Improved long-term survival rate in the responders to bortezomib, cyclophosphamide, dexamethasone induction therapy in a transplant-eligible cohort of predominantly middle-age multiple myeloma patients.

BACKGROUND: Multiple myeloma (MM) represents the second most common hematologic malignancy (15%). Induction with bortezomib, cyclophosphamide, and dexamthasone VCd (d: low dose dexamthasone) regimen is widely used due to its high effectiveness, low toxicity and good tolerability, particularly with renal impairment. Real-world data on the use of VCD in clinical practice is lacking. OBJECTIVES: Evaluate the real-world experience of the VCD regimen. DESIGN: Retrospective. SETTING: Tumor registry database of tertiary cancer care center. PATIENTS AND METHODS: newly diagnosed MM patients who received VCD induction and underwent autologous stem cell transplant (ASCT) from July 2007 to July 2020. MAIN OUTCOME MEASURES: response evaluation, progression-free survival (PFS) and overall survival (OS). SAMPLE SIZE: 87 patients. RESULTS: Of 102 patients who started induction with VCd, 87 patients experienced a partial response or more overall response rate of 85%). The median age of these 87 patients at diagnosis was 52 years, of which 29.9% presented with renal impairment and 60.3% of patients had stage 2 by the Revised International Staging System (R-ISS). Patients with a standard cytogenetic risk achieved a better response compared to those with a poor cytogenetic risk (P=.044). The post-induction response rates were 6.9% stringent complete remission (sCR), 35% complete remission (CR); 41.4% very good partial response (VGPR), and 16.1% partial response (PR), respectively; the response rates became greater for sCR and CR post-transplantation at day 100 with 16.1% sCR, 35.6% CR, 32.2% VGPR and 16.1% PR, respectively. The median PFS was 49 months and 5 years OS was 84%. PFS was better in patients who achieved sCR vs PR (83 vs 35 months, P=.037). High LDH, high-risk cytogenetic and stage 3 R-ISS showed a worse median PFS and OS. CONCLUSIONS: VCD induction in newly diagnosed MM is highly effective, convenient, tolerable and affordable regimen, especially in low and middle-income countries with limited resources, also with favorable outcomes and survival. while those who did not respond successfully shifted to VRD or VTD. LIMITATIONS: The usual limitations of a retrospective analysis using registry-level data, no data on quality of life.

Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast Saccharomyces cerevisiae and a Glioblastoma Cell Line.

Proteasome inhibitors are used in the therapy of several cancers, and clinical trials are underway for their use in the treatment of glioblastoma (GBM). However, GBM becomes resistant to chemotherapy relatively rapidly. Recently, the overexpression of ribonucleotide reductase (RNR) genes was found to mediate therapy resistance in GBM. The use of combinations of chemotherapeutic agents is considered a promising direction in cancer therapy. The present work aimed to evaluate the efficacy of the combination of proteasome and RNR inhibitors in yeast and GBM cell models. We have shown that impaired proteasome function results in increased levels of RNR subunits and increased enzyme activity in yeast. Co-administration of the proteasome inhibitor bortezomib and the RNR inhibitor hydroxyurea was found to significantly reduce the growth rate of S. cerevisiae yeast. Accordingly, the combination of bortezomib and another RNR inhibitor gemcitabine reduced the survival of DBTRG-05MG compared to the HEK293 cell line. Thus, yeast can be used as a simple model to evaluate the efficacy of combinations of proteasome and RNR inhibitors.

B-Myb deficiency boosts bortezomib-induced immunogenic cell death in colorectal cancer.

