Complex cytogenetic research of cryptic chromosomal aberrations in patients with multiple myeloma

Background . Multiple myeloma (MM) is a malignant lymphoproliferative B-cell disease characterization by clonal proliferation of plasma cells in the bone marrow and beyond its borders. Currently, a wide range of cytogenetic anomalies and molecular-biological parameters are studied as prognostic factors.Objective: a comparative study of the frequency, features and clinical significance of chromosomal abnormalities in MM by conventional cytogenetic and fluorescent in situ hybridization (FISH) methods.Materials and methods . 77 patients with MM, which admitted in N.N. Blokhin National Medical Research Center of Oncology, were included in the study from 2016 to 2017.Results . Chromosomal alterations were detected only in one case (1/77) by conventional cytogenetic method G-banding. However cytogenetic aberrations were revealed in 26 % of cases (20/77) using FISH. Deletions of different regions of chromosomes, indicating the possible presence of a hypodiploid clone or loss of some regions, were found in one patient in the second FISH analysis after 6 months. In the cohort of patients with chromosomal abnormalities (n = 20) a partial trisomy 11q, a deletion of the region q32 of the chromosome 14, a translocation t(4;14)(p16;q32) and IGHV gene rearrangement were determined in 30 % (6/20) as sole anomalies. Two or more cytogenetic aberrations were identified in the remaining 14 patients. Our study confirms that chromosomal abnormalities are more likely detected at later stages of MM (IA и IIA – 0 %, IIIA и IIIВ – 27 and 47 % respectively).Conclusion . FISH allows to detect chromosomal changes in tumor plasma cells regardless of the mitosis phase. In MM, it becomes particularly important in connection with low proliferative activity of plasma cells. Additionally, in the fourth of MM patients in the study submicroscopic chromosomal aberrations were discovered using FISH. The improvement of the probe panel and the widespread use of locus specific FISH don’t replace G-banding that allows to see damages of all chromosomes at once.

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The Chromosomal Abnormalities Del(17p), t(4;14), and +1q21 Predict Progression From Smoldering to Symptomatic Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.1806.1806 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1806-1806 ◽

Cited By ~ 1

Author(s):

Kai Neben ◽

Anna Jauch ◽

Thomas Hielscher ◽

Jens Hillengass ◽

Nicola Lehners ◽

...

Keyword(s):

Multiple Myeloma ◽

Risk Score ◽

Chromosomal Aberrations ◽

Plasma Cells ◽

Chromosomal Abnormalities ◽

Conflicts Of Interest ◽

Statistical Significance ◽

Entire Group ◽

Fish Analysis ◽

Prognostic Impact

Abstract Abstract 1806 Background: Smoldering Multiple Myeloma (SMM) is a plasma cell disorder defined by the presence of ≥10% plasma cells in bone marrow and/or a monoclonal protein level of ≥3 g/dl in serum without organ damage. The aim of the study was to analyze the prognostic impact of chromosomal aberrations on time to progression (TTP) from SMM to symptomatic MM. Design and Methods: For selection of the patients, we used the same criteria as previously described by Kyle (Kyle et al., NEJM, 2007). We analyzed the prognostic value of 5 chromosomal abnormalities and hyper-/non-hyperdiploidy (HD and NHD, respectively) in a series of 231 patients with SMM by fluorescent in situ hybridization (FISH). Gains of at least 2 of the 3 chromosomes 5, 9, and 15 defined HD status. Results: Interphase-FISH analysis on CD138-enriched plasma cells detected gains of chromosomes 1q21 (29.4%) as well as deletions of chromosomes 13q14 (19.3%) and 17p13 (6.1%). Furthermore, the IgH-translocations t(4;14) and t(11;14) were observed in a frequency of 9.2% and 22.3%, respectively. The presence of t(4;14) was correlated with the serum heavy chain IgA (p<0.001). For the entire group, the median TTP was 4.9 years (95% CI, 3.9 – NA). Of all analyzed chromosomal abnormalities, del(17p13), t(4;14), and +1q21 showed a significant impact on TTP, whereas the presence of t(11;14) and del(13q14) was of no statistical significance. The median TTP for patients with del(17p13) was 2.7 years (vs. 4.9 years without, p=0.019), with t(4;14) 2.9 years (vs. 5.2 years without, p=0.021), and with +1q21 3.7 years (vs. 5.3 years without, p=0.013), respectively. In addition, HD was associated with a statistically shorter median TTP of 3.9 vs. 5.7 years in patients with NHD, respectively (p=0.036). A multivariate analysis identified t(4;14), +1q21, HD, reduction of uninvolved immunoglobulins (no.), and the risk score defined by Kyle et al. as independent factors for adverse outcome. Conclusions: The study shows that the overall risk of progression in SMM is significantly influenced by markers for tumor burden (i.e. Kyle risk score) as well as the presence of the chromosomal aberrations del(17p13), t(4;14), and +1q21. Our findings provide evidence that specific chromosomal aberrations are not only associated with early tumor progression and drug resistance in patients with overt MM but also to drive transition from asymptomatic into symptomatic stage of disease. Disclosures: No relevant conflicts of interest to declare.

