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International Journal of Molecular... Jun 2024Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; = 395)... (Randomized Controlled Trial)
Randomized Controlled Trial
Molecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma-Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries.
Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront "novel agents" in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization ( = 354) and gene expression profiling ( = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with "conventional" (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to "outdated" treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront "novel agents".
Topics: Humans; Multiple Myeloma; Chromosome Aberrations; Female; Male; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Prognosis; Adult; Developing Countries; Dexamethasone; Bortezomib; Thalidomide
PubMed: 38928138
DOI: 10.3390/ijms25126431 -
Cancers Jun 2024The outcome of multiple myeloma (MM) has significantly improved in the last few decades due to several factors such as new biological discoveries allowing to better... (Review)
Review
The outcome of multiple myeloma (MM) has significantly improved in the last few decades due to several factors such as new biological discoveries allowing to better stratify disease risk, development of more effective therapies and better management of side effects related to them. However, handling all these aspects requires an interdisciplinary approach involving multiple knowledge and collaboration of different specialists. The hematologist, faced with a patient with MM, must not only choose a treatment according to patient and disease characteristics but must also know when therapy needs to be started and how to monitor it during and after treatment. Moreover, he must deal not only with organ issues related to MM such as bone disease, renal failure or neurological disease but also with adverse events, often very serious, related to novel therapies, particularly new generation immunotherapies such as CAR T cell therapy and bispecific antibodies. In this review, we provide an overview on the newer MM diagnostic and monitoring strategies and on the main side effects of MM therapies, focusing on adverse events occurring during treatment with CAR T cells and bispecific antibodies.
PubMed: 38927968
DOI: 10.3390/cancers16122263 -
Biomedicines May 2024After receiving different lines of treatment, multiple myeloma patients tend to present with less secretory and more frequent extramedullary disease. These features make...
INTRODUCTION
After receiving different lines of treatment, multiple myeloma patients tend to present with less secretory and more frequent extramedullary disease. These features make treatment monitoring and follow-up very complex since they have to be based on the use of imaging methods and/or bone marrow aspirations or biopsies.
OBJECTIVE
To present the case of a patient with myeloma progressing with non-secretory bone disease and to discuss the potential impact of mass spectrometry as a new highly sensitive method able to identify the monoclonal protein (MP) in the serum of these types of patients.
MATERIALS AND METHODS
Informed consent was signed by the patient prior to receiving each line of treatment. The clinical information and images were obtained from anonymized electronic files. The mass spectrometry was performed with the Immunoglobulin Isotypes (GAM) assay for the mass spectrometry EXENT Analyser Technology from Binding Site, part of Thermofisher.
RESULTS
A 73-year-old male with IgG kappa multiple myeloma progressing with a new lytic lesion after receiving 14 cycles of Talquetamab as a third line of therapy who, due to the non-secretory nature of the disease at this point, could not be enrolled in a clinical trial, thus limiting his therapeutic options. The mass spectrometry was able to identify and quantify the presence of the patient's MP when the serum protein electrophoresis and immunofixation were still negative and therefore could have been used to confirm the progression, to permit the inclusion of the patient in a clinical trial and to further monitor the disease response.
CONCLUSIONS
The higher sensitivity of the mass spectrometry methods to detect the MP in patients with myeloma and other monoclonal gammopathies translates into better identification of the disease progression, permits the inclusion of more patients in clinical trials and facilitates treatment monitoring.
PubMed: 38927360
DOI: 10.3390/biomedicines12061153 -
Biology May 2024The repurposing of previously clinically approved drugs as an alternative therapeutic approach to treating disease has gained significant attention in recent years. A... (Review)
Review
The repurposing of previously clinically approved drugs as an alternative therapeutic approach to treating disease has gained significant attention in recent years. A multitude of studies have demonstrated various and successful therapeutic interventions with these drugs in a wide range of neoplastic diseases, including multiple myeloma, leukaemia, glioblastoma, and colon cancer. Drug repurposing has been widely encouraged due to the known efficacy, safety, and convenience of already established drugs, allowing the bypass of the long and difficult road of lead optimization and drug development. Repurposing drugs in cancer therapy is an exciting prospect due to the ability of these drugs to successfully target cancer-associated genes, often dysregulated in oncogenic signalling pathways, amongst which are the classical cancer signalling pathways; WNT (wingless-related integration type) and Hippo signalling. These pathways play a fundamental role in controlling organ size, tissue homeostasis, cell proliferation, and apoptosis, all hallmarks of cancer initiation and progression. Prolonged dysregulation of these pathways has been found to promote uncontrolled cellular growth and malignant transformation, contributing to carcinogenesis and ultimately leading to malignancy. However, the translation of cancer signalling pathways and potential targeted therapies in cancer treatment faces ongoing challenges due to the pleiotropic nature of cancer cells, contributing to resistance and an increased rate of incomplete remission in patients. This review provides analyses of a range of potential anti-cancer compounds in drug repurposing. It unravels the current understanding of the molecular rationale for repurposing these drugs and their potential for targeting key oncogenic signalling pathways.
