Chemotherapy In Multiple Myeloma Research Articles

Loss of GABARAP mediates resistance to immunogenic chemotherapy in multiple myeloma

AbstractImmunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant antitumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABA type A receptor–associated protein (GABARAP) is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment. GABARAP is located on chromosome 17p, which is commonly deleted in patients with high risk MM. GABARAP deletion impaired the exposure of the eat-me signal CRT on the surface of dying MM cells in vitro and in vivo, thus reducing tumor cell phagocytosis by dendritic cells and the subsequent antitumor T-cell response. Low GABARAP was independently associated with shorter survival in patients with MM and reduced tumor immune infiltration. Mechanistically, we found that GABARAP deletion blocked ICD signaling by decreasing autophagy and altering Golgi apparatus morphology, with consequent defects in the downstream vesicular transport of CRT. Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure, and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, such as bortezomib, with an autophagy inducer, such as rapamycin, may improve patient outcomes in MM, in which low GABARAP in the form of del(17p) is common and leads to worse outcomes.

Abstract P24: GABARAP deficiency drives resistance to immunogenic chemotherapy in multiple myeloma

Abstract P24: GABARAP deficiency drives resistance to immunogenic chemotherapy in multiple myeloma

The immunological effect of high-dose chemotherapy in multiple myeloma

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CD38-targeted and erythrocyte membrane camouflaged nanodrug delivery system for photothermal and chemotherapy in multiple myeloma

Multiple myeloma (MM) is a malignant and incurable disease. Chemotherapy is currently the primary treatment option for MM. However, chemotherapeutic drugs can interrupt treatment because of serious side effects. Therefore, development of novel therapeutics for MM is essential. In this study, we designed and constructed an innovative nanoparticle-based drug delivery system, P-R@Ni3P-BTZ, and investigated its feasibility, effectiveness, and safety both in vitro and in vivo. P-R@Ni3P-BTZ is a nanocomposite that consists of two parts: (1) the drug carrier (Ni3P), which integrates photothermal therapy (PTT) with chemotherapy by loading bortezomib (BTZ); and (2) the shell (P-R), a CD38 targeting peptide P-modified red blood cell membrane nanovesicles. In vitro and in vivo, it was proven that P-R@Ni3P-BTZ exhibits remarkable antitumor effects by actively targeting CD38 + MM cells. P-R@Ni3P-BTZ significantly induces the accumulation of intracellular reactive oxygen species (ROS) and increases the apoptosis of MM cells, which underlies the primary mechanism of its antitumor effects. In addition, P-R@Ni3P exhibits good biocompatibility and biosafety, both in vitro and in vivo. Overall, P-R@Ni3P-BTZ is a specific and efficient MM therapeutic method.

Association of myeloid-derived suppressor cells with hematopoietic recovery after high-dose chemotherapy in multiple myeloma

