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Cell Reports. Medicine Jun 2024Iberdomide is a next-generation cereblon (CRBN)-modulating agent in the clinical development in multiple myeloma (MM). The analysis of biomarker samples from...
Iberdomide is a next-generation cereblon (CRBN)-modulating agent in the clinical development in multiple myeloma (MM). The analysis of biomarker samples from relapsed/refractory patients enrolled in CC-220-MM-001 (ClinicalTrials.gov: NCT02773030), a phase 1/2 study, shows that iberdomide treatment induces significant target substrate degradation in tumors, including in immunomodulatory agent (IMiD)-refractory patients or those with low CRBN levels. Additionally, some patients with CRBN genetic dysregulation who responded to iberdomide have a similar median progression-free survival (PFS) (10.9 months) and duration of response (DOR) (9.5 months) to those without CRBN dysregulation (11.2 month PFS, 9.4 month DOR). Iberdomide treatment promotes a cyclical pattern of immune stimulation without causing exhaustion, inducing a functional shift in T cells toward an activated/effector memory phenotype, including in triple-class refractory patients and those receiving IMiDs as a last line of therapy. This analysis demonstrates that iberdomide's clinical mechanisms of action are driven by both its cell-autonomous effects overcoming CRBN dysregulation in MM cells, and potent immune stimulation that augments anti-tumor immunity.
Topics: Humans; Multiple Myeloma; Thalidomide; Adaptor Proteins, Signal Transducing; Ubiquitin-Protein Ligases; Female; Male; Neoplasm Recurrence, Local; Drug Resistance, Neoplasm; Recurrence; Middle Aged; T-Lymphocytes; Aged
PubMed: 38776914
DOI: 10.1016/j.xcrm.2024.101571 -
Cell Reports. Medicine Jun 2024Iberdomide is a potent cereblon E3 ligase modulator (CELMoD agent) with promising efficacy and safety as a monotherapy or in combination with other therapies in patients...
Iberdomide is a potent cereblon E3 ligase modulator (CELMoD agent) with promising efficacy and safety as a monotherapy or in combination with other therapies in patients with relapsed/refractory multiple myeloma (RRMM). Using a custom mass cytometry panel designed for large-scale immunophenotyping of the bone marrow tumor microenvironment (TME), we demonstrate significant increases of effector T and natural killer (NK) cells in a cohort of 93 patients with multiple myeloma (MM) treated with iberdomide, correlating findings to disease characteristics, prior therapy, and a peripheral blood immune phenotype. Notably, changes are dose dependent, associated with objective response, and independent of prior refractoriness to MM therapies. This suggests that iberdomide broadly induces innate and adaptive immune activation in the TME, contributing to its antitumor efficacy. Our approach establishes a strategy to study treatment-induced changes in the TME of patients with MM and, more broadly, patients with cancer and establishes rational combination strategies for iberdomide with immune-enhancing therapies to treat MM.
Topics: Humans; Multiple Myeloma; Immunity, Innate; Bone Marrow; Adaptive Immunity; Female; Male; Killer Cells, Natural; Tumor Microenvironment; Middle Aged; Aged; Neoplasm Recurrence, Local
PubMed: 38776911
DOI: 10.1016/j.xcrm.2024.101584 -
Cancer Reports (Hoboken, N.J.) May 2024Thalidomide-containing regimens cause adverse events (AEs) that may require a reduction in treatment intensity or even treatment discontinuation in patients with... (Observational Study)
Observational Study
The efficacy and tolerability of bortezomib, thalidomide, and dexamethasone induction therapy with a thalidomide dose step-up strategy in patients with newly diagnosed multiple myeloma: A prospective observational study.
BACKGROUND
Thalidomide-containing regimens cause adverse events (AEs) that may require a reduction in treatment intensity or even treatment discontinuation in patients with multiple myeloma. As thalidomide toxicity is dose-dependent, identifying the most appropriate dose for each patient is essential.
AIMS
This study aimed to investigate the effects of a thalidomide dose step-up strategy on treatment response and progression-free survival (PFS).