B-Myb has received considerable attention for its critical tumorigenic function of supporting DNA repair. However, its modulatory effects on chemotherapy and immunotherapy have rarely been reported in colorectal cancer. Bortezomib (BTZ) is a novel compound with chemotherapeutic and immunotherapeutic effects, but it fails to work in colorectal cancer with high B-Myb expression. The present study was designed to investigate whether B-Myb deletion in colorectal cancer could potentiate the immune efficacy of BTZ against colorectal cancer and to clarify the underlying mechanism. Stable B-Myb knockdown was induced in colorectal cancer cells, which increased apoptosis of the cancer cells relative to the control group in vitro and in vivo. We found that BTZ exhibited more favourable efficacy in B-Myb-defective colorectal cancer cells and tumor-bearing mice. BTZ treatment led to differential expression of genes enriched in the p53 signaling pathway promoted more powerful downstream DNA damage, and arrested cell cycle in B-Myb-defective colorectal cancer. In contrast, recovery of B-Myb in B-Myb-defective colorectal cancer cells abated BTZ-related DNA damage, cell cycle arrest, and anticancer efficacy. Moreover, BTZ promoted DNA damage-associated enhancement of immunogenicity, as indicated by potentiated expression of HMGB1 and HSP90 in B-Myb-defective cells, thereby driving M1 polarization of macrophages. Collectively, B-Myb deletion in colorectal cancer facilitates the immunogenic death of cancer cells, thereby further promoting the immune efficacy of BTZ by amplifying DNA damage. The present work provides an effective molecular target for colorectal cancer immunotherapy with BTZ.

Histone deacetylase (HDAC) inhibitor specificity determinants are preserved in a class of dual HDAC/non-covalent proteasome inhibitors.

Many disease states require multiple drugs to inhibit multiple targets for their effective treatment/management, i.e. a drug cocktail regimen, or "polypharmacy". Polypharmacology, in contrast, is the development of single agents that can inhibit multiple targets. Each strategy is associated with advantages and disadvantages. Motivated by promising clinical trial data for the treatment of multiple myeloma with the combination of the HDAC6 inhibitor ricolinostat and the proteasome inhibitor bortezomib, we herein describe a focused family of dual HDAC/non-covalent proteasome inhibitors, and explore the impact of linker and zinc-binding group identities on HDAC1/6 isozyme selectivity. In general, previously reported specificity determinants of monovalent HDAC1/6 inhibitors were preserved in our dual HDAC/proteasome inhibitors.

Physicochemical stability of bortezomib solutions for subcutaneous administration.

For the majority of cytotoxic drug preparations, such as bortezomib, the unit dose information is not available. In addition, there is a lack of information on the physicochemical stability of the pharmaceutical preparation after opening; this information is crucial for its administration to patients in successive visits, and the per-patient cost can be affected. The purpose of our proposed physicochemical stability study is to determine the shelf life of the reconstituted liquid product under refrigeration and clinical practice conditions. This evaluation was extended to both vials and ready-to-use syringes prefilled with the contents of the open vial. The stability test design includes the specified storage conditions and the critical physicochemical parameters of reconstituted injectable bortezomib. Furthermore, this approach includes the determination of impurities, the monitoring of the purity of the mean peak using a photodiode array, the control of the mass balance, the monitoring of subvisible particles using a laser diffraction analyser, and the setting of stability specifications. For the chemical stability study, the amount of bortezomib and its degradation products were determined using a stability-indicating HPLC method. The physical inspection of the samples was performed throughout the stability study, and their pH values were also monitored. Bortezomib (2.5 mg/mL) in 0.9% sodium chloride remained stable for 7 days when stored in both polypropylene syringes and vials at 5 ± 3 °C (refrigeration) and shielded from light. Additionally, it exhibits stability for 24 h under storage conditions simulating clinical use (20-30 °C and protected from light). The proposed protocol provides the stability in the vials once reconstituted and in prefilled refrigerated syringes; this protocol can be used to reduce waste and increase cost savings.

Megalosplenia as an initial manifestation of multiple myeloma with a novel CYLD gene mutation: A case report and literature review.

