eligible NDMM patients. The treatment consisted of four cycles of ixazomib–lenalidomide–dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation and cytogenetic risk-based maintenance therapy with lenalidomide + ixazomib (IR) for HR patients and lenalidomide (R) alone for NHR patients. The main endpoint of the study was undetectable minimal residual disease (MRD) with sensitivity of −5 by flow cytometry at any time, and other endpoints were progression-free survival (PFS) and overall survival (OS). We present the preplanned analysis after the last patient has been two years on maintenance. At any time during protocol treatment, 28% (34/120) had MRD < 10⁻⁵ at least once. At two years on maintenance, 66% of the patients in the HR group and 76% in the NHR group were progression-free (p = 0.395) and 36% (43/120) were CR or better, of which 42% (18/43) had undetectable flow MRD −5. Altogether 95% of the patients with sustained MRD −5, 82% of the patients who turned MRD-positive, and 61% of those with positive MRD had no disease progression at two years on maintenance (p < 0.001). To conclude, prolonged maintenance with all-oral ixazomib plus lenalidomide might improve PFS in HR patients.