METHODS AND RESULTS
This prospective observational study included 93 patients with newly diagnosed multiple myeloma (NDMM) who received bortezomib, thalidomide, and dexamethasone (VTD). The present study assessed the incidence of thalidomide dose reduction and discontinuation, the overall dose intensity, and their effects on therapeutic efficacy. Furthermore, this study used Cox proportional hazard models to analyze the factors contributing to thalidomide intolerability. The results showed the overall response rates in all patients and the evaluable patients were 78.5% and 98.7%, respectively. The median PFS in the study cohort was not reached. The most common thalidomide-related AEs were constipation (32.3%) and skin rash (23.7%), resulting in dose reduction and discontinuation rates of 22.6% and 21.5%, respectively. The responders had a significantly higher average thalidomide dose intensity than the nonresponders (88.6% vs. 42.9%, p < .001).
CONCLUSION
The thalidomide dose step-up approach is a viable option for patients with NDMM receiving VTD induction therapy with satisfactory efficacy and tolerability. However, thalidomide intolerance may lead to dose reduction or discontinuation due to unpredictable AEs, leading to lower dose intensity and potentially inferior treatment outcomes. In addition to a dose step-up strategy, optimal supportive care is critical for patients with multiple myeloma receiving VTD induction therapy.
Topics: Humans; Multiple Myeloma; Thalidomide; Female; Dexamethasone; Male; Bortezomib; Prospective Studies; Aged; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Adult; Induction Chemotherapy; Progression-Free Survival; Aged, 80 and over; Dose-Response Relationship, Drug
PubMed: 38775249
DOI: 10.1002/cnr2.2102 -
F1000Research 2023Multiple myeloma is a common malignant bone-based disease. Pleural effusions reported in these patients remain rare. It is commonly due to congestive heart disease,...
Multiple myeloma is a common malignant bone-based disease. Pleural effusions reported in these patients remain rare. It is commonly due to congestive heart disease, pulmonary embolism, nephrotic syndrome or a second neoplasia. The true myelomatous pleural effusion resulting from a direct tumoral invasion of the pleural are extremely rare. We report here the case of a massive pleural effusion revealing multiple myeloma in a 71-year-old patient. The chest ultrasound showed a massive pleural effusion in the left side with a multinodular thickening of the pleura. The medical thoracoscopy showed a grape-cluster appearance. The diagnosis was made by pleural guided biopsy revealing abnormal plasma cells with an intense positive CD 138 (plasma cell marker) and MUM1 (multiple myeloma oncogene1) staining with a light kappa chain in the protein electrophoresis associated with a myeloma. Unfortunately, our patient died one month after the initial diagnosis. We present also a review of the recent literature in order to highlight the clinical presentations of the myelomatous pleural effusion, the diagnostic tools, the therapeutic strategies as well as the outcomes.
Topics: Humans; Multiple Myeloma; Aged; Male; Pleural Effusion; Pleural Effusion, Malignant; Fatal Outcome
PubMed: 38774309
DOI: 10.12688/f1000research.133007.3 -
Scientific Reports May 2024Multiple myeloma (MM) progression involves diminished tumor antigen presentation and an immunosuppressive microenvironment, characterized by diminished expression of...
Multiple myeloma (MM) progression involves diminished tumor antigen presentation and an immunosuppressive microenvironment, characterized by diminished expression of major histocompatibility complexes (MHC) class I molecule and elevated programmed death ligand 1 (PDL1) in MM cells, along with an enriched population of regulatory T cells (Tregs). To investigate Treg's influence on MM cells, we established a co-culture system using Tregs from MM patients and the MM cell lines (MM.1S and SK-MM-1) in vitro and assessed the effects of intervening in the relevant pathways connecting Tregs and MM cells in vivo. In vitro, Tregs induced transforming growth factor beta-1 (TGF-β1) production, downregulated MHC I members, and increased PDL1 expression in MM cells. Treg-derived TGF-β1 suppressed the cGAS-STING pathway, contributing to the loss of MHC I molecule expression and PDL1 upregulation. Correspondingly, neutralizing TGF-β1 or activating the cGAS-STING pathway restored MHC I and PDL1 expression, effectively countering the pro-tumorigenic effect of Tregs on MM cells in vivo. These data elucidated how Tregs influence tumor antigen presentation and immunosuppressive signal in MM cells, potentially providing therapeutic strategies, such as neutralizing TGF-β1 or activating the cGAS-STING pathway, to address the immune escape and immunosuppressive dynamics in MM.