Myeloid-derived suppressor cells (MDSCs) play an important role in the immune response regulation in many pathologies, primarily in malignant tumors, but their role in the hematopoietic stem cell engraftment and the hematopoietic recovery after high-dose chemotherapy and autologous stem cell transplantation remains practically unexplored. This study is aimed at studying the correlation between the number of MDSC subpopulations and blood parameters at the stage of hematopoietic recovery after high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with multiple myeloma (MM). Circulating MDSCs were assessed at the stage of leukopenia recovery (absolute leukocyte count in peripheral blood (PB) > 1 x 109/L) by flow cytometry. The number of transplanted CD34+CD45+ hematopoietic stem cells was 4.38 x 106/kg (IQR (3.1—5.6) x 106/kg). The duration of recovery from leukopenia varied from 8 to 18 days (Me 12 days). The number of MDSCs at the engraftment was not associated with the number of CD34+ cells/kg in the graft. The relative number of monocytic MDSCs (M-MDSCs, CD14+HLA-DRlow/-) directly correlated with the number of monocytes at the stage of recovery from leukopenia (R = 0.417, p = 0.002). Granulocytic MDSCs (PMN-MDSCs, Lin-HLA-DR-CD33+CD66b+) were characterized by an inverse correlation with the number of monocytes (R = -0.493, p = 0.0003) while the association with the absolute number of neutrophils was weak (R = 0.273, p = 0.048). The number of lymphocytes at the stage of recovery from leukopenia had an inverse correlation with PMN-MDSCs (R = -0.347, p = 0.014) and did not correlate with M-MDSCs. When analyzing the duration of leukopenia, an inverse correlation with this indicator was revealed for the percentage and absolute number of M-MDSCs (R = -0.347, p = 0.018 and R = -0.469, p = 0.0008, respectively). Multiple regression analysis showed dependence of the lymphopenia duration on the proportion of circulating M-MDSCs (p = 0.014) and the number of transplanted CD34+ cells/kg (p = 0.032). According to the data of multivariate analysis of variance, the number of transplanted CD34+ cells/kg and the number of M-MDSCs were significant factors for the duration of leukopenia. At the same time, such clinical parameters as the depth of response and minimal residual disease status before high-dose chemotherapy and hematopoietic stem cell transplantation, as well as the MM stage, did not affect the duration of hematopoietic recovery. Thus, the obtained results indicate the association of a higher number of M-MDSCs with a shorter duration of leukopenia after high-dose chemotherapy with autologous stem cell transplantation and indicate a positive role of M-MDSCs in hematopoietic recovery in the early post-transplant period in patients with MM.

Evaluating process utilities for the treatment burden of chemotherapy in multiple myeloma in Japan: a time trade-off valuation study

AimsThis study estimated the “process utilities” of treatment options for patients with relapsed/refractory multiple myeloma (RRMM) in Japan using the time trade-off (TTO) method. Chimeric antigen receptor (CAR) T cell immunotherapy is available for patients with RRMM who are triple-class exposed (TCE) after treatment with immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies. However, the impact of available treatment options on health state utilities has not been well characterized, particularly in relation to process utilities.MethodsEight vignettes of health states and daily activity restrictions related to each of the following RRMM therapies were prepared: no treatment, CAR T cell therapy with idecabtagene vicleucel (ide-cel), regular intravenous infusion, and oral administration. A face-to-face survey of healthy Japanese adults who were representative of the general population was conducted. The TTO method was used to evaluate each vignette and to generate utility scores for each treatment regimen.ResultsThree hundred and nineteen respondents participated in the survey (mean age: 44 years [range: 20–64]; female: 50%). Utility scores for no treatment, ide-cel, oral pomalidomide, and dexamethasone (Pd) therapy ranged from ∼0.7 to 0.8. Utility scores for regular intravenous infusion regimens ranged from 0.50 to 0.56. There was a difference of ∼0.2 between the utility scores for no treatment/ide-cel/oral administration and regular intravenous infusions.ConclusionsDifferences in treatment administration across RRMM therapies showed a substantial impact on health state utilities. When quantifying the value of treatments, process utility gains should be considered as an independent factor in health technology assessments.

Preliminary analysis of explainable machine learning methods for multiple myeloma chemotherapy treatment recognition

Preliminary analysis of explainable machine learning methods for multiple myeloma chemotherapy treatment recognition

Promises and Challenges of Immunogenic Chemotherapy in Multiple Myeloma.

Immunological tolerance of myeloma cells represents a critical obstacle in achieving long-term disease-free survival for multiple myeloma (MM) patients. Over the past two decades, remarkable preclinical efforts to understand MM biology have led to the clinical approval of several targeted and immunotherapeutic agents. Among them, it is now clear that chemotherapy can also make cancer cells “visible” to the immune system and thus reactivate anti-tumor immunity. This knowledge represents an important resource in the treatment paradigm of MM, whereas immune dysfunction constitutes a clear obstacle to the cure of the disease. In this review, we highlight the importance of defining the immunological effects of chemotherapy in MM with the goal of enhancing the clinical management of patients. This area of investigation will open new avenues of research to identify novel immunogenic anti-MM agents and inform the optimal integration of chemotherapy with immunotherapy.