PubMed: 38927266
DOI: 10.3390/biology13060386 -
Biomolecules Jun 2024Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some...
Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance. We designed, synthesized, and screened a new class of polyfluorinated thalidomide analogs and investigated their anti-cancer, anti-angiogenic, and anti-inflammatory activity using in vitro and ex vivo biological assays. We identified four lead compounds that exhibit potent anti-myeloma, anti-angiogenic, anti-inflammatory properties using three-dimensional tumor spheroid models, in vitro tube formation, and ex vivo human saphenous vein angiogenesis assays, as well as the THP-1 inflammatory assay. Western blot analyses investigating the expression of proteins downstream of cereblon (CRBN) reveal that Gu1215, our primary lead candidate, exerts its activity through a CRBN-independent mechanism. Our findings demonstrate that the lead compound Gu1215 is a promising candidate for further preclinical development to overcome intrinsic and acquired IMiD resistance in multiple myeloma.
Topics: Multiple Myeloma; Humans; Thalidomide; Drug Resistance, Neoplasm; Antineoplastic Agents; Angiogenesis Inhibitors; Cell Line, Tumor; Anti-Inflammatory Agents; Drug Evaluation, Preclinical
PubMed: 38927128
DOI: 10.3390/biom14060725 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024Multiple myeloma (MM) is an incurable malignant plasma cell diseases, the incidence of which is increasing year by year. The application of immunomodulators drugs,... (Review)
Review
Multiple myeloma (MM) is an incurable malignant plasma cell diseases, the incidence of which is increasing year by year. The application of immunomodulators drugs, proteasome inhibitors, anti-CD38 antibodies, CAR-T, and HSCT have significantly improved the prognosis of patients with MM, however new therapeutic tools need to be developed to improve the prognosis of patients with relapsed/refractory after conventional regimens treatment. Bispecific antibodies are a novel immunotherapeutic approach that generates immune synapses by binding to targets on malignant plasma cells and cytotoxic immune effector cells (T cells/natural killer cells), leading to T/NK cells activation and malignant plasma cell lysis. Several preclinical and phase I clinical studies have shown good efficacy, bringing new possibilities for patients with relapsed/refractory MM to improve their prognosis in the future in combination with the rest of the treatment options. This article summarizes the classification of bispecific antibodies developed in recent years, and the results of preclinical and clinical trials, which will provide some reference for treating MM.
Topics: Humans; Antibodies, Bispecific; Multiple Myeloma; Immunotherapy; Killer Cells, Natural; Prognosis; T-Lymphocytes
PubMed: 38926994
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.046 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the correlation between the stimulator of interferon genes ( ) promoter polymorphism and the susceptibility to infection after chemotherapy for multiple...
OBJECTIVE
To investigate the correlation between the stimulator of interferon genes ( ) promoter polymorphism and the susceptibility to infection after chemotherapy for multiple myeloma.
METHODS
A total of 102 patients who had undergone chemotherapy for multiple myeloma in our hospital from January 2016 to July 2022 were selected. Depending on the presence or absence of infection after chemotherapy, the enrolled patients were divided into infection group (53 cases) and non-infection group (49 cases). The infection sites and distribution characteristics of pathogenic bacteria of the infection group were analyzed. The genotype distribution of gene promoter rs587777609 was compared between the two groups, and the risk factors of infection after chemotherapy for multiple myeloma were analyzed.
RESULTS
For infection site, digestive system, respiratory system, urinary system, skin and mucous membranes accounted for 43.40%, 26.42%, 20.75%, and 9.43%, respectively. For pathogenic bacteria, Gram-negative bacteria, Gram-positive bacteria and fungi accounted for 57.14%, 26.98%, and 15.87%, respectively. The CC genotype frequency of gene rs587777609 locus in the infection group was lower than that in the non-infection group, while the TT genotype frequency was higher than that in the non-infection group ( < 0.05). The proportions of patients with diabetes, chronic obstructive pulmonary disease, renal insufficiency, serum albumin level< 35 g/L, ISS stage III, mechanical ventilation, and indwelling catheter in the infection group were higher than those in the non-infection group ( < 0.05). Multivariate logistic regression analysis showed that diabetes ( =1.992), serum albumin level< 35 g/L ( =2.782), ISS stage III ( =2.707), mechanical ventilation ( =3.031), and TT genotype ( =2.401) were risk factors of infection after chemotherapy for multiple myeloma ( < 0.05).