INTRODUCTION: Megalosplenia in newly diagnosed multiple myeloma (MM) is extremely rare, posing diagnostic and therapeutic challenges due to its unusual location and clinical manifestations and lack of optimal therapeutic strategies. CASE PRESENTATION: A 65-year-old female who was previously healthy presented with a history of ecchymosis on her right leg accompanied by progressive fatigue for 2 weeks. She was admitted to our center in July 2019 due to thrombocytopenia. The patient presented with megalosplenia, anemia, monoclonal protein (λ-light chain type) in the serum and urine, and 45.6% malignant plasma cells in the bone marrow. Splenectomy was performed due to persistent splenomegaly after 3 cycles of the bortezomib plus dexamethasone regimen, and immunohistochemistry results indicated λ-plasmacytoma of the spleen. The same cytogenetic and molecular abnormalities, including t(14;16), 14q32 amplification, 16q32 amplification, 20q12 amplification, and a novel CYLD gene mutation, were identified using fluorescence in situ hybridization and next-generation sequencing in both bone marrow and spleen samples. Therefore, a diagnosis of MM (λ-light chain type, DS III, ISS III, R-ISS III, high-risk) with spleen infiltration was proposed. The patient did not achieve remission after induction treatment with bortezomib plus lenalidomide and dexamethasone or salvage therapy with daratumumab plus ixazomib and dexamethasone. However, she ultimately did achieve very good partial remission with a regimen of bendamustine plus lenalidomide and dexamethasone. Unfortunately, she died of pneumonia associated with chemotherapy. CONCLUSION: To our knowledge, only 8 cases of spleen plasmacytoma at MM diagnosis have been described previously. Extramedullary myeloma patients with spleen involvement at diagnosis are younger and that the condition is usually accompanied by splenic rupture with aggressive clinical features and poor prognosis. Further studies are needed to explore pathogenesis and effective therapies to prolong the survival of such patients.

GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells.

GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, has undergone phase I evaluation in patients with solid tumors (NCT03775525) with a recommended phase 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as a single agent at killing multiple myeloma cells than had previously been observed in solid tumor cell types. GZ17-6.02 interacted with proteasome inhibitors in a greater than additive fashion to kill myeloma cells and alone it killed inhibitor-resistant cells to a similar extent. The drug combination of GZ17-6.02 and bortezomib activated ATM, the AMPK and PERK and inactivated ULK1, mTORC1, eIF2α, NFκB and the Hippo pathway. The combination increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM, and reduced the levels of BCL-XL and MCL1. GZ17-6.02 interacted with bortezomib to enhance autophagosome formation and autophagic flux, and knock down of ATM, AMPKα, ULK1, Beclin1 or ATG5 significantly reduced both autophagy and tumor cell killing. Knock down of BAK and BIM significantly reduced tumor cell killing. The expression of HDACs1/2/3 was significantly reduced beyond that previously observed in solid tumor cells and required autophagy. This was associated with increased acetylation and methylation of histone H3. Combined knock down of HDACs1/2/3 caused activation of ATM and the AMPK and caused inactivation of ULK1, mTORC1, NFκB and the Hippo pathway. HDAC knock down also enhanced ATG13 phosphorylation, increased BAK levels and reduced those of BCL-XL. Collectively, our present studies support performing additional in vivo studies with multiple myeloma cells.

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation.

Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT. Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment. Results: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week. Discussion: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

Impact of Genetic Polymorphisms in NF-ĸB2 and TRAF3 Genes on Response to Bortezomib-Based Therapy in Multiple Myeloma Patients.