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Correlation between Immunoglobulin Gene Rearrangements and Chromosomal Abnormalities in Multiple Myeloma.

Blood ◽

10.1182/blood.v110.11.4771.4771 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4771-4771

Author(s):

Giovanna Piras ◽

Maria Monne ◽

Antonella Uras ◽

Laura Pilo ◽

Luciana Arca ◽

...

Keyword(s):

Multiple Myeloma ◽

Chromosomal Abnormalities ◽

Normal Karyotype ◽

Fish Analysis ◽

Immunoglobulin Gene ◽

Cytogenetic Aberrations ◽

Oncogenic Pathways ◽

Clonality Analysis ◽

Conventional Cytogenetics ◽

Clonogenic Cell

Abstract Background: Multiple Myeloma (MM) is characterized by frequent and complex genetic abnormalities that contribute to the pathogenesis and its prognostic eterogeneity. There is evidence for two oncogenic pathways in the early development of clonal plasma cell disorder: i) non-hyperdiploid carring translocation of the immunoglobulin heavy-chain locus and various oncogenes ii) hyperdiploid tumors with infrequent IgH translocation. The MM clonogenic cell is positively selected during the development and reaction of the germinal center. The immunoglobulin gene (IG) repertoire in MM follows a pattern similar to that of the normal repertoire. However, available data from analysis of IGH and IGK/L genes according to cytogenetic aberrations are limited. In the present study we investigated the frequency and characteristics of IGK and incomplete DJH as well as complete VDJH rearrangements in parallel with chromosomal abnormalities in a series of untreated MM patients. Materials and Methods. Bone marrow aspirates were collected from 53 MM patients with a mean age of 69.6 (range 48–84) between 2003–2007. The serum monoclonal component was IgG and IgA in the 77% and 22% patients respectively; 1 patient presented with IgD k MM. Cytogenetics and FISH analysis were performed simultaneously in 37 MM. In 18 (50.5%) samples kariotype analysis was successful. Interphase FISH analysis was perfomed using a set of probes specific for RB-1 (13q14), D13S319 (13q14.3), IgH (14q32), and p53 (17p13.1) loci, t(4;14), t(14;16), t(11;14) and a multicolor probe set for detection of aneuploidy (Vysis, Downers Grove, IL, USA). Genomic DNA was isolated for clonality analysis. IGHV-J, IGHD-J, IGKV-J, IGKV-KDE, IGKJ-C-INTRON-KDE rearrangements were amplified by PCR and analyzed following the BIOMED-2 protocol. Results: Conventional cytogenetics allowed to detect 16 patients with a normal kariotype, 1 hyperdiploid kariotype with monosomy 13, 1 hyperdiploid kariotype with 3q21 deletion. FISH panel analysis resulted in 4 patients with hyperdiploid kariotype and 7 with abnormalities for RB-1 and/or D13S319. IGH rearrangements were detected in 3 patients and the t (4;14) was found in 1 case. The p53 deletion, t(11;14) and t(14;16) were not detected. The overall detection rate of clonality by amplifying VDJH and DJH rearrangements using family-specific primers was 90%. We found a high frequency (71.7%) of DJH rearrangements with DH3 segment under represented (4%). The DH7 segment was rearranged in the 15% of MM. Incomplete DJH and complete VDJH rearrangements were present at frequencies of 20% and 29.5%, respectively. IGK locus rearrangements were detected in 38 out of 53 MM and the 60% presented the non-productive IGKV-KDE and IGKJ-C-INTRON-KDE rearrangements. Parallel analysis of clonality pattern and chromosomal abnormalities showed that complete VDJH rearrangements were present in all hyperdiploid MM and in a small proportion (4/16) of the MM with normal karyotype. Conclusions: Our results confirm previous estimations about IgH repertoire usage. Despite the small numbers, our findings indicate that complete Ig rearrangements might be correlated with hyperdiploid MM. Combining cytogenetics and IgH clonality studies might help to identify distinct subgroups of MM and provide a framework for dissection of disease prognosis and clinical management. Research funded by Regione Autonoma Sardegna.