Montelukast Performs Synergistic Effect with Carfilzomib in Multiple Myeloma by Inhibiting the Deubiquitinase UCHL1

Immunomodulators play an important role in combination chemotherapy of multiple myeloma. Besides, it has been reported that leukotriene-D4 receptors play an important role in carcinogenesis. The current study was carried out to assess the possible antitumor effects of montelukast (both an immunomodulator and a CysLT1R antagonist) both in single and in combination with carfilzomib in multiple myeloma cells and the potential mechanisms. We performed our experiment using cell apoptosis assay, cell cycle assay, western blot analysis, mitochondrial transmembrane potential, and chemical proteomics based on protein activity. The results showed that montelukast inhibits cell proliferation and leads to cell apoptosis in multiple myeloma cell lines. Then we performed combination of montelukast and carfilzomib on multiple myeloma cells to explore whether they are synergistic. We demonstrated that the combination treatment leads to stronger effect of cell apoptosis. Furthermore, we demonstrated the combination effect is performed independent of the leukotriene-D4 receptors inhibition. Given that protesome inhibitor leads to accumulation of ubiquitin by inhibiting the degradation of these proteins, we tested ubiquitin levels of different groups. We found that montelukast induces ubiquitin accumulation by inhibiting Ubiquitin-Specific Protease UCHL1. All of these lead to the activity of indoplasmic reticulum stress and therefore result in cell apoptosis. This brings us a new idea in the treatment of multiple myeloma. Since montelukast is cheap and widely used in clinic, if it is proved to be effective in the treatment of multiple myeloma, it will greatly reduce the economic pressure of patients and bring new hope to patients.

Transient receptor potential channels in multiple myeloma.

Multiple myeloma is the second most commonly diagnosed hematologic malignancy. As an incurable disease, the molecular mechanisms underlying its many aspects remain unclear. Intracellular calcium ion is an essential signaling molecule that modulates malignant cell behavior, and abnormal regulation of cellular calcium homeostasis may promote cancer cell survival and induce drug resistance. Transient receptor potential (TRP) cation channels are a superfamily of non-selective Ca2+-permeable channels that regulate intracellular calcium signaling and are involved in the regulation of various characteristics of cancer cells. Emerging evidence shows a close connection between TRP channels and multiple myeloma. This review summarizes the roles of TRP channels in multiple myeloma progression, metastasis, bone destruction, and drug resistance. TRPV1 and TRPV2 orchestrate the progression of multiple myeloma, while TRPM7 promotes myeloma cell dissemination and spreading. TRPV2 and TRPV4, that activate osteoclasts, contribute to the development of osteolytic bone disease caused by multiple myeloma. Both TRPV1 inhibition and TRPV2 activation synergize with bortezomib in the chemotherapy of multiple myeloma, and TRPC1 can determine the responsiveness of multiple myeloma to MTI-101, a cyclic beta-hairpin peptide. Antagonizing TRPA1 can alleviate bortezomib-induced painful peripheral neuropathy. Future studies in this field may identify certain TRP channels as markers or therapeutic targets for predicting the prognosis, preventing progression, and improving drug responsiveness in patients with multiple myeloma.

Circular RNA circ-CCT3 promotes bortezomib resistance in multiple myeloma via modulating miR-223-3p/BRD4 axis.

