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Journal of the Peripheral Nervous... Jun 2024Monoclonal gammopathy-related peripheral neuropathies encompass a spectrum of clinical presentations in which the monoclonal protein directly damages the tissues,... (Review)
Review
Monoclonal gammopathy-related peripheral neuropathies encompass a spectrum of clinical presentations in which the monoclonal protein directly damages the tissues, including the peripheral nervous system. Given the prevalence of both peripheral neuropathy and monoclonal gammopathy in the general population, these conditions may overlap in clinical practice, posing a challenge for clinicians in determining causality. Therefore, a comprehensive understanding of primary clinical syndromes and their neurophysiological patterns is of great importance for accurate differential diagnoses and effective treatment strategies. In this article, we examine the main forms of monoclonal gammopathies that affect the peripheral nerve. We explore the clinical and electrophysiological aspects and their correlation with each syndrome's corresponding monoclonal protein type. This knowledge is essential for healthcare professionals to diagnose better and manage patients presenting with monoclonal gammopathy-related peripheral nervous system involvement.
Topics: Humans; Paraproteinemias; Peripheral Nervous System Diseases
PubMed: 38873841
DOI: 10.1111/jns.12638 -
Hematological Oncology Jul 2024Current treatment guidelines of myeloma cast nephropathy (MCN) recommend the institution of plasma cell-directed therapy and consideration of therapeutic plasma exchange...
Current treatment guidelines of myeloma cast nephropathy (MCN) recommend the institution of plasma cell-directed therapy and consideration of therapeutic plasma exchange (TPE), with the goal of rapid reduction of the serum free light chain (sFLC). However, the role of TPE continues to remain a subject of debate. The goal of this retrospective bi-institutional study was to evaluate the clinical outcomes of TPE in combination with systemic therapy. Eighty patients were included in this analysis, of whom 72.5% had ≥50% drop in their initial involved sFLC. At 3 months from TPE initiation, the overall hematologic response rate (ORR) was 67.5% with a very good partial response or better (≥VGPR) rate of 40%. At 6 months, ORR was 57.5%, with ≥VGPR rate of 49%. The renal response rate at 3 and 6 months was 47.5% and 43.75%, respectively; the overall renal response rate was 48.75%. On multivariable analysis, every one unit increase in baseline creatinine (odds ratio [OR] 0.76, p = 0.006), and achievement of ≥VGPR (OR 21.7 p < 0.0001) were significantly associated with renal response. Also, a ≥50% drop in sFLC was favorably associated with renal response (OR 3.39, p = 0.09). With a median follow-up of 36.4 months, the median overall survival (OS) was 11 months. On multivariable analysis, achievement of renal response (hazard ratio [HR] 0.3, p < 0.0001) and newly diagnosed disease (NDMM; HR 0.43, p = 0.0055) were associated with improved OS. Among NDMM patients, those treated with daratumumab-based regimens had a trend for better OS (p = 0.15), compared to other regimens, but the difference was not significant. At the end of follow-up, an estimated 40.4% of patients who were on dialysis were able to become dialysis independent. In conclusion, our study highlights the poor survival of patients with MCN. Achievement of early renal response is crucial for prolonged OS, with daratumumab-based therapies showing promise.
Topics: Humans; Multiple Myeloma; Male; Female; Plasma Exchange; Middle Aged; Aged; Retrospective Studies; Treatment Outcome; Adult; Aged, 80 and over; Kidney Diseases
PubMed: 38872511
DOI: 10.1002/hon.3293 -
Blood Jun 2024
Topics: Humans; Multiple Myeloma; Cytoplasmic Granules; Male; Recurrence; Middle Aged; Aged; Female
PubMed: 38869920
DOI: 10.1182/blood.2024024221 -
Journal of Comparative Effectiveness... Jul 2024Eligibility criteria are pivotal in achieving clinical trial success, enabling targeted patient enrollment while ensuring the trial safety. However, overly restrictive...
Eligibility criteria are pivotal in achieving clinical trial success, enabling targeted patient enrollment while ensuring the trial safety. However, overly restrictive criteria hinder enrollment and study result generalizability. Broadening eligibility criteria enhances the trial inclusivity, diversity and enrollment pace. Liu proposed an AI pathfinder method leveraging real-world data to broaden criteria without compromising efficacy and safety outcomes, demonstrating promise in non-small cell lung cancer trials. To assess the robustness of the methodology, considering diverse qualities of real-world data and to promote its application. We revised the AI pathfinder method, applied it to relapsed and refractory multiple myeloma trials and compared it using two real-world data sources. We modified the assessment and considered a bootstrap confidence interval of the AI pathfinder to enhance the decision robustness. Our findings confirmed the AI pathfinder's potential in identifying certain eligibility criteria, in other words, prior complications and laboratory tests for relaxation or removal. However, a robust quantitative assessment, accounting for trial variability and real-world data quality, is crucial for confident decision-making and prioritizing safety alongside efficacy.