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Occurrence of Chromosomal Abnormalities In Bone Marrow CD14+ monocytes of Multiple Myeloma Patients

Blood ◽

10.1182/blood.v116.21.2968.2968 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2968-2968

Author(s):

Hana Svachova ◽

Henrieta Greslikova ◽

Aneta Mikulasova ◽

Kristina Berankova ◽

Pavel Nemec ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Pilot Study ◽

Chromosomal Aberrations ◽

Gene Rearrangement ◽

Plasma Cells ◽

Chromosomal Abnormalities ◽

Common Precursor ◽

Igh Gene Rearrangement ◽

Endothelial Precursors

Abstract Abstract 2968 Introduction: Increased bone marrow angiogenesis is a characteristic feature of multiple myeloma (MM). New blood vessels formation is provided by recruiting vascular endothelial cells from existing capillaries or circulating endothelial progenitor cells (EPC). EPCs have distinct monocytic features and can be cultured from CD14+ cells. In addition, monocytes were shown to contribute to angiogenesis as EPCs in vivo. It has been established that myeloid progenitor cells participate in the development of endothelial precursors. In MM, it has been reported that circulating EPCs carried the same chromosomal aberrations as neoplastic plasma cells (PC). It is possible that EPCs originate from common precursor that gives rise to both PCs and endothelial cells. The purpose of our pilot study was to clarify whether myeloid cells, CD14+ monocytes (CD14+MO), in MM might carry the same chromosomal abnormalities as CD138+PC. Methods: Total of 15 MM patients were enrolled in this pilot study; 93 % (14/15) typical MM; 7 % (1/15) plasma cell leukemia (PCL). CD138+PCs were isolated by magnetic-activated cell separation (MACS) from bone marrow mononuclear cells (BMMNC). CD14+MOs were isolated by fluorescence-activated cell sorting (FACS) from BMMNC after isolation of CD138+PCs. The purity of both cell populations was > 90%. Distinct BM cell fractions were analyzed for del(13q14), del(17p53), IgH gene rearrangement, hyperdiploidy and trisomy of chromosomes 5, 9, 15 by interphase fluorescence in situ hybridization (FISH) according to standard protocol. The cut-off level for detection of choromosomal aberarations was set to 20%. Results: FISH analysis proved at least one of studied chromosomal abnormalities in 20% (3/15) of MM patients (See Table 1; No.1 – No.3). In case No.1, a patient with PCL, CD14+MOs were positive for del(13q14)(31%), IgH gene rearrangement (46%) and trisomy 9 (47%). The same aberrations were found in CD138+PCs but with higher frequency (Table 1). Patient No.2 was positive for del(13q14)(35%) and for del(17p53)(39%) in CD14+MO but in CD138+PCs, the patient was positive further for hyperdiploidy (53%) and trisomy 5 (28%), 9 (56%) and 15 (60%). CD14+MOs of patient No.3 were positive only for trisomy 15 (25%) which corresponded to trisomy 15 (24%) in CD138+PCs. Other chromosomal abnormalities found in CD138+PCs of No.3 were not detected in CD14+MOs. Chromosomal aberrations identified in CD14+MOs of No.4 – No.15 did not reach the cut-off level for positivity (Table 1). Conclusion: In our pilot study, we demonstrated for the first time that bone marrow CD14+ monocytes of MM patients carried the same chromosomal aberrations as CD138+ plasma cells. The possible explanation is that CD14+MOs and CD138+PCs may origin from a common precursor. We hypothesize that myeloid cells might play a role in blood vessel formation as endothelial precursors and might be important in pathogenesis of multiple myeloma. It requires further study to elucidate the relationship between two distinct bone marrow populations and a potential role of CD14+cells in disease severity. Supported with research program MSM of Czech republic Nr. 0021622434 and LC06027. Disclosures: No relevant conflicts of interest to declare.