CONCLUSION
There is a correlation between promoter polymorphism and the susceptibility to infection after chemotherapy for multiple myeloma, and patients with TT genotype have a higher risk of infection.
Topics: Humans; Multiple Myeloma; Membrane Proteins; Promoter Regions, Genetic; Genotype; Risk Factors; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Male; Infections; Female
PubMed: 38926990
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.042 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the role of levofloxacin combined with recombinant human granulocyte colony-stimulating factor (G-CSF) or only G-CSF supportive therapy in preventing...
OBJECTIVE
To investigate the role of levofloxacin combined with recombinant human granulocyte colony-stimulating factor (G-CSF) or only G-CSF supportive therapy in preventing infection in autologous hematopoietic stem cell transplantation(ASCT), and to analyze the length of hospital stay, hospitalization cost and post-transplant survival of the patients.
METHODS
A retrospective analysis was performed in the patients with hematological malignancies who accepted ASCT at our hospital from January 2012 to July 2022, the febrile neutropenia, the incidence of bacterial infection and the use rate of intravenous antibiotics in the levofloxacin+G-CSF group and only G-CSF support group during ASCT were observed. The length of hospital stay, total cost during hospitalization and survival after 90 days of transplantation between the two groups were compared.
RESULTS
A total of 102 cases were included in this study, including 57 cases of multiple myeloma, 36 cases of acute leukaemia, 7 cases of lymphoma, 3 cases of myelodysplastic syndrome, 1 case of light chain amyloidosis, and 1 case of POEMS syndrome. 47 patients received levofloxacin+ G-CSF antibacterial prophylaxis, and 55 patients received G-CSF supportive therapy. In the levofloxacin+ G-CSF group, 40 cases (85.11%) developed febrile neutropenia, and 13 cases (27.66%) were confirmed as bacterial infection. In the G-CSF group, 44 cases (80.00%) developed febrile neutropenia, and 16 cases (29.09%) were bacterial infection. There was no statistically significant difference in the incidence of febrile neutropenia and bacterial infection between the two groups (χ=0.46, =0.50; χ=0.03, =0.87). The use rate of intravenous antibiotics in the levofloxacin+ G-CSF group was 85.11% (40/47), which was not statistically different from 85.45% (47/55) in the G-CSF group (χ=0.04, =0.84). The detection rates of levofloxacin-resistant bacteria in the levofloxacin+ G-CSF group and G-CSF group were 8.57% (3/35) and 21.43% (6/28), respectively, with no statistical difference (χ=0.65, >0.05). The median length and median cost of hospitalization in the levofloxacin+ G-CSF group and G-CSF group were 25 d 22 d and 78 216.24 yuan 80 724.38 yuan, with no statistically significant differences ( =3.00, =0.09; =0.94, =0.09). Within 90 days after transplantation, two cases (4.26%) died in the levofloxacin+ G-CSF group and one case (1.82%) died in the G-CSF group, with no statistically significant difference between the two groups (χ=0.53, =0.47).
CONCLUSION
Application of levofloxacin+ G-CSF showed no significant benefit compared to G-CSF support for the prevention of bacterial infections during ASCT.
Topics: Humans; Levofloxacin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Retrospective Studies; Transplantation, Autologous; Bacterial Infections; Anti-Bacterial Agents; Male
PubMed: 38926987
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.039 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To evaluate the clinical and prognostic value of prothrombin time (PT) and activated partial thromboplastin time (APTT) in newly diagnosed patients with multiple myeloma...
OBJECTIVE
To evaluate the clinical and prognostic value of prothrombin time (PT) and activated partial thromboplastin time (APTT) in newly diagnosed patients with multiple myeloma (MM).
METHODS
The clinical data of 116 newly diagnosed MM patients in the Second Hospital and Third Hospital of Shanxi Medical University from October 2014 to March 2022 were analyzed retrospectively, and the patients were divided into two groups: normal PT and APTT group and prolonged PT or APTT group. The differences in sex, age, classification, staging, bleeding events, laboratory indicators [including hemoglobin (Hb), platelet count (PLT), serum calcium, serum albumin (ALB), lactate dehydrogenase (LDH), serum creatinine and β-microglobulin], and cytogenetic characteristics between the two groups of patients were compared. The effect of prolonged PT or APTT on survival of patients with MM was analyzed.