BACKGROUND: Multiple myeloma (MM), being the second most common hematological malignancy, has garnered significant attention. The ubiquitin proteasomal pathway (UPP), crucial for normal cell function, plays a pivotal role in myeloma pathophysiology, especially with the advent of bortezomib (BTZ). Dysregulation of the UPP has implications ranging from developmental abnormalities to cancer. OBJECTIVES: This study aimed to delineate the clinical characteristics of newly diagnosed multiple myeloma patients and investigate the influence of single nucleotide polymorphisms (SNPs) in NF-ĸB2 and TRAF3 genes on the risk and treatment response to bortezomib-based chemotherapy. MATERIALS AND METHODS: Conducted at JIPMER, Pondicherry, this prospective study enrolled 184 participants, comprising cases and controls. DNA extraction from peripheral blood samples was followed by SNP analysis through Real-time Polymerase Chain Reaction. Patients were categorized into Good and Poor responders, and SNP associations with treatment response, response rates, and survival outcomes were assessed using chi-square and Kaplan-Meier analyses. RESULTS: The median age of participants was 55 years, with backache being the most prevalent symptom (66.3%). Hypercalcemia (22%), renal failure (8.7%), and bone fractures (45.7%) were also observed, alongside high prevalence of anemia. Notably, the frequency of the TRAF3 rs12147254 A allele was lower in cases compared to controls (31% vs. 49%, P-value=0.002). Poor responders exhibited higher frequencies of the GA+AA genotypes in TRAF3 rs12147254 (OR-3.882(1.629-9.251), P-value-0.002) and NFKB2 rs1056890 (OR-3.308(1.366-8.012), P-value-0.008) when compared to good responders. The GA+AA genotype in TRAF3 rs11160707 SNP correlated with improved progression-free survival. CONCLUSION: The study findings underscore a significant association between genetic polymorphisms and treatment response outcomes, suggesting their utility in prognostic determinations and clinical outcomes prediction in multiple myeloma patients.

In Vitro Low-Bortezomib Doses Induce Apoptosis and Independently Decrease the Activities of Glutathione S-Transferase and Glutathione Peroxidase in Multiple Myeloma, Taking into Account the GSTT1 and GSTM1 Gene Variants.

BACKGROUND: Multiple myeloma (MM) is a malignancy derived from plasma cells. Bortezomib affects the concentration of reduced glutathione (GSH) and the activity of glutathione enzymes. The aim of our study was to analyze deletion (null/present) variants of GSTT1 and GSTM1 genes and their association with the levels of glutathione and its enzymes in bortezomib-treated cell cultures derived from MM patients. MATERIALS AND METHODS: This study included 180 individuals (80 MM patients and 100 healthy blood donors) who were genotyped via multiplex PCR (for the GSTT1/GSTM1 genes). Under in vitro conditions, MM bone marrow cells were treated with bortezomib (1-4 nM) to determine apoptosis (via fluorescence microscopy), GSH concentration, and activity of glutathione enzymes (via ELISA). RESULTS: Bortezomib increased the number of apoptotic cells and decreased the activity of S-glutathione transferase (GST) and glutathione peroxidase (GPx). We found significant differences in GST activity between 1 nM (GSTT1-null vs. GSTT1-present), 2 nM (GSTT1-null vs. GSTT1-present), and 4 nM (GSTM1-null vs. GSTM1-present) bortezomib: 0.07 vs. 0.12, p = 0.02; 0.06 vs. 0.10, p = 0.02; and 0.03 vs. 0.08, p = 0.01, respectively. CONCLUSIONS: Bortezomib affects the activities of GST and GPx. GST activity was associated with GSTT1 and GSTM1 variants but only at some bortezomib doses.

Optimal strategies of oncolytic virus-bortezomib therapy via the apoptotic, necroptotic, and oncolysis signaling network.

Bortezomib and oncolytic virotherapy are two emerging targeted cancer therapies. Bortezomib, a proteasome inhibitor, disrupts protein degradation in cells, leading to the accumulation of unfolded proteins that induce apoptosis. On the other hand, virotherapy uses genetically modified oncolytic viruses (OVs) to infect cancer cells, trigger cell lysis, and activate anti-tumor response. Despite progress in cancer treatment, identifying administration protocols for therapeutic agents remains a significant concern, aiming to strike a balance between efficacy, minimizing toxicity, and administrative costs. In this work, optimal control theory was employed to design a cost-effective and efficient co-administration protocols for bortezomib and OVs that could significantly diminish the population of cancer cells via the cell death program with the NF$ \kappa $B-BAX-RIP1 signaling network. Both linear and quadratic control strategies were explored to obtain practical treatment approaches by adapting necroptosis protocols to efficient cell death programs. Our findings demonstrated that a combination therapy commencing with the administration of OVs followed by bortezomib infusions yields an effective tumor-killing outcome. These results could provide valuable guidance for the development of clinical administration protocols in cancer treatment.