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Multiple Myeloma: Clinical Implications of Cytogenetic Aberrations on Selected Plasma Cells on Conventional Cytogenetics and Interphase Flourescence In Situ Hibridization (FISH)

Blood ◽

10.1182/blood.v116.21.4987.4987 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4987-4987 ◽

Cited By ~ 1

Author(s):

Rakesh Verma ◽

Lalit Kumar ◽

Ashutosh Halder ◽

Atul Sharma ◽

Ritu Gupta ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Chromosomal Abnormalities ◽

Conflicts Of Interest ◽

Response To Therapy ◽

Novel Agents ◽

Cytogenetic Aberrations ◽

Bone Marrow Plasma ◽

Conventional Cytogenetics

Abstract Abstract 4987 Purpose: We prospectively studied patients of multiple myeloma (MM) for presence of t(14q32), and del13q14 on FISH and numerical chromosomal abnormalities on conventional cytogenetics(CC). Methods: Between February 2007 and June 2009, 90 previously untreated patients of MM were enrolled, Patient's median age was 55 years (range, 34 to 75 years) and 67 were males (M: F: 2.9: 1). 24 patients had ISS stage I, stage II-46 & 20 patients had stage III. Purified bone marrow plasma cells, using magnetic activated cell sorter with CD138 micro beads were used. Conventional cytogenetics for numerical chromosomal abnormalities and FISH for deletion 13q14 (RB-1) and 14q32 (IgH) translocations was carried out on these purified plasma cells. 65/90 (72%) patients received therapy; using novel agents, n=54 (thalidomide-dexamethasone (n=50), Lenalidomide-dexamethasone (n=4)) and melphalan, prednisolone and thalidomide (MPT, n=11). Response was evaluated post 4 cycles using EBMT response criteria. Results: Metaphases could be obtained on CC in 53/90 patients (58%); with numerical abnormalities in 21: hyperdiploid -16 & hypodiploid in 5. Del 13q14 and t (14q32) by FISH was present in 51 (56%) and 75 (83%) patients, respectively. t (14q32) was present more in patients with ISS-III (p<.008). Presence of del13q14 correlated with BM plasma cells >40% (P<.007) and Hb ≤9.2G/dl (p=.06). Following therapy, 49/65 patients (75.2%) achieved significant response (CR+VGPR+PR). Patients aged ≤55 years (P = 0.07), those with ISS- I (P <0.05), IgG-kappa (P<0.04) and with absence of del13q14 (P = 0.04) responded better. The median overall survival (OS) has not reached yet, median event-free survival (EFS) is 33 months (95% CI 18–48). Estimated OS and EFS at 2 years is 77% and 50 %, respectively. Durie Salmon stage IIIB (HR 3.6) and response to therapy (HR 7.8) were significant predictors of OS. For EFS - del13q14 (HR 2.7, P <0.036), response to therapy (HR 2.7,P<0.01) and use of novel agents (HR 3.1, (P<0.008) were important predictors. Conclusion: Chromosomal abnormalities including IgH translocations and del13q14 with numerical chromosomal abnormalities are common in MM patients at diagnosis and can predict the treatment outcome and survival. Disclosures: No relevant conflicts of interest to declare.

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Extramedullary Relapse of Multiple Myeloma - Plasma Cells Characteristics.

Blood ◽

10.1182/blood.v120.21.2935.2935 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2935-2935

Author(s):

Ludek Pour ◽

Sabina Sevcikova ◽

Lucie Rihova ◽

Lenka Kubiczkova ◽

Henrietta Greslikova ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Soft Tissues ◽

