Browsing by Subject "Multiple Myeloma"

Now showing 1 - 5 of 5
  • Thumbnail Image
    ItemOpen Access
    Characterizing the role of the immune microenvironment in multiple myeloma progression at a single-cell level.
    (Blood advances, 2022-11) Schinke, Carolina; Poos, Alexandra M; Bauer, Michael; John, Lukas; Johnson, Sarah; Deshpande, Shayu; Carrillo, Luis; Alapat, Daisy; Rasche, Leo; Thanendrarajan, Sharmilan; Zangari, Maurizio; Al Hadidi, Samer; van Rhee, Frits; Davies, Faith; Raab, Marc S; Morgan, Gareth; Weinhold, Niels
    Early alterations within the bone marrow microenvironment that contribute to the progression of multiple myeloma (MM) from its precursor stages could be the key to identifying novel therapeutic approaches. However, the intrinsic variability in cellular populations between patients and the differences in sample processing and analysis methods have made it difficult to identify consistent changes between data sets. Here, we used single-cell RNA sequencing of bone marrow cells from precursor stages, monoclonal gammopathy of unknown significance, smoldering MM, and newly diagnosed MM and analyzed our data in combination with a previously published data set that used a similar patient population and sample processing. Despite the vast interpatient heterogeneity, some alterations were consistently observed in both data sets. We identified changes in immune cell populations as the disease progressed, which were characterized by a substantial decrease in memory and naïve CD4 T cells, and an increase in CD8+ effector T cells and T-regulatory cells. These alterations were further accompanied by an enrichment of nonclonal memory B cells and an increase in CD14 and CD16 monocytes in MM compared with its precursor stages. These results provide crucial information on the immune changes associated with the progression to clinical MM and can help to develop immune-based strategies for patient stratification and early therapeutic intervention.
  • Thumbnail Image
    ItemOpen Access
    Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial.
    (Nature medicine, 2023-10) Bahlis, Nizar J; Costello, Caitlin L; Raje, Noopur S; Levy, Moshe Y; Dholaria, Bhagirathbhai; Solh, Melhem; Tomasson, Michael H; Damore, Michael A; Jiang, Sibo; Basu, Cynthia; Skoura, Athanasia; Chan, Edward M; Trudel, Suzanne; Jakubowiak, Andrzej; Gasparetto, Cristina; Chu, Michael P; Dalovisio, Andrew; Sebag, Michael; Lesokhin, Alexander M
    Multiple myeloma (MM) is a plasma cell malignancy expressing B cell maturation antigen (BCMA). Elranatamab, a bispecific antibody, engages BCMA on MM and CD3 on T cells. The MagnetisMM-1 trial evaluated its safety, pharmacokinetics and efficacy. Primary endpoints, including the incidence of dose-limiting toxicities as well as objective response rate (ORR) and duration of response (DOR), were met. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Eighty-eight patients with relapsed or refractory MM received elranatamab monotherapy, and 55 patients received elranatamab at efficacious doses. Patients had received a median of five prior regimens; 90.9% were triple-class refractory, 29.1% had high cytogenetic risk and 23.6% received prior BCMA-directed therapy. No dose-limiting toxicities were observed during dose escalation. Adverse events included cytopenias and cytokine release syndrome. Exposure was dose proportional. With a median follow-up of 12.0 months, the ORR was 63.6% and 38.2% of patients achieving complete response or better. For responders, the median DOR was 17.1 months. All 13 patients evaluable for minimal residual disease achieved negativity. Even after prior BCMA-directed therapy, 53.8% achieved response. For all 55 patients, median PFS was 11.8 months, and median OS was 21.2 months. Elranatamab achieved durable responses, manageable safety and promising survival for patients with MM. ClinicalTrials.gov Identifier: NCT03269136 .
  • Thumbnail Image
    ItemOpen Access
    Expanding anti-CD38 immunotherapy for lymphoid malignancies.
    (Journal of experimental & clinical cancer research : CR, 2022-06-28) Wang, Xu; Yu, Xinfang; Li, Wei; Neeli, Praveen; Liu, Ming; Li, Ling; Zhang, Mingzhi; Fang, Xiaosheng; Young, Ken H; Li, Yong

    Background

    Lymphoid neoplasms, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and NK/T cell neoplasms, are a major cause of blood cancer morbidity and mortality. CD38 (cyclic ADP ribose hydrolase) is a transmembrane glycoprotein expressed on the surface of plasma cells and MM cells. The high expression of CD38 across MM and other lymphoid malignancies and its restricted expression in normal tissues make CD38 an attractive target for immunotherapy. CD38-targeting antibodies, like daratumumab, have been approved for the treatment of MM and tested against lymphoma and leukemia in multiple clinical trials.

    Methods

    We generated chimeric antigen receptor (CAR) T cells targeting CD38 and tested its cytotoxicity against multiple CD38high and CD38low lymphoid cancer cells. We evaluated the synergistic effects of all-trans retinoic acid (ATRA) and CAR T cells or daratumumab against cancer cells and xenograft tumors.

    Results

    CD38-CAR T cells dramatically inhibited the growth of CD38high MM, mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), T-cell acute lymphoblastic leukemia (T-ALL), and NK/T-cell lymphoma (NKTCL) in vitro and in mouse xenografts. ATRA elevated CD38 expression in multiple CD38low cancer cells and enhanced the anti-tumor activity of daratumumab and CD38-CAR T cells in xenograft tumors.

    Conclusions

    These findings may expand anti-CD38 immunotherapy to a broad spectrum of lymphoid malignancies and call for the incorporation of ATRA into daratumumab or other anti-CD38 immunological agents for cancer therapy.
  • Thumbnail Image
    ItemOpen Access
    Inhibition of Sphingosine Kinase 2 Results in PARK2-Mediated Mitophagy and Induces Apoptosis in Multiple Myeloma.
    (Current oncology (Toronto, Ont.), 2023-03) Wu, Jian; Fan, Shengjun; Feinberg, Daniel; Wang, Xiaobei; Jabbar, Shaima; Kang, Yubin
    Mitophagy plays an important role in maintaining mitochondrial homeostasis by clearing damaged mitochondria. Sphingosine kinase 2 (SK2), a type of sphingosine kinase, is an important metabolic enzyme involved in generating sphingosine-1-phosphate. Its expression level is elevated in many cancers and is associated with poor clinical outcomes. However, the relationship between SK2 and mitochondrial dysfunction remains unclear. We found that the genetic downregulation of SK2 or treatment with ABC294640, a specific inhibitor of SK2, induced mitophagy and apoptosis in multiple myeloma cell lines. We showed that mitophagy correlates with apoptosis induction and likely occurs through the SET/PP2AC/PARK2 pathway, where inhibiting PP2AC activity may rescue this process. Furthermore, we found that PP2AC and PARK2 form a complex, suggesting that they might regulate mitophagy through protein-protein interactions. Our study demonstrates the important role of SK2 in regulating mitophagy and provides new insights into the mechanism of mitophagy in multiple myeloma.
  • Thumbnail Image
    ItemOpen Access
    Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma in Older Adults.
    (Clin Geriatr Med, 2016-02) Guerard, Emily J; Tuchman, Sascha A
    Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are plasma cell disorders of aging. The landscape of the diagnosis and management of MM and MGUS are rapidly changing. This article provides an updated understanding of the clinical presentation, evaluation, diagnosis, and management of older adults with MM and MGUS. Because most oncology providers are not formally trained in geriatric medicine, geriatricians play a key role in providing oncologists with a broader understanding of patient health status in the hope of improving outcomes for older adults with MM.