This is a preview of subscription content, access via your institution. Halapi E, et al. Guillerey C, Nakamura K, Vuckovic S, Hill GR, Smyth MJ. Multiple myeloma is complicated by organ dysfunction: hypercalcaemia, renal insufficiency, anaemia, and bone destruction (known as the CRAB criteria). FD declares that she has no competing interests. The most successful combination to date is the administration of a DC/myeloma fusion vaccination after ASCT (140). McLellan AD, Ali Hosseini Rad SM. Marrow infiltrating lymphocytes: their role in adoptive immunotherapy. We now have a wide range of active agents to choose from for the treatment of myeloma, and while many of these are immunostimulatory (e.g., IMiDs, elotuzumab), many are immunosuppressive (e.g., dexamethasone, proteasome inhibitors). [2]Kyle RA, Rajkumar SV. Dysregulated IL-18 is a key driver of immunosuppression and a possible therapeutic target in the multiple myeloma microenvironment. The cancer’s spread in the body, how a patient likely will respond to treatment factors, blood levels of certain proteins and other substances, kidney function, the patient’s age and overall health -- all indicate how well a patient will do during therapy. Calcinotto A, et al. Leukemia. Nat Rev Cancer. Boosting cancer immunotherapy with anti-CD137 antibody therapy. and JavaScript. Therapeutic efficacy of 4-1BB costimulation is abrogated by PD-1 blockade in a model of spontaneous B-cell lymphoma. Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma. Consistent with this, aberrant IL-6 levels in the myeloma milieu have been associated with dysfunctional antigen presentation (63, 69). As a library, NLM provides access to scientific literature. Outlook. PubMed Central  Arce Vargas F, et al. http://www.ncbi.nlm.nih.gov/pubmed/15509819?tool=bestpractice.com Definition. Indeed, several key immunological changes associated with ASCT suggest that disease plateau after transplant may arise from more than just cytoreduction. In a murine myeloma model, adoptive transfer of MILs resulted in superior survival compared with peripheral blood lymphocytes (130). Download our free mobile app — exclusively for physicians and physician offices — for direct access to a directory of Roswell Park physicians. For MM patients, common first-line drug . It is important to note that the Vk*MYC model of myeloma used in these preclinical studies generates similar disease to that in patients, with lytic lesions, renal impairment, clonal plasma cell expansion, and associated M bands (27). Guillerey C, et al. Surprisingly, in patients with myeloma, alloreactive T cells are limited in their ability to generate a potent graft-versus-myeloma (GVM) response, and allo-SCT is not used in this patient cohort outside of clinical trials. “When patients are in a so-called maintenance phase, they often can live an otherwise normal life,” he says. Gormley NJ, Pazdur R. Immunotherapy combinations in multiple myeloma — known unknowns. Importantly, myeloma progression has been associated with accumulation of CSF-1R–expressing macrophages in preclinical studies, and targeting these populations using CSF-1R–blocking antibodies has proven effective, particularly after ASCT (14, 82, 85). Shi X, et al. Initiation of chemotherapy and assessment of eligibility for autologous stem cell transplantation require referral to an oncologist. The curative potential of allo-SCT is largely mediated by alloreactive T cells, referred to as the graft-versus-leukemia effect (125). Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing. Signatures of mutational processes in human cancer. These cells displayed markers for both exhaustion and senescence, possibly representing a composite state of dysfunction. Multiple myeloma is diagnosed in an estimated 34 920 people in the US and in approximately 588 161 people worldwide each year. MM typically causes end-organ damage consisting of anemia, renal impairment, lytic bony lesions, and hypercalcemia (1). doi: 10.1002/ccr3.7069. Hanahan D, Weinberg RA. Several studies suggest that DCs from patients with myeloma are not only dysfunctional, but also promote myeloma cell survival and may be key determinants of the progression from MGUS to active myeloma (63–66). Mateos MV, et al. Thus, extrinsic factors are likely an additional determinant of subclonal evolution and progression from premalignant states to clinical myeloma (17). Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies. In November 2022, FasTCAR was named the winner of the Biotech Innovation category of the 2022 Fierce Life Sciences Innovation Awards for its ability to address major industry obstacles. These data suggest that alternative mechanisms may underpin responses after ASCT, although this has yet to be definitively investigated in a clinical setting. In those with MGUS, myeloma or another cancer develops at a rate of 1% per year. Notably, the patients with 12-month sustained MRD negativity demonstrated an estimated PFS of 100% at 36 months, reinforcing the clinical importance of achieving a deep response. Bailur JK, et al. Furthermore, in a small clinical trial with 25 patients, an approximately 30% CR rate was observed in patients receiving MILs early after ASCT, and median overall survival had not been reached at 7 years (130). A preclinical study using a bortezomib-resistant Vk*MYC myeloma clone demonstrated a synergistic antitumor effect with coadministration of bortezomib and reovirus (113). New immunotherapies based on checkpoint inhibition targeting the immune receptor TIGIT and the deletion of suppressive myeloid populations appear attractive, particularly after ASCT. Tigit, CD226 and PD-L1/PD-1 are highly expressed by marrow-infiltrating T cells in patients with multiple myeloma. Blood Cancer J. Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden. Daratumumab, a fully human mAb that binds to CD38, also has FDA approval for previously treated myeloma patients after several phase III trials demonstrated strikingly improved outcomes for RRMM patients in the daratumumab arms when it was administered in combination with dexamethasone and lenalidomide ({"type":"clinical-trial","attrs":{"text":"NCT02076009","term_id":"NCT02076009"}}NCT02076009) (109) or bortezomib ({"type":"clinical-trial","attrs":{"text":"NCT02136134","term_id":"NCT02136134"}}NCT02136134) (110). 2019;10:3835. Lenalidomide enhances anti-myeloma cellular immunity. Smoldering multiple myeloma (SMM) is a second precursor state of active MM wherein patients have higher frequencies of BM clonal plasma cells than do MGUS patients, but have yet to develop symptoms of myeloma-related end-organ damage (5). Alterations in the antigen processing-presenting machinery of transformed plasma cells are associated with reduced recognition by CD8. Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, et al. D’Souza A, et al. About Multiple Myeloma Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow. Bolli N, Maura F, Minvielle S, Gloznik D, Szalat R, Fullam A, et al. Peripheral γδ T-lymphocytes as an innovative tool in immunotherapy for metastatic renal cell carcinoma. Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial). Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Elotuzumab, described above, showed clinical efficacy in combination with IMiDs and dexamethasone and is FDA-approved for use in previously treated myeloma patients (103). Use of immunotherapy in myeloma patients has had a somewhat tumultuous start, with early clinical studies reporting a lack of efficacy of nivolumab monotherapy (87). Notably, the rate of CRs increased dramatically between day 100 and 1 year after vaccination, in the absence of other maintenance therapy. Dispenzieri A, Stewart AK, Chanan-Khan A, Rajkumar SV, Kyle RA, Fonseca R, et al. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: updated results of a first-in-human (FIH) phase I dose escalation study. Elimination is mediated by collaboration of the adaptive and the innate immunity to eradicate malignant cells prior to the onset of clinical presentation. 2019;3:2400–8. N Engl J Med. [Figure caption and citation for the preceding image starts]: A: serum protein electrophoresis demonstrating the M component. JAMA Oncol. Malignant transformation is a consequence of a combination of factors including both primary and secondary genetic events, genetic heterogeneity with subsequent clonal evolution, and changes in the BM microenvironment (6, 7). Bone marrow transplantation generates T cell-dependent control of myeloma in mice. Br J Haematol. “Since most symptoms myeloma patients have are either pain from bone destruction or side effects from treatment, pain management and treatment of neuropathic pain are the most important symptomatic treatments. T cell exhaustion and a suppressive bone marrow microenvironment have been implicated in disease progression, and once these are established, immunotherapy appears largely ineffective. 