Plasma Cells ◽

Chromosomal Abnormalities ◽

Conflicts Of Interest ◽

Fish Analysis ◽

Extramedullary Relapse ◽

Igh Rearrangement ◽

Lower Expression

Abstract Abstract 2935 Background: Multiple myeloma (MM) is the second most common hematological malignancy in the world. The introduction of new drugs (thalidomide, bortezomib, revlimid) has dramatically improved survival of MM patients, but MM still remains an incurable disease. Unfortunately, an increase in the incidence of extramedullary relapse of MM (EM), an aggressive mostly resistant entity with abysmal prognosis for patients has been reported. EM can affect any area of tissue - soft tissue involvement can be with or without relationship to bone. A recent study of 936 MM patients by Usmani et al (2012) reported presence of EM in the skin and soft tissues at the time of diagnosis while liver involvement was common at relapse or progression. Aims: The objective of this study was to evaluate cytogenetic and flowcytometric data of available set of EM patients, and also to compare characteristics of plasma cells isolated from bone marrow and the extramedullary tumor. Material and methods: In total, we evaluated 29 EM patients. Patients' characteristics were as follows: males/females 18/11, median age was 61.2 years, ISS stage I/II/III 1/5/23, IgG/IgA/ LC only 20/6/3. I-FISH analysis was performed on bone marrow (BM) samples obtained at the time of diagnosis of EM. Flowcytometric analysis was performed on plasma cells (PC) isolated from BM as well as the EM tumor. Results: Using flowcytometry, PC were identified as CD138+CD38+ leukocytes and surface expression of CD20, CD27, CD28, CD33, CD40, CD54, CD117, CD19 and CD56 were analysed on PC in whole BM and the tumor. We found statistically significant decrease of CD27 (60.0 vs. 9.1% positivity in BM vs. tumor, resp.; p<0.02) and CD19 (35.0 vs. 8.3%; p=0.001). Other markers were non-significantly decreased: CD33 (27.3 vs. 12.5%), CD40 (84.6 vs. 75.0%), CD54 (84.6 vs. 50.0%), CD117 (26.7 vs. 16.7%), CD56 (70.0 vs. 58.3%) while expression of CD28 was increased (13.3 vs. 33.3%) on tumor PC compared to BM PC. In the BM PC, we found del(13)(q14) in 67% (18/27), del(17)(p13) in 22% (6/27), IGH rearrangement in 58% (11/19), t(4;14) in 33% (6/18), 1q21 gain in 58% (15/26), hyperdiploidy in 43% (10/23) of EM patients. The total number of aberrations per patient was: 0–1 aberration in 31%, 2–3 aberrations in 62%, 4 aberrations in 7% of MM patients BM. For 4 patients, we were able to analyze both BM and the EM tumor. We found that in 2/4 patients, there was no agreement in chromosomal abnormalities found in the BM and EM tumor. The differences were in del(13)(q14) and IGH rearrangement. del(13)(q14) was present in all 100% (4/4) samples of BM but only 75% (3/4) of EM tumors. del(17)(p13) was present in 25% (1/4) of patients in the BM as well as EM. IGH rearrangement was present in 75% (3/4) of BM but only 25% (1/4) of EM. 1q21 gain was present in 50% (1/2) of patients in the BM and EM and hyperdiploidy was not present in the BM or EM tumor (0/2). Conclusion: Chromosomal abnormalities connected to worse prognosis are more common in EM patients. PC phenotype seems to be different in cells obtained from BM and EM tumor. PC from EM tumor had significantly lower expression of CD27 and CD19. CD27 is a tumor necrosis factor receptor and plays a key role in regulating B-cell activation and immunoglobulin synthesis. Its low expression could be one of the main reasons for resistance in MM while loss of CD19 can create a proliferative advantage for the malignant plasma cell clone. Other interesting markers are CD54 and CD56 which were non-significantly decreased. CD54 also known as ICAM-1 plays a key role in stabilizing cell-cell interactions and migration, and CD56 (NCAM) is important for adhesion of PC to the bone marrow microenvironment. CD54 and CD56 lower expression may be the reason for EM development in MM but their role needs to be further elucidated. Acknowledgment: This study was supported by grants NT12130, MSM0021622434, NS10207, NT11154. Disclosures: No relevant conflicts of interest to declare.

