OBJECTIVE: Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM.
METHODS: Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential.
RESULTS: The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells had a total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430.
CONCLUSIONS: Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy.

UNASSIGNED: In recent years, chimeric antigen receptor T (CAR-T) cell therapy has resulted in a breakthrough in the treatment of patients with refractory or relapsed hematological malignancies. However, the identification of patients suitable for CAR-T cell therapy needs to be improved.
UNASSIGNED: CAR-T cell therapy has demonstrated excellent efficacy in hematological malignancies; however, views on determining when to apply CAR-T cells in terms of the evaluation of patient characteristics remain controversial.
UNASSIGNED: We reviewed the current feasibility and challenges of CAR-T cell therapy in the most common hematological malignancies and classified them according to the disease type and treatment priority, to guide clinicians and researchers in applying and investigating CAR-T cells furtherly.

暂无摘要。

Multiple myeloma (MM) is a malignancy of plasma cells, terminally differentiated B cells, with complications like hypercalcemia, renal failure, anemia, and bone disease, which are also known as CRAB criteria. MM develops from monoclonal gammopathy of unknown significance (MGUS), a pre-malignant plasma cell dyscrasia. Over some time, MGUS has the potential to progress into smoldering multiple myeloma (SMM), which can evolve into MM. MM rarely progresses into plasma cell leukemia (PCL), a condition in which malignant plasma cells no longer stay in the bone marrow niche and circulate in the peripheral blood. In MM, various soluble factors play important roles, and interleukin-6 has different vital roles.  Interleukin-6, an inflammatory cytokine, has significant roles in the growth, survival, angiogenesis, metastasis, and apoptosis resistance in MM. Interleukin-6 is produced and secreted by both autocrine from myeloma cells and paracrine from bone marrow stromal cells. To tackle MM, various therapeutic approaches were applied over many years, and according to the results, most patients with MM can respond well to first-line treatment. However, the majority of patients may relapse as conventional treatment may not be curative. So, there is an urgent need for novel cell-based and cell-free therapeutic strategies, such as mesenchymal stem cell-based therapies and their products to offer new therapeutic strategies for MM. Materials and Methods: In the present study, we investigated the impacts of exosomes derived from human placental mesenchymal stem cells (hPMSCs) on apoptosis and interleukin-6 expression in a myeloma cell line, U-266, for the first time. hPMSCs were isolated from the human placenta and cultured in a DMEM medium. After characterizing the cells and acknowledging their identity, they underwent several passages and their supernatant was collected to harvest exosomes. The exosomes were isolated by ultracentrifugation and characterized by DLS and TEM, and their concentration was measured by BCA protein assay. U266 cells were treated with different concentrations of exosomes and then MTT and annexin/propidium iodide flow cytometry tests were performed to evaluate cell viability. Afterward, a real-time PCR test was performed to evaluate interleukin-6 gene expression. Results: According to our findings, treatment of U-266 cells with hPMSCS-derived exosomes led to the preservation of myeloma cells without changes in their cell cycle. Surprisingly, treatments did not hinder the expression of interleukin-6 in the myeloma cells. Conclusion: In MM patients, interleukin-6 pl ays different roles, and it is a desirable target to design new therapeutic strategies. To evaluate the effects of new therapeutic strategies, we designed and performed our study to estimate the effects of cell-free therapeutic strategy.  In the present study, the impacts of hPMSCS-derived exosomes on the viability of MM cells and interleukin-6 gene expression were evaluated. The results showed that hPMSCS-derived exosomes resulted in the perseverance of myeloma cells without changes in the cell cycle.  Furthermore, the interleukin-6 gene expression level showed no significant change.