Multiple myeloma is a frequent hematologic malignancy. Bortezomib is the first-line drug for multiple myeloma chemotherapy. The present study aimed to investigate the potential role and mechanism of circular RNA chaperonin containing TCP1 subunit 3 (circ-CCT3) in bortezomib resistance of multiple myeloma. The levels of circ-CCT3, microRNA-223-3p (miR-223-3p), and bromodomain-containing 4 (BRD4) were detected by quantitative real-time PCR or western blot. Cell Counting Kit-8 (CCK-8) method was used to measure the half-inhibitory concentration of bortezomib and cell viability. Cell cycle distribution, apoptosis, proliferation and migration were determined by flow cytometry, 5-ethynyl-2'-deoxyuridine, and wound healing assay. The levels of relevant proteins were checked via western blot. The binding association between miR-223-3p and circ-CCT3/BRD4 was validated via a dual-luciferase reporter assay. Circ-CCT3 and BRD4 were upregulated, while miR-223-3p was downregulated in bortezomib-resistant multiple myeloma patients and cells. Silencing of circ-CCT3 enhanced the sensitivity of bortezomib-resistant multiple myeloma cells to bortezomib. Circ-CCT3 knockdown weakened bortezomib resistance via modulating miR-223-3p. Moreover, miR-223-3p increased bortezomib sensitivity by inhibiting BRD4. Downregulation of circ-CCT3 attenuated bortezomib resistance of multiple myeloma via regulating miR-223-3p/BRD4 pathway, which provided a new potential target for multiple myeloma chemoresistance.

Hsa_Circ_0007841 Enhances Multiple Myeloma Chemotherapy Resistance Through Upregulating ABCG2.

The current researches have reported that circular RNA is an important regulatory factor in the progression of various human disease. However, the function and mechanism of most circular RNAs remain unknown in cancers including multiple myeloma. Our study has confirmed that hsa_circ_0007841 is up regulated in U266 doxorubicin resistant cells (U266R) and 8226 doxorubicin resistant cells (8226R) compared to U266 parent cells (U266P) and 8226 parent cells (8226P). Silence of hsa_circ_0007841 in U266R and 8226R could reduce the half-maximal inhibitory concentration which indicated reduction in chemoresistance. In doxorubicin resistant cells, the messenger RNA and protein level of ATP-binding cassette transporters G2 increased. Silence of hsa_circ_0007841 in drug resistant cells could decrease both the messenger RNA and protein levels of ATP-binding cassette transporters G2; reexpression of hsa_circ_0007841 could block the reduction. However, overexpression of hsa_circ_0007841 could effectively upregulate the ATP-binding cassette transporters G2 messenger RNA and protein level. Inhibition of ATP-binding cassette transporters G2 could block hsa_circ_0007841 overexpression induced chemoresistance in U266P and 8226P cells. What’s more, inhibition of ATP-binding cassette transporters G2 could reduce differences of half-maximal inhibitory concentration between parent cell lines and drug-resistant cell lines. Our data collectively suggest a new model in which hsa_circ_0007841 promotes acquired chemotherapy resistance by upregulating ATP-binding cassette transporters G2 providing a novel molecular basis of chemotherapy in multiple myeloma cancer.

Abstract 694: Mathematical modeling of stromal fibroblast-mediated adaptive resistance to bortezomib in multiple myeloma

Abstract Understanding intrinsic and adaptive resistance is crucial to overcoming multiple myeloma chemotherapy failure. We recently demonstrated that standard chemotherapy can induce cancer cells to phenotypically transition to a transient state of dormancy and drug tolerance. Further, targeting cells precisely during this transition can thwart the emergence of adaptive resistance (Goldman, 2015). However, it is not yet understood how the stromal contexture may contribute to this chemotherapy-induced drug tolerance. We developed a deterministic mathematical model containing a system of differential equations to examine how stromal fibroblasts temporally affect phenotypic switching between active and dormant, bortezomib-tolerant cancer cell states. The equations describe the total growth rate of each cell state population, which is influenced by that population’s count and baseline growth rate, the frequencies of transitions to and from the other cell state, the drug treatment concentration, and the population carrying capacity. The model also establishes that the presence of fibroblasts affects the frequency of transitions between the cell states. This framework is calibrated to in vitro data, and model simulations predict that bortezomib-tolerant myeloma cells may escape more quickly from dormancy and proliferate when they are incubated in the presence of fibroblasts than in their absence. This prediction is supported by preliminary experimental observations. The mathematical model could be adapted to predict how stromal fibroblasts, or the tumor microenvironment generally, may influence phenotypic switching in other cancers. Citation Format: Elliot Eton, Kamran Kaveh, Sachin Khiste, Andrea Fernandes, Ashima Agarwal, Shiladitya Sengupta, Aaron Goldman. Mathematical modeling of stromal fibroblast-mediated adaptive resistance to bortezomib in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 694.