2016;175:623–30. Global burden of multiple myeloma: a systematic analysis for the Global Burden of Disease Study 2016. 2009;113:5412–7. In multiple myeloma, cancerous plasma cells accumulate in the bone marrow and crowd out healthy blood cells. Google Scholar. Palumbo A, et al. Introduction. Br J Cancer. Zheng Y, et al. Attal M, et al. To date, the field has combined agents without a clear regard for the immunological consequences and has largely taken a “more agents is better” approach. Cell. Brimnes MK, et al. Google Scholar. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Serody JS, Hill GR. 17 February 2023, Scientific Reports Multiple myeloma experts at the Johns Hopkins Kimmel Cancer Center have two main research interests in developing new therapies: (1) Medications that target multiple myeloma stem cells: Dr. William Matsui's research laboratory in 2004 was the first to identify multiple myeloma stem cells, and then demonstrate that these cells were relatively . Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. Defining ‘T cell exhaustion’. 2015;5:e365. To obtain Autologous stem cell transplantation (ASCT) disrupts the tumor microenvironment (TME), directly eliminates myeloma cells, and promotes T cell–mediated antimyeloma responses. 2013;369:438–47. Gámez B, Edwards CM. Durie BG, Kyle RA, Belch A, Bensinger W, Blade J, Boccadoro M, et al. FOIA Multiple myeloma Approximate Synonyms Hypogammaglobulinemia co-occurrent and due to multiple myeloma Light chain disease Light chain nephropathy Light chain nephropathy due to multiple myeloma Multiple myeloma Multiple myeloma stage i Multiple myeloma stage ii Multiple myeloma stage iii Multiple myeloma w hypogammaglobulinemia Leukemia. Nat Commun. npj Vaccines. No Grade 4/5 CRS events occurred; No neurotoxicity or immune effector cell-associated toxicity (ICANS) of any grade was observed. Beyond the current standard of care therapy at Roswell Park, Dr. Hillengass and his colleagues focus on offering treatments using the patient’s own immune system as it is or with cellular therapies, in which cells of the immune system are manipulated to be able to fight the cancer again. [Multiple Myeloma - Current Status in Diagnostic Testing and Therapy]. IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos. 2014;5:2997. 2003;4:379–98. Dhodapkar MV, et al. June 5, 2023 Order Reprints Print Article Whole-exome sequencing of paired patient samples collected at diagnosis of MGUS/SMM and again at MM found that most somatic mutations preceded diagnosis of clinical MM (16, 17), suggesting that although genetic mutations are necessary for tumorigenesis, they are not sufficient for transformation of myeloma. Leukemia 34, 3111–3125 (2020). Blood Cancer Journal ASCT remains an effective therapy for eligible patients and provides a survival benefit beyond novel agents alone (116–119). BCMA-targeted CAR T cells have produced very promising results in phase I clinical trials in RRMM patients, with many reporting ORRs of 64%–88% in this historically difficult-to-treat patient cohort ({"type":"clinical-trial","attrs":{"text":"NCT03090659","term_id":"NCT03090659"}}NCT03090659, {"type":"clinical-trial","attrs":{"text":"NCT03093168","term_id":"NCT03093168"}}NCT03093168, {"type":"clinical-trial","attrs":{"text":"NCT03288493","term_id":"NCT03288493"}}NCT03288493, {"type":"clinical-trial","attrs":{"text":"NCT03318861","term_id":"NCT03318861"}}NCT03318861, {"type":"clinical-trial","attrs":{"text":"NCT02658929","term_id":"NCT02658929"}}NCT02658929, {"type":"clinical-trial","attrs":{"text":"NCT02215967","term_id":"NCT02215967"}}NCT02215967) (156–158). Patient population with multiple myeloma and transitions across different lines of therapy in the USA: an epidemiologic model. FasTCAR is designed to lead the next generation of therapy for cancer and autoimmune diseases, and improve outcomes for patients by enhancing effect, reducing costs, and enabling more patients to access critical CAR-T treatment. It is important to note that BiTEs rely on the presence of a functional T cell response, and this therapy is likely to be most efficacious after ASCT or in newly diagnosed patients. Br J Haematol. Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. cancer center/ cancer a-z list/symptom checker/multiple myeloma symptoms and signs symptoms. Parrish C, Scott GB, Coffey M, Melcher A, Errington-Mais F, Cook G. Combination therapy with reovirus and immunomodulatory drugs induces direct oncolytic and immune-mediated killing of multiple myeloma cells and overcomes stromal-mediated microenvironmental protection. Plasma cells normally produce our antibodies. Nooka AK, Wang ML, Yee AJ, Kaufman JL, Bae J, Peterkin D, et al. Cherry BM, Korde N, Kwok M, Manasanch EE, Bhutani M, Mulquin M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Interestingly, MM often progresses from a premalignant state, monoclonal gammopathy of undetermined significance (MGUS), that displays a lifelong rate of progression of 1% per year (3, 4). Multiple myeloma is a haematological cancer characterised by clonal proliferation of plasma cells in the bone marrow, and typically associated with a monoclonal component in the serum and/or urine. Best Pr Res Clin Haematol. Clinical trials are currently ongoing of daratumumab and nivolumab/pembrolizumab in RRMM patients, and results are eagerly awaited ({"type":"clinical-trial","attrs":{"text":"NCT02431208","term_id":"NCT02431208"}}NCT02431208, {"type":"clinical-trial","attrs":{"text":"NCT01592370","term_id":"NCT01592370"}}NCT01592370, {"type":"clinical-trial","attrs":{"text":"NCT03357952","term_id":"NCT03357952"}}NCT03357952). Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. Furthermore, both IFN-γ production and CD107a production are decreased in mice with high myeloma burdens, and loss of effector function correlated with disease progression (14, 26). 2001;67:158–64. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. National Library of Medicine ??accessibility.screen-reader.external-link_en_US?? Aschan J, Lönnqvist B, Ringdén O, Kumlien G, Gahrton G. Graft-versus-myeloma effect. SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7. Consistent with this, the mutational burden of MGUS/SMM patients who did not progress to MM was found to be equivalent to the mutational burden of progressors (18). Overview. Tests used to establish a diagnosis include serum and urine protein electrophoresis, serum and urine immunofixation, serum free light-chain assay, bone marrow examination, and whole-body low-dose computed tomography or skeletal survey. Furthermore, a large prospective study found that allografting patients with myeloma did not provide a survival advantage above ASCT, and relapse remained the major cause of death (48%) (128). Safety and efficacy of targeting CD138 with a chimeric antigen receptor for the treatment of multiple myeloma. Email or call to refer a patient or ask a question with a click of a button. Walker BA, Wardell CP, Melchor L, Brioli A, Johnson DC, Kaiser MF, et al. Hallmarks of cancer: the next generation. Clipboard, Search History, and several other advanced features are temporarily unavailable. N Engl J Med. Myeloma Group of Western Sweden. Cooperative Group of Study and Treatment of Multiple Myeloma. Manz RA, Thiel A, Radbruch A. Landgren O, et al. Kidney involvement and renal manifestations in non-Hodgkin’s lymphoma and lymphocytic leukemia: a retrospective study in 700 patients. How to train your T cells: overcoming immune dysfunction in multiple myeloma. PLoS ONE. Bahlis NJ, et al. Cancer. Interestingly, although daratumumab targets CD38+ myeloma cells, it also depletes suppressive CD38+ Tregs and myeloid populations. HHS Vulnerability Disclosure, Help 2003;121:749–57. See additional information. Targeting multiple myeloma with AMG 424, a novel anti-CD38/CD3 bispecific T-cell-recruiting antibody optimized for cytotoxicity and cytokine release. Plasma cells are a type of white blood cell that make antibodies to help fight infections. CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma. Boursi B, Weiss BM, Haynes K, Mamtani R, Yang YX. N Engl J Med. Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma. Increased level of both CD4+FOXP3+ regulatory T cells and CD14. Gracell has also initiated an investigator-initiated trial evaluating GC012F for the treatment of systemic lupus erythematosus (SLE).
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