BACKGROUND: This study aimed to explore the changes in Th cells and cytokines in the peripheral blood of patients with multiple myeloma before and after treatment and at the time of the bacterial infection.
METHODS: In total, 23 newly diagnosed MM patients admitted to the Hospital and 23 healthy individuals were selected as the study group and the control group, respectively. Flow cytometry was used to detect the Th1 and Th2 lymphocytes and cytokines, such as IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, INF-γ, IL-17A, IL-1b, TNF-α, TNF-β, and IL-12P70, in the peripheral blood of the patients at initial diagnosis, before and after treatment, and at the time of the bacterial infection.
RESULTS: The Th1% and Th1/Th2 ratio at the time of the initial diagnosis were lower in the MM patients than in the control group, whereas the Th2% at initial diagnosis was higher in the MM patients than in the control group. The levels of IL-6, IL-8, IL-10, and IL-17A at initial diagnosis were higher in the MM patients than in the control group. After 4 cycles of treatment, the Th2% in the patients was lower than before the treatment and the Th1/Th2 ratio in the patients was higher than before the treatment. The Th1% and the levels of IL-6, IL-8, IL-10, and INF-γ increased, while the level of IL-12P70 decreased, when MM patients got a bacterial infection. The abovementioned differences were statistically significant (p < 0.05).
CONCLUSIONS: The Th1/Th2 deviation affects the immune function of the MM patients. There were significant changes in the Th1 and Th2 lymphocytes and cytokines in newly diagnosed MM patients after the treatment. The changes in the Th lymphocytes and cytokines may be an indicator of bacterial infection.

BACKGROUND: Interferon gamma release assay (IGRA) is an important method to detect the specific antigen of tuberculosis, which is crucial to the diagnosis of tuberculosis or potential tuberculosis infection.
METHODS: We report a case of myelosuppression caused by the use of Melphalan in the treatment of multiple myeloma, resulting in an abnormal decrease in interferon gamma release assay results.
RESULTS: We collected blood samples from the patient for retesting and the result of the test did not differ significantly. Upon reviewing the case, it was found that the patient\'s use of Melphalan treatment resulted in bone marrow suppression and extreme reduction of peripheral blood lymphocytes. Therefore, it is speculated that the abnormal decrease of the interferon gamma release assay result is caused by bone marrow suppression, which is caused by the use of Melphalan.
CONCLUSIONS: When patients with multiple myeloma are treated with Melphalan, it can lead to bone marrow suppression and result in false negative interference gamma release assay results. Laboratory staff should consider the existence of such interference and communicate with clinical doctors in a timely manner.

Multiple myeloma is a hematological cancer caused by the uncontrolled proliferation of abnormal plasma cells in the bone marrow, leading to excessive immunoglobulin production. Our study aimed to examine the anticancer properties of BRF1A, a cannabinoid (CBD)-enriched product, on 2 myeloma cell lines: U266 and ARH-7. We treated U266 and ARH-77 myeloma cells with varying doses of BRF1A and measured the production of IgE and IgG antibodies using ELISA. Cell viability was assessed using trypan blue and CCK-8 assays. We measured the expression of genes related to the production of IgE and IgG antibodies, IgEH, and IgGH. We determined its effect on the expression of telomerase and its phosphorylated form as an indicator of telomere stabilization. Furthermore, we determined its effect on other cancer-related targets such as NF-ĸB, c-Myc, and TP53 in U266 cells using reverse transcription polymerase chain reaction (RT-PCR) and western blotting. BRF1A reduced myeloma cell IgE and IgG production in a time and dose-dependent manner. It also suppressed the expression of p-IκBα, p-NFκB (p65), and total NFκB protein, as well as XBP1u and XBP1s. It increased the gene and protein expression of telomere and hTERT and significantly increased cancer suppressor TP53 gene and p53 protein expression. Additionally, BRF1A decreased the c-Myc gene and protein expression. Our study has shown that a CBD-enriched product can reduce the growth of myeloma cells by suppressing the critical functions of IgE- and IgG-producing cells. This study could help bridge the gap in understanding how cannabinoid-containing products affect cancer, aging, telomere, and cancer-suppressor gene activity.

Multiple myeloma (MM) is a malignancy of plasma cells accompanied by immune dysfunction. This study aimed to provide a comprehensive and dynamic characterization of the peripheral immune environment in MM patients and find its diagnostic and prognostic values for therapy. The peripheral immune profiles of MM inpatients and healthy controls were assessed by flow cytometry. A longitudinal study of immune subsets was observed during cycles of chemotherapy. The diagnostic and prognostic models were established based on immune subsets by the absolute shrinkage and selection operator (LASSO) and multivariate regression. MM patients possessed an impeded immune landscape, including reduced activation of B cells, increased effective T cells and regulatory T cells (Tregs), augmented CD16 expression on monocytes and dendritic cell percentages, decreased CD56dimCD16+ natural killer cells (NKs), and amplified CD56bright and HLA-DR+ natural killer T cells (NKTs). Chemotherapy has different dynamic effects on specific cells, of which 2 cycles is the key turning point. NKT, dendritic cells, naïve Tc and Th cells, HLA-DR+ Tc cells, CD56dim NKTs, CD16++ monocytes, and CD25+ B cells could have the diagnostic value, and a prognostic model including neutrophils, naïve Tc cells, CD56brightCD16dim NKs, and CD16+ dendritic cells was established with acceptable accuracy. Our data showed dynamic and abnormal peripheral immune profiles in MM patients, which had prognostic values and could provide the basis for clinical therapy.