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Cytogenetic Abnormalities in Histologically Confirmed Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.5082.5082 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5082-5082

Author(s):

Anwar N. Mohamed ◽

Gail Bentley ◽

Michelle L. Bonnett ◽

Margareta Palutke ◽

Ayad M. Al-Katib

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Chromosomal Abnormalities ◽

Molecular Genetic ◽

Fish Analysis ◽

Abnormal Karyotype ◽

Proliferation Activity ◽

Genetic Techniques ◽

Conventional Cytogenetics ◽

Monitor Treatment Response

Abstract In multiple myeloma, conventional cytogenetics is limited by low proliferation activity of plasma cells in culture. Despite that, nonrandom chromosomal abnormalities have been reported in one third of cases. Recently, the karyotype has emerged as an important prognostic factor in multiple myeloma. In this study, we identified 104 histologically confirmed multiple myeloma cases with satisfactory cytogenetic evaluation and abnormal karyotype. FISH analysis was used to evaluate certain chromosome abnormalities or to monitor treatment response. Hyperdiploid karyotype was found in 67 cases (64%), hypodiploid in 25 cases (24%), and the remaining 12 cases (12%) had a pseudodiploid karyotype. The most common numerical abnormalities were gains of chromosomes 9, 15, 3 followed by chromosomes 19, 21, 11, 7, and 5. Whole chromosome losses were also frequent involving primarily chromosomes 13, 8, 14, 22, and 16. In the hypodiploid cases, loss of chromosome 13 was more evident, seen in 19/25 (76%) cases. Most cases showed also structural rearrangements leading to del(1p), dup(1q), del(6q), del(9p), del(13q), del(17p), del(8p), 3p/3q abnormalities, and 11p/11q abnormalities. Translocations affecting 14q32/IGH region was the most frequent seen 36 times in 34/104 (33%) cases; t(11;14)(q13;q32) in 13 cases, t(1;14), t(6;14), and t(8;14) in 2 cases each, and the remaining cases had various t(V;14) partners or of an undetermined origin. The 14q32/IGH translocations were less frequent in the hyperdiploid karyotypes than the hypodiploid and pseudodiploid karyotypes (18% vs 60%). Nine cases showed break at 8q24/CMYC site; six of those had Burkitt’s-type translocations. Other non-random translocation was t(1;16) seen in three cases. Coventional cytogenetic remains an important tool in elucidating the complex and diverse genetic anomalies of multiple myeloma. Acccordingly well defined cytogenetic subgroups can be identified. At the present time, FISH and other molecular genetic techniques are important adjuncts, but should not be a substitute for conventional karyotyping. The clinical and hematological correlates of the karyotype in our series is being evaluated.

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Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma

Applied Sciences ◽

10.3390/app11104451 ◽

2021 ◽

Vol 11 (10) ◽

pp. 4451

Author(s):

Coralia Cotoraci ◽

Alina Ciceu ◽

Alciona Sasu ◽

Eftimie Miutescu ◽

Anca Hermenean

Keyword(s):

Multiple Myeloma ◽

Survival Rate ◽

Plasma Cells ◽

Inhibition Of Proliferation ◽

In Vivo Experiments ◽

Clonal Proliferation ◽

Hematological Cancers ◽

Monoclonal Proteins

Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.

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Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects

Current Oncology ◽

10.3390/curroncol28010063 ◽

2021 ◽

Vol 28 (1) ◽

pp. 640-660

Author(s):

Grace Lassiter ◽

Cole Bergeron ◽

Ryan Guedry ◽

Julia Cucarola ◽

Adam M. Kaye ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Hematologic Malignancy ◽

Drug Efficacy ◽

Treatment Modalities ◽

Blurred Vision ◽

Refractory Multiple Myeloma ◽

Therapeutic Modalities ◽

Clonal Proliferation ◽

Refractory State

Multiple myeloma (MM) is a hematologic malignancy characterized by excessive clonal proliferation of plasma cells. The treatment of multiple myeloma presents a variety of unique challenges due to the complex molecular pathophysiology and incurable status of the disease at this time. Given that MM is the second most common blood cancer with a characteristic and unavoidable relapse/refractory state during the course of the disease, the development of new therapeutic modalities is crucial. Belantamab mafodotin (belamaf, GSK2857916) is a first-in-class therapeutic, indicated for patients who have previously attempted four other treatments, including an anti-CD38 monoclonal antibody, a proteosome inhibitor, and an immunomodulatory agent. In November 2017, the FDA designated belamaf as a breakthrough therapy for heavily pretreated patients with relapsed/refractory multiple myeloma. In August 2020, the FDA granted accelerated approval as a monotherapy for relapsed or treatment-refractory multiple myeloma. The drug was also approved in the EU for this indication in late August 2020. Of note, belamaf is associated with the following adverse events: decreased platelets, corneal disease, decreased or blurred vision, anemia, infusion-related reactions, pyrexia, and fetal risk, among others. Further studies are necessary to evaluate efficacy in comparison to other standard treatment modalities and as future drugs in this class are developed.