Expression of the chemokine receptor CCR1 decreases sensitivity to bortezomib in multiple myeloma cell lines.

BACKGROUND: The proteasome inhibitor bortezomib is one of the primary therapies used for the haematological malignancy multiple myeloma (MM). However, intrinsic or acquired resistance to bortezomib, via mechanisms that are not fully elucidated, is a barrier to successful treatment in many patients. Our previous studies have shown that elevated expression of the chemokine receptor CCR1 in MM plasma cells in newly diagnosed MM patients is associated with poor prognosis. Here, we hypothesised that the poor prognosis conferred by CCR1 expression is, in part, due to a CCR1-mediated decrease in MM plasma cell sensitivity to bortezomib. METHODS: In order to investigate the role of CCR1 in MM cells, CCR1 was knocked out in human myeloma cell lines OPM2 and U266 using CRISPR-Cas9. Additionally, CCR1 was overexpressed in the mouse MM cell line 5TGM1. The effect of bortezomib on CCR1 knockout or CCR1-overexpressing cells was then assessed by WST-1 assay, with or without CCL3 siRNA knockdown or addition of recombinant human CCL3. NSG mice were inoculated intratibially with OPM2-CCR1KO cells and were treated with 0.7 mg/kg bortezomib or vehicle twice per week for 3 weeks and GFP+ tumour cells in the bone marrow were quantitated by flow cytometry. The effect of CCR1 overexpression or knockout on unfolded protein response pathways was assessed using qPCR for ATF4, HSPA5, XBP1, ERN1 and CHOP and Western blot for IRE1α and p-Jnk. RESULTS: Using CCR1 overexpression or CRIPSR-Cas9-mediated CCR1 knockout in MM cell lines, we found that CCR1 expression significantly decreases sensitivity to bortezomib in vitro, independent of the CCR1 ligand CCL3. In addition, CCR1 knockout rendered the human MM cell line OPM2 more sensitive to bortezomib in an intratibial MM model in NSG mice in vivo. Moreover, CCR1 expression negatively regulated the expression of the unfolded protein response receptor IRE1 and downstream target gene XBP1, suggesting this pathway may be responsible for the decreased bortezomib sensitivity of CCR1-expressing cells. CONCLUSIONS: Taken together, these studies suggest that CCR1 expression may be associated with decreased response to bortezomib in MM cell lines.

Cisplatin Disrupts Proteasome Bounce-Back Effect through Suppressing ZEB1/Nfe2l1 in Cholangiocarcinoma.

BACKGROUND: Bortezomib (BTZ) is a powerful proteasome inhibitor that has been approved for the treatment of haematologic malignancies. Its effectiveness has been assessed against different types of solid tumours. BTZ is ineffective in most solid tumours because of drug resistance, including cholangiocarcinoma, which is associated with a proteasome bounce-back effect. However, the mechanism through which proteasome inhibitors induce the proteasome bounce-back effect remains largely unknown. METHODS: Cholangiocarcinoma cells were treated with BTZ, cisplatin, or a combination of both. The mRNA levels of Nfe2l1 and proteasome subunit genes (PSMA1, PSMB7, PSMD1, PSMD11, PSMD14, and PSME4) were determined using quantitative real time polymerase chain reaction (qPCR). The protein levels of nuclear factor-erythroid 2-related factor 1 (Nfe2l1) and proteasome enzyme activity were evaluated using western blotting and proteasome activity assays, respectively. Transcriptome sequencing was performed to screen for potential transcription factors that regulate Nfe2l1 expression. The effect of zinc finger E-box-binding homeobox 1 (ZEB1) on the expression of Nfe2l1 and proteasome subunit genes, as well as proteasome enzyme activity, was evaluated after the knockdown of ZEB1 expression with siRNA before treatment with BTZ. The transcriptional activity of ZEB1 on the Nfe2l1 promoter was detected using dual-luciferase reporter gene and chromatin immunoprecipitation assays. Cell viability was measured using the cell counting kit-8 (CCK-8) assay and cell apoptosis was assessed using western blotting and flow cytometry. RESULTS: Cisplatin treatment of BTZ-treated human cholangiocarcinoma cell line (RBE) suppressed proteasome subunit gene expression (proteasome bounce-back) and proteasomal enzyme activity. This effect was achieved by reducing the levels of Nfe2l1 mRNA and protein. Our study utilised transcriptome sequencing to identify ZEB1 as an upstream transcription factor of Nfe2l1, which was confirmed using dual-luciferase reporter gene and chromatin immunoprecipitation assays. Notably, ZEB1 knockdown using siRNA (si-ZEB1) hindered the expression of proteasome subunit genes under both basal and BTZ-induced conditions, leading to the inhibition of proteasomal enzyme activity. Furthermore, the combination treatment with BTZ, cisplatin, and si-ZEB1 significantly reduced the viability of RBE cells. CONCLUSIONS: Our study uncovered a novel mechanism through which cisplatin disrupts the BTZ-induced proteasome bounce-back effect by suppressing the ZEB1/Nfe2l1 axis in cholangiocarcinoma. This finding provides a theoretical basis for developing proteasome inhibitor-based strategies for the clinical treatment of cholangiocarcinoma and other tumours.