Plasmacytoma-like post-kidney-transplant lymphoproliferative disorder confined to renal allograft and urinary tract: A case report

Post-transplantation lymphoproliferative disorder (PTLD) is a well-know complication after organ transplantation. We report a case of a patient who developed an extramedullary plasmacytoma-like PTLD around his transplanted kidney treated with standard multiple myeloma chemotherapy. Three years after benefiting of a deceased donor kidney transplant for an end stage kidney disease secondary to nephroangiosclerosis, our patient developed an extra-medullary plasmacytoma confined to the transplant compartment. The transplant function was unaltered, and due to the absence of reduction of the lesion after immunosuppression reduction, a chemotherapy by bortezomib-cyclophosphamide-dexamethasone (VCD) known to be efficient in multiple myeloma was initiated. After 6 cycles, positron emission tomography (PET) scan showed complete metabolic remission confirming the biological exams. This case report suggests that a chemotherapy such as VCD can efficiently treat plasmacytoma-like PTLD allowing graft survival. Therefore, transplant removal may not be mandatory as the best second line treatment after unsuccessfulness reduction of immunosuppression.

Alteration of metabolite profiling by cold atmospheric plasma treatment in human myeloma cells

BackgroundDespite new progress of chemotherapy in multiple myeloma (MM) clinical treatment, MM is still a refractory disease and new technology is needed to improve the outcomes and prolong the survival. Cold atmospheric plasma is a rapidly developed technology in recent years, which has been widely applied in biomedicine. Although plasma could efficiently inactivate various tumor cells, the effects of plasma on tumor cell metabolism have not been studied yet.MethodsIn this study, we investigated the metabolite profiling of He plasma treatment on myeloma tumor cells by gas-chromatography time-of-flight (GC-TOF) mass-spectrometry. Meanwhile, by bioinformatic analysis such as GO and KEGG analysis we try to figure out the metabolism pathway that was significantly affected by gas plasma treatment.ResultsBy GC-TOF mass-spectrometry, 573 signals were detected and evaluated using PCA and OPLS-DA. By KEGG analysis we listed all the differential metabolites and further classified into different metabolic pathways. The results showed that beta-alanine metabolism pathway was the most significant change after He gas plasma treatment in myeloma cells. Besides, propanoate metabolism and linoleic acid metabolism should also be concerned during gas plasma treatment of cancer cells.ConclusionsCold atmospheric plasma treatment could significantly alter the metabolite profiling of myeloma tumor cells, among which, the beta-alanine metabolism pathway is the most susceptible to He gas plasma treatment.

Effects of DTX3L on the cell proliferation, adhesion, and drug resistance of multiple myeloma cells.

Cell adhesion-mediated drug resistance is an important factor that influences the effects of chemotherapy in multiple myeloma. DTX3L, a ubiquitin ligase, plays a key role in cell-cycle-related process. Here, we found that the expression of DTX3L gradually increased during the proliferation of myeloma cells, which resulted in arrest of the cell cycle in the G1 phase and promoted the adherence of myeloma cells to fibronectin or bone marrow stromal cells. In addition, silencing of DTX3L improved sensitivity to chemotherapy drugs in multiple myeloma cell lines adherent to bone marrow stromal cells and increased the expression of caspase-3 and poly-adenosine diphosphate-ribose polymerase, two markers of apoptosis. Finally, we also found that DTX3L expression was regulated by focal adhesion kinase. Taken together, the results of this study show that DTX3L plays an important role in the proliferation and cell adhesion-mediated drug resistance of multiple myeloma cells and as such may play a key role in the development of multiple myeloma.