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The Evolution in The Treatment of Multiple Myeloma Towards Targeted Magnetic Molecularly Imprinted Nanomedicines

Edelweiss: Cancer Open Access ◽

10.33805/2689-6737.101 ◽

2015 ◽

pp. 1-2

Author(s):

Edgar Pérez-Herrero

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bacterial Infections ◽

Plasma Cells ◽

The Body ◽

Western World ◽

Bone Lesions ◽

Non Hodgkin Lymphoma ◽

Clonal Proliferation ◽

Tract Infections

Multiple myeloma is the second more frequently haematological cancer in the western world, after non-Hodgkin lymphoma, being about the 1-2 % of all the cancers cases and the 10-13% of hematologic diseases. The disease is caused by an uncontrolled clonal proliferation of plasma cells in the bone marrow that accumulate in different parts of the body, usually in the bone marrow, around some bones, and rarely in other tissues, forming tumor deposits, called plasmocytomas. This uncontrolled clonal proliferation of plasma cells produces the secretion of an abnormal monoclonal immunoglobulin (paraprotein or M-protein) and prevents the formation of the other antibodies produced by the normal plasma cells that are destroyed. The anormal secretion of paraproteins unbalance the osteoblastosis and osteoclastosis processes, leading to bone lesions that cause lytic bone deposits and the release of calcium from bones (hypercalcemia) that may produce renal failure. Regions affected by bone lesions are the skull, spine, ribs, sternum, pelvis and bones that form part of the shoulders and hips. The substitution of the healthy bone marrow by infiltrating malignant cells and the inhibition of the normal production of red blood cells produce anaemia, thrombocytopenia and leukopenia. Multiple myeloma patients are immunosuppressed because of leukopenia and the abnormal immunoglobulin production caused by the uncontrolled clonal proliferation of plasma cells, being susceptible to bacterial infections, like pneumonias and urinary tract infections. The interaction of immunoglobulin with hemostatic mechanisms may lead to haemorrhagic diathesis or thrombosis. Also, disorders of the central and peripheral nervous system are part of the disease, being the more common neurological manifestations the spinal cord compressions and the peripheral neuropathies.

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Identification of the Cysteine Protease Legumain as a Potential Chronic Hypoxia-Specific Multiple Myeloma Target Gene

Cells ◽

10.3390/cells11020292 ◽

2022 ◽

Vol 11 (2) ◽

pp. 292

Author(s):

Ada-Sophia Clees ◽

Verena Stolp ◽

Björn Häupl ◽

Dominik C. Fuhrmann ◽

Frank Wempe ◽

...

Keyword(s):

Multiple Myeloma ◽

Cysteine Protease ◽

Chronic Hypoxia ◽

Plasma Cells ◽

Hematologic Malignancy ◽

Low Oxygen ◽

Clonal Proliferation ◽

Temporal Adaptation ◽

Specific Regulation

Multiple myeloma (MM) is the second most common hematologic malignancy, which is characterized by clonal proliferation of neoplastic plasma cells in the bone marrow. This microenvironment is characterized by low oxygen levels (1–6% O2), known as hypoxia. For MM cells, hypoxia is a physiologic feature that has been described to promote an aggressive phenotype and to confer drug resistance. However, studies on hypoxia are scarce and show little conformity. Here, we analyzed the mRNA expression of previously determined hypoxia markers to define the temporal adaptation of MM cells to chronic hypoxia. Subsequent analyses of the global proteome in MM cells and the stromal cell line HS-5 revealed hypoxia-dependent regulation of proteins, which directly or indirectly upregulate glycolysis. In addition, chronic hypoxia led to MM-specific regulation of nine distinct proteins. One of these proteins is the cysteine protease legumain (LGMN), the depletion of which led to a significant growth disadvantage of MM cell lines that is enhanced under hypoxia. Thus, herein, we report a methodologic strategy to examine MM cells under physiologic hypoxic conditions in vitro and to decipher and study previously masked hypoxia-specific therapeutic targets such as the cysteine protease LGMN.

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