Topics: Humans; Multiple Myeloma; Patient Selection; Artificial Intelligence; Clinical Trials as Topic; Eligibility Determination
PubMed: 38869838
DOI: 10.57264/cer-2023-0164 -
Clinical Laboratory Jun 2024Both humoral and cell-mediated immunity of the patient affected by multiple myeloma (MM) are impaired; thus, infection is the main cause of the onset of symptoms and... (Review)
Review
BACKGROUND
Both humoral and cell-mediated immunity of the patient affected by multiple myeloma (MM) are impaired; thus, infection is the main cause of the onset of symptoms and death caused by MM. Bortezomib is a first-line drug approved for patients with multiple myeloma (MM) and has significantly increased their overall survival. However, bortezomib-induced peripheral neuropathy (PN) remains a significant side effect that has led to its discontinuation in some patients. Guillain-Barre syndrome (GBS) is thought to be related to immune damage, and most patients have cytomegalovirus (CMV), Epstein-Barr virus (EBV), or mycoplasma infection before onset. Cases of GBS secondary to MM are rare.
METHODS
We provide a case of GBS caused by cytomegalovirus infection after MM treatment, and briefly review the existing literature.
RESULTS
Secondary GBS after MM. This patient received active treatment. The clinical symptoms are gradually improving.
CONCLUSIONS
The use of bortezomib has the risk of reactivating the virus. It is more about the reactivation of hep-atitis B virus. Nonetheless, cytomegalovirus and Epstein-Barr virus shall have our attention. Patients with MM need to monitor CMV, regularly, especially during the treatment of bortezomib. At the same time, they also need to closely monitor the symptoms and signs of the nervous system to guard against the occurrence of GBS.
Topics: Female; Humans; Middle Aged; Antineoplastic Agents; Bortezomib; Cytomegalovirus; Cytomegalovirus Infections; Guillain-Barre Syndrome; Multiple Myeloma
PubMed: 38868867
DOI: 10.7754/Clin.Lab.2024.231224 -
The New England Journal of Medicine Jun 2024Indolent CD4+ cytotoxic chimeric antigen receptor (CAR) T-cell lymphoma involving the small intestine was diagnosed in a patient who had previously received...
Indolent CD4+ cytotoxic chimeric antigen receptor (CAR) T-cell lymphoma involving the small intestine was diagnosed in a patient who had previously received ciltacabtagene autoleucel (cilta-cel) CAR T-cell therapy for treatment of myeloma. Targeted messenger RNA sequencing revealed the presence of CAR gene product in tumor cells. Whole-genome sequencing of samples of tumor and peripheral blood identified a single lentiviral insertion site within the second intron of the gene. In addition, numerous genetic alterations that may have contributed to malignant transformation were identified in the tumor sample. (Funded by MedStar Georgetown University Hospital.).
Topics: Humans; Male; Middle Aged; Biological Products; CD4-Positive T-Lymphocytes; Immunotherapy, Adoptive; Lymphoma, T-Cell; Multiple Myeloma; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Antineoplastic Agents, Immunological
PubMed: 38865661
DOI: 10.1056/NEJMoa2401530 -
Clinical and Experimental Medicine Jun 2024Despite improvements in multiple myeloma (MM) survival rates, data on cardiovascular outcomes in long-term survivors remain lacking.
PURPOSE
Despite improvements in multiple myeloma (MM) survival rates, data on cardiovascular outcomes in long-term survivors remain lacking.
METHODS
This retrospective case-control study utilized the Korean National Health Insurance Service database (2009-2020) to compare the incidence of cardiovascular disease (CVD) between patients with MM and a matched control group, focusing on long-term (> 5 years) survivors. A preliminary case cohort (n = 15,402 patients with MM) and a matched control cohort (n = 123,216 patients without MM) were established based on birth year and sex. Following 1:1 propensity score matching, the final matched cohorts each comprised 15,402 participants.
RESULTS
The case and control cohorts were comparable in mean age (66.2 ± 11.5 years vs. 66.1 ± 11.3 years), sex, age distribution, and comorbidities. By the 8-year follow-up, the cumulative incidence of CV events (12.5% vs. 22.1%) and CVD risk were significantly lower in the case cohort. The 5-year landmark analysis revealed significant differences in CVD incidence between the cohorts (7.8% [case cohort] vs. 9.8% [control cohort]), with variations across age groups and sex, highlighting a significantly higher CVD risk among patients aged < 50 years in the case cohort (P < 0.001).