MAGE-a Mediate Resistance to Chemotherapy in Multiple Myeloma through Regulation of Bcl-2 Proteins

Type I Melanoma Antigen Genes of the MAGE-A family are commonly expressed in multiple myeloma (MM). Their frequency of expression is higher in patients who have relapsed after chemotherapy compared to newly diagnosed patients, with a significant association with progression of disease. MAGE were also associated with high-risk disease in gene expression profiling studies. They belong to the Cancer-Testis group of oncofetal genes that are normally restricted to germ cells and trophoblastic tissue, and are aberrantly expressed in a broad range of human cancers. Type I MAGE proteins partner with the RING domain protein Kap1 to form ubiquitin ligase complexes, and in laboratory models of solid tumors they ubiquitinylate cancer-associated targets involved in metabolism, autophagy, and metastasis. We demonstrated that expression of MAGE-A genes, especially MAGE-A3, was correlated with progression of disease in MM and that MAGE-A inhibit p53-dependent and independent apoptosis in MM cells. These results lead us to investigate the hypothesis that MAGE-A promote resistance to chemotherapy-induced apoptosis in MM cells. We performed gene expression profiling by RNAseq of primary tumor specimens from an open label phase 2 clinical trial of panobinostat, a pan-HDAC inhibitor approved for treatment of relapsed MM, in combination with lenalidomide and dexamethasone (NCT01651039). These GEP data were analyzed for differential expression based on progression free survival (PFS) < 90 days (short PFS) versus PFS > 90 days (long PFS). MAGE-A1 was the most overexpressed gene in the short PFS group compared to long (p<0.005), and this correlation was confirmed at the protein level (p<0.05). We then silenced MAGE-A expression in human myeloma cell lines (HMCL) by transduction of a MAGE-A-specific shRNA lentivirus, which resulted in nearly complete loss of MAGE-A protein at 24-48 hrs. HMCL were transduced with MAGE-A shRNA lenti or a negative control construct containing a non-target shRNA sequence, and untreated cells served as an additional negative control. Silencing of MAGE-A increased sensitivity to cell death induced by panobinostat. Similar results were seen with melphalan, an alkylating agent, and bortezomib, a proteasome inhibitor, both of which are approved for treatment of MM. These results indicate that MAGE-A play a critical role in resistance to chemotherapy-induced apoptosis in relapsed myeloma patients. To investigate the mechanisms of inhibition of apoptosis, we analyzed the impact of MAGE-A on Bcl-2 family members, including Bim, Bid, and PUMA, BH3-only family members that initiate apoptosis, Mcl-1, which plays a role in chemotherapy-induced apoptosis in myeloma cells, and the prototypical survival proteins Bcl-2 an Bcl-xl. HMCL were transduced with MAGE-A shRNA lenti or controls and cells were harvested after disappearance of MAGE-A protein. Heavy membrane preparations were made from these cells and probed by Western blot for Bcl-2 proteins. Loss of MAGE-A resulted in higher levels of Bim compared to controls. Of note, the short isoform of Bim (Bim S), which is the most potent activator of apoptosis, demonstrated relatively higher expression compared to the long and extra long isoforms (Bim L and EL). Phosphorylation of Bim at Ser69 and 77 by Erk1/2 and other kinases leads to ubiquitinylation and proteasomal degradation. In the absence of MAGE-A, phosphorylated Bim is stabilized, suggesting MAGE-A inhibits apoptosis by promoting ubiquitinylation and degradation of phospho-Ser69/77-Bim. These results demonstrate that MAGE-A/Kap1 is a key regulator of Bim that promotes survival of MM cells. Loss of MAGE-A also resulted in increased protein levels of Mcl-1 and decreased protein expression of Bcl-2. No significant changes in Bid or Bcl-xl proteins were observed and PUMA was not detected under these conditions. These results support a model in which MAGE-A mediates resistance to panobinostat and other chemotherapeutic agents through differential regulation of protein expression of Bim, Mcl-1, and Bcl-2. Therefore, MAGE-A is a promising novel therapeutic target, and inhibition of its anti-apoptotic activity may directly induce apoptosis or increase sensitivity to chemotherapy-induced apoptosis. DisclosuresCho:Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Agenus, Inc.: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chari:Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding. Jagannath:Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Merck: Consultancy.

Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma

AbstractTo elucidate the mechanisms underlying relapse from chemotherapy in multiple myeloma, we performed a longitudinal study of 33 patients entered into Total Therapy protocols investigating them using gene expression profiling, high-resolution copy number arrays, and whole-exome sequencing. The study illustrates the mechanistic importance of acquired mutations in known myeloma driver genes and the critical nature of biallelic inactivation events affecting tumor suppressor genes, especially TP53, the end result being resistance to apoptosis and increased proliferation rates, which drive relapse by Darwinian-type clonal evolution. The number of copy number aberration changes and biallelic inactivation of tumor suppressor genes was increased in GEP70 high risk, consistent with genomic instability being a key feature of high risk. In conclusion, the study highlights the impact of acquired genetic events, which enhance the evolutionary fitness level of myeloma-propagating cells to survive multiagent chemotherapy and to result in relapse.

Applied value of apoptosis inhibitory protein survivin in FVAD chemotherapy efficacy for refractory multiple myeloma

Objective To investigate the applied value of apoptosis inhibitory protein Survivin in FVAD (fludarabine, vincristine, epirubicin and dexamethasone) chemotherapy afficay for refractory multiple myeloma. Methods Eighty-three cases of multiple myeloma from hematology inpatient department were selected, including 40 cases of initial multiple myeloma (initial treatment group), who were given VAD scheme (vincristine, epirubicin, dexamethasone) chemotherapy, and 43 cases of refractory multiple myeloma (refractory group), who were given FVAD chemotherapy. Bone marrow was collected from marrow aspiration, and Survivin protein expression was detected by immunohistochemistry. Survival was analyzed using Kaplan-Meier. The difference in Survivin positive expression rate between groups was analyzed, and the relationship between Survivin expressoon and FVAD chemotherapy short- and long-term efficacy was also analyzed. Results The positive Survivin expression rate in refractory group (72.09%) was significantly higher than in initial treatment group (42.50%) with significant differences between two groups (P<0.05). Complete remission rate (4.20%) and the effective rate (22.92%) in positive Survivin group were significantly lower than those (14.20% and 57.14%) in Survivin negative group with differences being significant between two groups (P<0.05). Overall survival and progression free survival in Survivin positive group were significantly lower than those in Survivin negative group (P<0.05). Conclusion Survivin protein positive expression increased significantly in refractory multiple myeloma tissue, indicating the short- and long-term curative effectineness of FVAD chemotherapy is worse. Key words: Apoptosis inhibitory protein; Survivin; Refractory multiple myeloma chemotherapy; Chemotherapy

RBQ3 participates in multiple myeloma cell proliferation, adhesion and chemoresistance

Cell adhesion mediated drug resistance (CAM-DR) is a major factor that impedes the effect of chemotherapy in multiple myeloma (MM). RBQ3, which is a RB-binding protein, played a crucial role in cell cycle process. Here, we reported that RBQ3 expression was increased gradually during the proliferation process of myeloma cells. Knocking down of RBQ3 resulted in cell cycle arrest in G1 phase and increased myeloma cells adherent to fibronectin or bone marrow stromal cells (BMSCs). Furthermore, silencing of RBQ3 reduced sensitivity to chemotherapeutic drugs in myeloma cell lines adherent to BMSCs and reduced two apoptotic marker proteins cleaved caspase-3 and cleaved PARP expression. Besides, we also found that RBQ3 participated in MAPK/ERK signal transduction pathway. In summary, these results may shed new insights into the role of RBQ3 in the development of multiple myeloma.