RESULTS
Compared with patients in normal PT and APTT group, patients in prolonged PT or APTT group were more likely to experience bleeding events (=5.087, =0.024), with lower ALB levels (=4.962, =0.026) and PLT levels (=4.309, =0.038), and higher serum calcium levels (=5.056, =0.025). The positive rates of del17p, del13q and 1q21+ in prolonged PT or APTT group were higher than those in normal PT and APTT group, but the difference was not statistically significant ( >0.05). K-M survival analysis showed that the prolonged PT or APTT group had a shorter median progression-free survival (PFS) ( =0.032) and overall survival (OS) ( =0.032). Multivariate Cox analysis showed that prolonged PT or APTT (=2.116, 95% :1.025-4.372, =0.043) and age ≥65 years (=2.403, 95% : 1.195-4.836, =0.014) were independent risk factor for OS in newly diagnosed MM patients. However, prolonged PT or APTT had no significant effect on PFS of newly diagnosed MM patients (=1.162, 95% : 0.666-2.026, =0.597).
CONCLUSION
Newly diagnosed MM patients with prolonged PT or APTT have worse clinical indicators, shorter PFS and OS. Prolonged PT or APTT is an independent risk factor for OS in MM patients.
Topics: Humans; Multiple Myeloma; Partial Thromboplastin Time; Prognosis; Retrospective Studies; Prothrombin Time; Male; Female; Middle Aged
PubMed: 38926971
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.023 -
[Bone Metabolism of Multiple Myeloma Bone Disease Patients with Different Blood Separation Results].Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the clinical significance of bone metabolic indexes for disease assessment and curative effect monitoring in multiple myeloma (MM) bone disease (MBD)...
OBJECTIVE
To investigate the clinical significance of bone metabolic indexes for disease assessment and curative effect monitoring in multiple myeloma (MM) bone disease (MBD) patients with different blood separation results.
METHODS
A total of 134 newly diagnosed MM patients treated in Cangzhou Hospital of Integrated TCM-WM-Hebei were enrolled and divided into control group [119 cases, serum, colloid and red blood cell (RBC) from top to bottom of sample] and abnormal group (15 cases, serum, mixed layer of RBC and serum, colloid and RBC from top to bottom of sample) according to the results of blood separation. According to the imaging findings, MBD was classified into grade 0-4, grade 0-2 was mild, and grade 3-4 was severe. The MBD grade of patients in the two groups was analyzed. The curative effect of MBD patients after chemotherapy and the changes of blood separation results and bone metabolic indexes before and after treatment were evaluated. The correlation between β-microglobulin (MG) and bone metabolic indexes was analyzed by Pearson correlation analysis.
RESULTS
In the control group, there were 69 cases of grade 0-2 and 50 cases of grade 3-4, while in the abnormal group, there were 5 cases of grade 0-2 and 10 cases of grade 3-4, the difference was statistically significant ( < 0.05). The serum β-MG, β-CTX levels in abnormal group were both significantly higher than those in control group, while the levels of P1NP and osteocalcin (OC) were significantly lower (all < 0.001). In the control group, there were 95 patients with ≥ partial response (PR) and the blood separation results were not changed, while 24 patients with
0.05). Compared with before treatment, the levels of β-CTX and β-MG in the control group with unchanged blood separation results were significantly decreased (both < 0.001), while the levels of P1NP and OC were significantly increased ( < 0.01, < 0.001), and the level of each index in the patients transformed to abnormal blood separation result after treatment did not significantly change ( >0.05); the levels of β-CTX and β-MG in the abnormal group transformed to normal blood separation result were significantly decreased (both < 0.01), while the levels of P1NP and OC were significantly increased ( < 0.001, < 0.01), and the level of each index in patients with unchanged blood separation results did not significantly change (P>0.05). Pearson correlation analysis showed that serum β-MG was positively correlated with β-CTX ( =0.709, < 0.001), and negatively correlated with P1NP and OC ( =-0.410, =-0.412, both < 0.001). CONCLUSION
MBD patients with abnormal blood separation results have higher bone disease grade and poor prognosis, which is closely related to the significant increase of bone resorption index β-CTX level and decrease of bone formation index P1NP and OC levels, leading to more serious bone metabolic homeostasis disorder. The results of blood separation combined with the changes of bone metabolic indexes can be used as one of the comprehensive predictors of disease condition, efficacy monitoring and prognosis evaluation of MBD patients.
Topics: Humans; Multiple Myeloma; Bone and Bones; Bone Diseases; beta 2-Microglobulin; Collagen Type I; Osteocalcin; Male; Middle Aged
PubMed: 38926970
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.022