Once-weekly versus twice-weekly bortezomib in newly diagnosed multiple myeloma: a real-world analysis.

Induction regimens for multiple myeloma (MM) commonly include bortezomib, which has typically been administered twice weekly despite studies demonstrating comparable efficacy and less peripheral neuropathy (PN) with once-weekly bortezomib. We aimed to analyze the real-world prevalence and efficacy of once-weekly versus twice-weekly bortezomib regimens in newly diagnosed MM. We analyzed 2497 US patients aged 18-70 years treated with commercial first-line bortezomib using nationwide Flatiron Health electronic health record-derived data, including 910 (36.4%) patients who received twice-weekly and 1522 (63.2%) who received once-weekly bortezomib. Once-weekly bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving once-weekly bortezomib. Real-world progression-free survival (median 37.2 months with once-weekly versus 39.6 months with twice-weekly, p = 0.906) and overall survival (medians not reached in either cohort, p = 0.800) were comparable. PN rates were higher in patients receiving twice-weekly bortezomib (34.7% versus 18.5%, p < 0.001). In conclusion, once-weekly bortezomib is clearly associated with similar efficacy and fewer toxicities compared to twice-weekly bortezomib. Our findings support once-weekly bortezomib as a standard-of-care regimen for newly diagnosed patients with MM.

DeepAEG: a model for predicting cancer drug response based on data enhancement and edge-collaborative update strategies.

MOTIVATION: The prediction of cancer drug response is a challenging subject in modern personalized cancer therapy due to the uncertainty of drug efficacy and the heterogeneity of patients. It has been shown that the characteristics of the drug itself and the genomic characteristics of the patient can greatly influence the results of cancer drug response. Therefore, accurate, efficient, and comprehensive methods for drug feature extraction and genomics integration are crucial to improve the prediction accuracy. RESULTS: Accurate prediction of cancer drug response is vital for guiding the design of anticancer drugs. In this study, we propose an end-to-end deep learning model named DeepAEG which is based on a complete-graph update mode to predict IC50. Specifically, we integrate an edge update mechanism on the basis of a hybrid graph convolutional network to comprehensively learn the potential high-dimensional representation of topological structures in drugs, including atomic characteristics and chemical bond information. Additionally, we present a novel approach for enhancing simplified molecular input line entry specification data by employing sequence recombination to eliminate the defect of single sequence representation of drug molecules. Our extensive experiments show that DeepAEG outperforms other existing methods across multiple evaluation parameters in multiple test sets. Furthermore, we identify several potential anticancer agents, including bortezomib, which has proven to be an effective clinical treatment option. Our results highlight the potential value of DeepAEG in guiding the design of specific cancer treatment regimens.