UNASSIGNED: Even with significant advancements, treating multiple myeloma (MM) remains difficult. At present, the main treatment methods include combined treatment of stem cell transplantation, drug treatment, etc. With the clarification of the molecular biological mechanism of MM, as well as the in-depth study of the internal signal of myeloma cells and the microenvironment of MM patients, more and more new drugs targeting myeloma and microenvironment are gradually used in clinical maintenance treatment, such as inhibit the proteosome: ixazomib, bortezomib and carfilzomib, immune - modulators: thalidomide and lenalidomide, monoclonal antibodies, etc. have made great progress in MM maintenance treatment. With the continuous development of proteasome inhibitor maintenance treatment in MM, the prognosis of the disease has been significantly improved. Our aim is to evaluate the effectiveness and adverse reactions of proteasome inhibitors in maintenance therapy for multiple myeloma, providing new ideas for clinical medication.
UNASSIGNED: Four databases containing randomized controlled studies on the effectiveness and safety of proteasome inhibitors in the maintenance therapy of multiple myeloma are retrieved by the computer. Once the quality of the literature has been thoroughly evaluated, run the data via the RevMan 5.3 software.
UNASSIGNED: Eventually 8 studies were added in this systematic review. Compared with the placebo group, proteasome inhibitor in maintenance treatment of multiple myeloma patients with prolonged the survival without progression and overall existence. 5 studies reported the peripheral neuropathy of multiple myeloma in the treatment group compared to placebo group, which was remarkably greater (OR: 1.98; 95 % Cl: 1.35, 2.92; P < 0.001) compared to placebo group, Serious adverse events (OR: 1.60; 95 % Cl: 1.19, 2.14; P < 0.01), Rash (OR: 2.23; 95 % Cl: 1.62, 3.05; P < 0.001) and Vomiting (OR: 5.12; 95 % Cl: 3.36, 7.80; P < 0.001). The Serious adverse events of the treatment group were remarkably greater compared with the untreated group (OR: 1.60; 95 % Cl: 1.19, 2.14; P < 0.01).
UNASSIGNED: The study results proposed that proteasome inhibitors are effective in the multiple myeloma maintenance treatment compared with the placebo group. Bortezomib has certain advantages in prolonging PFS, followed by ixazomib and carfilzomib in terms of efficacy. Bortezombib may be superior to carfilzombib in extending OS. However, the adverse reactions caused by proteasome inhibitors, such as Peripheral neuropathy, Serious adverse events, Rash, Vomiting, etc., should be paid enough attention.

An 83-year-old female patient presented to our nephrology outpatient clinic with complaints of weakness, edema, abdominal pain, and constipation, with a preliminary diagnosis of chronic kidney failure related to heart failure. The patient had undergone mitral valve replacement surgery 10 years prior and was diagnosed with chronic renal failure six years prior. Laboratory tests revealed mild normochromic normocytic anemia, consistently high erythrocyte sedimentation rate (ESR) above 100 mm/h, and nephrotic-range proteinuria, prompting suspicion of multiple myeloma. Further investigations, including bone marrow aspiration, confirmed the diagnosis of multiple myeloma. During follow-up, the patient began to complain of difficulty swallowing and symptoms of microstomia. Upon further questioning, it was discovered that these symptoms had been present for more than 10 years. Immunoblot tests revealed positive centromere protein B (CENP-B), suggesting a diagnosis of scleroderma. Subsequently, during follow-up, bullous lesions appeared on the patient\'s chest. Biopsy samples confirmed a diagnosis of bullous pemphigoid (BP). The co-occurrence of scleroderma, multiple myeloma, and superimposed BP represents a rare and noteworthy case for publication.