CONCLUSIONS
These findings underscore the need for vigilant CVD monitoring in MM long-term survivors, particularly those aged < 50 years at first diagnosis.
IMPLICATION FOR CANCER SURVIVORS
This study highlights the importance of integrating cardiovascular monitoring and risk management into long-term care for MM survivors, with a focus on younger patients and personalized interventions.
Topics: Humans; Multiple Myeloma; Male; Female; Aged; Middle Aged; Republic of Korea; Case-Control Studies; Cardiovascular Diseases; Retrospective Studies; Incidence; Cancer Survivors; Aged, 80 and over; Risk Factors; Adult
PubMed: 38864999
DOI: 10.1007/s10238-024-01368-2 -
Cancer Medicine Jun 2024Promising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR-T) cell therapy. However, a...
BACKGROUND
Promising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR-T) cell therapy. However, a portion of MM patients do not respond to CAR-T therapy, and the reasons for this lack of response remain unclear. The objective of this study was to investigate the impact of miR-34a on the immunosuppressive polarization of macrophages obtained from MM patients.
METHODS
The levels of miR-34a and TLR9 (Toll-like receptor 9) were examined in macrophages obtained from both healthy individuals and patients with MM. ELISA was employed to investigate the cytokine profiles of the macrophage samples. Co-culture experiments were conducted to evaluate the immunomodulatory impact of MM-associated macrophages on CAR-T cells.
RESULTS
There was an observed suppressed activation of macrophages and CD4 T lymphocytes in the blood samples of MM patients. Overexpression of miR-34a in MM-associated macrophages dampened the TLR9 expression and impaired the inflammatory polarization. In both the co-culture system and an animal model, MM-associated macrophages suppressed the activity and tumoricidal effect of CAR-T cells in a miR-34a-dependent manner.
CONCLUSION
The findings imply that targeting the macrophage miR-34a/TLR9 axis could potentially alleviate the immunosuppression associated with CAR-T therapy in MM patients.
Topics: Multiple Myeloma; MicroRNAs; Toll-Like Receptor 9; Humans; Animals; Mice; Signal Transduction; Coculture Techniques; Tumor-Associated Macrophages; Macrophages; Immunotherapy, Adoptive; Male; Female; Macrophage Activation; Cell Line, Tumor
PubMed: 38864479
DOI: 10.1002/cam4.7387 -
Cell Communication and Signaling : CCS Jun 2024Multiple Myeloma (MM), a cancer of terminally differentiated plasma cells, is the second most prevalent hematological malignancy and is incurable due to the inevitable... (Review)
Review
Multiple Myeloma (MM), a cancer of terminally differentiated plasma cells, is the second most prevalent hematological malignancy and is incurable due to the inevitable development of drug resistance. Intense protein synthesis is a distinctive trait of MM cells, supporting the massive production of clonal immunoglobulins or free light chains. The mammalian target of rapamycin (mTOR) kinase is appreciated as a master regulator of vital cellular processes, including regulation of metabolism and protein synthesis, and can be found in two multiprotein complexes, mTORC1 and mTORC2. Dysregulation of these complexes is implicated in several types of cancer, including MM. Since mTOR has been shown to be aberrantly activated in a large portion of MM patients and to play a role in stimulating MM cell survival and resistance to several existing therapies, understanding the regulation and functions of the mTOR complexes is vital for the development of more effective therapeutic strategies. This review provides a general overview of the mTOR pathway, discussing key discoveries and recent insights related to the structure and regulation of mTOR complexes. Additionally, we highlight findings on the mechanisms by which mTOR is involved in protein synthesis and delve into mTOR-mediated processes occurring in MM. Finally, we summarize the progress and current challenges of drugs targeting mTOR complexes in MM.
Topics: Humans; Multiple Myeloma; TOR Serine-Threonine Kinases; Signal Transduction; Animals; Molecular Targeted Therapy; MTOR Inhibitors; Mechanistic Target of Rapamycin Complex 2
PubMed: 38862983
DOI: 10.1186/s12964-024-01699-3 -
Blood Cancer Journal Jun 2024
Topics: Humans; Multiple Myeloma; Neoplasm Staging; Female; Male; Middle Aged; Aged; Adult; Aged, 80 and over; Cohort Studies
PubMed: 38862493
DOI: 10.1038/s41408-024-01076-w