Topics: Humans; Multiple Myeloma; Transforming Growth Factor beta1; T-Lymphocytes, Regulatory; Signal Transduction; Histocompatibility Antigens Class I; Membrane Proteins; Nucleotidyltransferases; B7-H1 Antigen; Cell Line, Tumor; Animals; Down-Regulation; Mice; Female; Coculture Techniques; Male; Gene Expression Regulation, Neoplastic
PubMed: 38773213
DOI: 10.1038/s41598-024-62298-3 -
American Society of Clinical Oncology... Jun 2024Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk... (Review)
Review
Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature. The heterogeneous risk definition across trials, the few trials available designed for HR patients, and the small HR subgroups in all-comers trials make it difficult to generate recommendations with high levels of evidence. Nevertheless, regardless of treatment administered, several studies consistently showed that achieving and maintaining measurable residual disease negativity is now considered the main factor able to mitigate the adverse prognosis related to baseline features. For fit patients with HR transplant-eligible (TE) NDMM, quadruplet induction/consolidation treatment with anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors and dexamethasone, and autologous stem-cell transplant and maintenance with, if available, at least a doublet combination could be considered the option of choice. For non-TE NDMM, considering the recent data generated and carefully reviewing those upcoming, quadruplet treatment consisting of anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors, and dexamethasone should also be considered. Future trials integrating BCMA-directed novel generation immunotherapies hold great potential for further advancing the treatment landscape in all NDMM patients with HR disease.
Topics: Humans; Multiple Myeloma; Prognosis; Risk Factors; Antineoplastic Combined Chemotherapy Protocols; Risk Assessment
PubMed: 38772002
DOI: 10.1200/EDBK_433520 -
Cancer Medicine May 2024Medical mistrust, rooted in unethical research, is a barrier to cancer-related health care for Black/African American (AA) persons. Understanding trust, mistrust, and...
BACKGROUND
Medical mistrust, rooted in unethical research, is a barrier to cancer-related health care for Black/African American (AA) persons. Understanding trust, mistrust, and health care experiences is crucial, especially in multiple myeloma (MM), which disproportionately burdens Black/AA persons in incidence and survival.
STUDY PURPOSE
This study qualitatively examines the experiences of Black/AA and White dyads (patient with MM and adult caregiver) to gain insights into these phenomena.
METHODS
From November 2021 to April 2022, we recruited 21 dyads from the UNC Lineberger Comprehensive Cancer Center. Participants completed a sociodemographic survey and a 60-90 min semi-structured interview. We used ATLAS.ti v9 for project management and to facilitate data analysis using the Sort and Sift, Think and Shift approach (ResearchTalk Inc).
RESULTS
We interviewed 21 racially concordant dyads (11 Black/AA, 10 White) with mean patient ages of 70 (Black/AA) and 72 (White) at enrollment. Both Black/AA and White caregivers had a mean enrollment age of 68. The mean duration from MM diagnosis to enrollment for all patients was 5.5 years. Four key themes emerged: (1) knowledge and trust, (2) heightened emotions and discomfort, (3) differing mental constructs of health care experiences, and (4) mitigating mistrust, which varied by self-identified race. Black/AA participants had greater knowledge of historical events like the U.S. Public Health Service Untreated Syphilis Study at Tuskegee and carried the emotional burden longer. They also emphasized self-learning and self-guided research about MM for informed medical decision-making. Both Black/AA and White dyads emphasized the pivotal role of patient-provider relationships and effective communication in fostering trust and addressing concerns.
CONCLUSION
Our study offers contextual insights into the enduring challenges of medical mistrust, particularly within the Black/AA community, and its implications for patients and caregivers accessing and receiving MM-related care. Future studies should leverage these insights to guide the development of multilevel interventions addressing medical mistrust within the Black/AA community.
Topics: Humans; Multiple Myeloma; Trust; Male; Female; Aged; Caregivers; Black or African American; Middle Aged; White People; Aged, 80 and over; Qualitative Research
PubMed: 38770636
DOI: 10.1002/cam4.7297 -
Journal of Cancer Research and Clinical... May 2024Carfilzomib, commonly used for relapsed/refractory multiple myeloma (RRMM), has been associated with various adverse events in randomized controlled trials (RCTs).... (Observational Study)
Observational Study
PURPOSE
Carfilzomib, commonly used for relapsed/refractory multiple myeloma (RRMM), has been associated with various adverse events in randomized controlled trials (RCTs). However, real-world safety data for a more diverse population are needed, as carfilzomib received expedited approval. This study aimed to evaluate carfilzomib's safety in Korea by comparing new users of KRd (carfilzomib, lenalidomide, and dexamethasone) to Rd (lenalidomide and dexamethasone) using a nationwide administrative claims database.
METHODS
The retrospective cohort study utilized target trial emulation, focusing on adverse events in various organ systems similar to the ASPIRE trial.
RESULTS
This study included 4,580 RRMM patients between 2007 and 2020, and the KRd group showed significantly higher risks of hematologic adverse events (anemia, neutropenia, thrombocytopenia) and some non-hematologic adverse events (cough, hypokalemia, constipation, hypertension, heart failure) compared to the Rd group. Among non-hematologic adverse events, cardiovascular events (heart failure [HR 2.04; 95% CI 1.24-3.35], hypertension [HR 1.58; 95% CI 1.15-2.17]) had the highest risk in the KRd group.
CONCLUSION
The safety profile of carfilzomib in Korean patients was similar to previous RCTs. Therefore, caution should be exercised when using carfilzomib in Asian individuals with RRMM due to the increased risk of cardiovascular adverse events.
Topics: Humans; Multiple Myeloma; Oligopeptides; Male; Female; Republic of Korea; Retrospective Studies; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Neoplasm Recurrence, Local; Lenalidomide
PubMed: 38769166
DOI: 10.1007/s00432-024-05800-8 -
Frontiers in Immunology 2024This study presents two cases of type II mixed cryoglobulinemia. One case is essential, while the other is presumably associated with hepatitis B virus (HBV) infection....
This study presents two cases of type II mixed cryoglobulinemia. One case is essential, while the other is presumably associated with hepatitis B virus (HBV) infection. Both patients tested positive for monoclonal IgMκ, but negative for MyD88 mutation. They showed resistance to rituximab combined with a glucosteroid regimen, but responded positively to BTK inhibitors. These cases highlight the remarkable effectiveness of BTK inhibitors in treating refractory type II cryoglobulinemia without MyD88 mutation. The first patient achieved rapid complete remission of nephrotic syndrome within one month of starting ibrutinib, along with a significant reduction in cryoglobulin levels and abnormal clonal cells. The second patient had a rapid disappearance of rash within three days and accelerated wound healing within one week of initiating orelabrutinib, accompanied by a reduction in C-reactive protein. However, there was no reduction in cryoglobulin levels during the 12-month follow-up. These findings suggest varied mechanisms of action of BTK inhibitors in type II cryoglobulinemia through different mechanisms.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Cryoglobulinemia; Myeloid Differentiation Factor 88; Protein Kinase Inhibitors; Middle Aged; Male; Female; Adenine; Aged; Piperidines; Treatment Outcome
PubMed: 38765016
DOI: 10.3389/fimmu.2024.1390958 -
Blood Cancer Journal May 2024Autologous stem cell transplantation (autoHCT) is considered standard of care for newly diagnosed multiple myeloma (MM). Although most patients eventually progress after...
Autologous stem cell transplantation (autoHCT) is considered standard of care for newly diagnosed multiple myeloma (MM). Although most patients eventually progress after autoHCT, a small proportion achieve a durable response. In this retrospective study we included 1576 patients, 244 (15%) of whom were long-term responders (LTR), defined as having a progression-free survival (PFS) of ≥8 years after transplant. Patients in the LTR group were younger than the non-LTR group (median age 58.4 vs. 59.5 years; p = 0.012), less likely to have high-risk cytogenetics (4% vs. 14%; p < 0.001), more often had <50% bone marrow plasma cells (67% vs. 58%; p = 0.018) and R-ISS stage I disease (43% vs. 34%). More patients in the LTR group received post-transplant maintenance (63% vs. 52%; p = 0.002). Patients in the LTR group had higher rates of complete response (CR) at day100 (41% vs. 27%; p < 0.001) and at best post-transplant response (70% vs. 37%; p < 0.001), compared to the non-LTR group. Patients in the LTR groups had a median PFS of 169.3 months and the median overall survival (OS) had not been reached. The leading cause of death in the LTR was disease progression. In conclusion, 15% of patients in the cohort were LTR after upfront autoHCT, with distinct characteristics and a median PFS of more than 14 years.
Topics: Humans; Multiple Myeloma; Middle Aged; Hematopoietic Stem Cell Transplantation; Male; Female; Transplantation, Autologous; Aged; Retrospective Studies; Adult; Remission Induction; Treatment Outcome
PubMed: 38760362
DOI: 10.1038/s41408-024-01062-2