Bortezomib Therapy Research Articles

A case of multiple myeloma with AL amyloidosis showing giant Russel bodies.

A 67-year-old male patient presented to our hospital with streptococcus pneumonia and a neck phlegmon. As part of an initial workup, a review of an intravenous immunoglobulin order for a possible secondary hypogammaglobinaemia and pneumosepsis showed low IgA and IgM subsets but overall increased IgG class proteins (0.08, 0.3, and 22.8 g/L respectively). The IgG class subset analysis showed decreased IgG class 2–4 but elevated IgG class 1 levels (28.7 g/L). For lack of bona fide hypogammaglobinemia, intravenous immunoglobulin therapy was denied, and further workup including a bone marrow biopsy was undertaken. Patient also presented with secondary erythrocytosis (Haemoglobin 195, janus kinase 2 [Jak2] negative, with increasing erythropoietin [EPO] level), attributed to severe sleep apnea and asthma. A serum electrophoresis (SPEP) showed an IgG lambda monoclonal protein (19 g/L) with elevated serum lambda free light chain (588.5 mg/L) with a marked concomitnat background gamma globulin suppression. A bone marrow biopsy showed scanty background residual trilinear hematopoiesis with an increase in lambda clonal plasma cells (90% of cellularity). Specifically the bone marrow aspirate showed frequent inclusions overlaying the nucleus (Dutcher bodies) and cytoplasm (Russel bodies) of the plasma cells (Figure 1, panel A, white and black arrows respectively, stained by May-Grünwald- Giemsa x 40 objective). Many of the inclusions seen were smaller leaving the cellular morphology intact. Having said this, within the aspirate particles, large/giant inclusions were seen (panel B, aspirate granule x40 magnification). Moreover, a trephine biopsy showed many large spherical bodies which showed cytoplasmic ballooning and resulted in complete cellular effacement and displacement of the nucleus (Figure 1, panels C–E Hematoxylin and Eosin stain x40 (C) and x50 (D,E) magnification respectively; black arrows point to overstuffed plasma cells with eccentric nuclei). CD138/lambda stains confirmed that these were not cell-free but were inclusions within the plasma cell cytoplasm (Figure 1, panels F and G, CD138 and lambda stains respectively, x20 magnification). Lastly a Congo red stain for amyloid showed salmon pink deposits with apple green birefringence under polarized light (panels H&I showing a bone marrow blood vessel, Congo red ×20 magnification). With a confirmed diagnosis of plasma cell myeloma the patient was treated with cyclophosphamide, bortezomib and dexamethasone therapy, forgoing any intravenous immunoglobulin. The first description of intracytoplasmic inclusion in multiple myeloma were provided by Russel (1890) and subsequently termed Russel bodies. Mott cells refer to plasma cells with multiple inclusions such as Russel bodies. Dutcher bodies refer to cytoplasmic inclusions that overlay the nucleus. These cytoplasmic inclusions have been observed in both reactive and malignant plasma cells. They represent accumulations of mucopolysaccarides and immunoglobulin, which highlights the common nature of these inclusions. There is no established prognostic significance of such inclusions. One study by Jiang et al. reveals a correlation between the presence of Dutcher bodies and t(4;14), which is an adverse prognostic marker in multiple myeloma. Both authors were involved with taking photos, and writing and editing the manuscript. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported The authors received no specific funding for this work. There are no patient identifiers in this study. Verbal consent has been obtained at the time of bone marrow biopsy. All data have been presented and are available for review.

Экспрессия генов семейства WNT у больных множественной миеломой с различным ответом на противоопухолевую терапию

Aim. To compare the expression levels of the WNT family genes in mesenchymal stromal cells (MSC) of the bone marrow (BM) hematopoietic niche in multiple myeloma (MM) patients vs. healthy donors.
 Materials & Methods. The study enrolled 12 MM patients aged 49–71 years (the median age 61 years) after standard induction bortezomib therapy. The treatment efficacy was assessed in accordance with the criteria of International Myeloma Working Group (IMWG). Patients were stratified in groups with complete and partial response (CPR; group 1, n = 9) and no response (group 2, n = 3). Besides, a group of primary untreated patients was formed (n = 2). The control group included healthy donors of BM (n = 3). The levels of the WNT and CTNNB1 gene expression were assessed by real-time PCR on cDNA isolated from MSC.
 Results. In the group of 2 primary patients, two genes (WNT2B and WNT9B) considerably differed in the degree of expression. In non-responders (n = 3), the WNT2B expression could not be determined, whereas the WNT15 expression appeared to be increased. In group CPR (n = 9), mRNA level of the WNT5A gene increased after therapy, whereas the WNT3A gene expression returned to the normal level. The WNT7B gene transcription level did not differ in the control and comparison groups. In group CPR, a significant expression increase in the β-catenin-coding CTNNB1 gene was detected.
 Conclusion. The differences identified in the expression of the WNT2B, WNT9B, and CTNNB1 genes suggest the possibility of their use as prognostic molecular markers in MM.

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach.

Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution. We hypothesize that the dual targeting solution containing bone-seeking 224Ra and cell-directed complexes of progeny 212Pb is a promising approach to treat metastatic cancers with bone and soft tissue lesions as well as skeletal metastases of mixed lytic/osteoblastic nature. A novel liquid 224Ra/212Pb-generator for rapid preparation of a dual targeting solution is described. Cancer cell targeting monoclonal antibodies, their fragments, synthetic proteins or peptides can all be radiolabeled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, 224Ra targets stromal elements in sclerotic bone metastases and 212Pb-chelated-conjugate targets tumor cells of metastatic prostate cancer or osteosarcoma. The dual targeting solution may also be explored to treat metastatic breast cancer or multiple myeloma after manipulation of bone metastases to a more osteoblastic phenotype by the use of bisphosphonates, denosumab, bortezomib or hormone therapy prior to treatment. This may improve targeting of bone-seeking 224Ra and render an augmented radiation dose deposited within metastases. Our preliminary preclinical studies provide conceptual evidence that the dual 224Ra-solution with bone or tumor-targeted delivery of 212Pb has potential to inhibit cancer metastases without significant toxicity. In some settings, the use of a booster dose of purified 212Pb-conjugate alone could be required to elevate the effect of this tumor cell directed component, if needed, e.g., in a fractionated treatment regimen, where the dual targeting solution will act as maintenance treatment.

Left Kidney Undifferentiated Spindle Cell Sarcoma with Myeloid Cell Leukemia-1 Amplification: Therapeutic Response to Bortezomib, Venetoclax, and Dexamethasone Therapy

Abstract The overexpression of myeloid cell leukemia-1 (MCL-1) has been identified in numerous hematologic malignancies and solid tumors. Currently, there are no selective MCL-1 inhibitors. Here, we present a case of left kidney undifferentiated spindle cell sarcoma with MCL-1 amplification. The tumor showed primary resistance to chemotherapy and immune checkpoint inhibitors. Combination therapy of bortezomib, venetoclax, and dexamethasone demonstrated a positive response, resulting in a stable tumor condition for 6 months. To our knowledge, this is the first report to mention the clinical efficacy of bortezomib, venetoclax, and dexamethasone therapy in an MCL-1-amplified solid tumor.

Bortezomib abrogates temozolomide-induced autophagic flux through an ATG5 dependent pathway.

Introduction: Glioblastoma (GBM) is invariably resistant to temozolomide (TMZ) chemotherapy. Inhibiting the proteasomal pathway is an emerging strategy to accumulate damaged proteins and inhibit their lysosomal degradation. We hypothesized that pre-treatment of glioblastoma with bortezomib (BTZ) might sensitize glioblastoma to temozolomide by abolishing autophagy survival signals to augment DNA damage and apoptosis. Methods: P3 patient-derived glioblastoma cells, as well as the tumour cell lines U87, HF66, A172, and T98G were investigated for clonogenic survival after single or combined treatment with temozolomide and bortezomib in vitro. We investigated the requirement of functional autophagy machinery by utilizing pharmacological inhibitors or CRISPR-Cas9 knockout (KO) of autophagy-related genes -5 and -7 (ATG5 and ATG7) in glioblastoma cells and monitored changes in autophagic flux after temozolomide and/or bortezomib treatments. P3 wild-type and P3 ATG5-/- (ATG5 KO) cells were implanted orthotopically into NOD-SCID mice to assess the efficacy of bortezomib and temozolomide combination therapy with and without functional autophagy machinery. Results: The chemo-resistant glioblastoma cells increased autophagic flux during temozolomide treatment as indicated by increased degradation of long-lived proteins, diminished expression of autophagy markers LC3A/B-II and p62 (SQSTM1), increased co-localisation of LC3A/B-II with STX17, augmented and no induction of apoptosis. In contrast, bortezomib treatment abrogated autophagic flux indicated by the accumulation of LC3A/B-II and p62 (SQSTM1) positive autophagosomes that did not fuse with lysosomes and thus reduced the degradation of long-lived proteins. Bortezomib synergistically enhanced temozolomide efficacy by attenuating cell proliferation, increased DNA double-strand breaks, and apoptosis in an autophagy-dependent manner. Abolishing autophagy in ATG5 KOs reversed the bortezomib-induced toxicity, rescued glioblastoma cell death and reduced animal survival. Discussion: We conclude that bortezomib abrogates temozolomide induced autophagy flux through an ATG5 dependent pathway.

The Evidence That 25(OH)D3 and VK2 MK-7 Vitamins Influence the Proliferative Potential and Gene Expression Profiles of Multiple Myeloma Cells and the Development of Resistance to Bortezomib.

Multiple myeloma (MM) remains an incurable hematological malignancy. Bortezomib (BTZ) is a proteasome inhibitor widely used in MM therapy whose potent activity is often hampered by the development of resistance. The immune system is vital in the pathophysiology of BTZ resistance. Vitamins D (VD) and K (VK) modulate the immune system; therefore, they are potentially beneficial in MM. The aim of the study was to evaluate the effect of BTZ therapy and VD and VK supplementation on the proliferation potential and gene expression profiles of MM cells in terms of the development of BTZ resistance. The U266 MM cell line was incubated three times with BTZ, VD and VK at different timepoints. Then, proliferation assays, RNA sequencing and bioinformatics analysis were performed. We showed BTZ resistance to be mediated by processes related to ATP metabolism and oxidative phosphorylation. The upregulation of genes from the SNORDs family suggests the involvement of epigenetic mechanisms. Supplementation with VD and VK reduced the proliferation of MM cells in both the non-BTZ-resistant and BTZ-resistant phenotypes. VD and VK, by restoring proper metabolism, may have overcome resistance to BTZ in vitro. This observation forms the basis for further clinical trials evaluating VD and VK as potential adjuvant therapies for MM patients.

IATROGENIC SYSTEMIC LYMPHEDEMA FOLLOWING MULTIPLE MYELOMA TREATMENT

Lymphedema is a debilitating disease characterized by abnormal lymphatic drainage, either due to primary maldevelopment of the lymphatic system or to secondary injury. The clinical features of primary and secondary lymphedema differ, with primary lymphedema more often involving progressive bilateral lower extremity disease as compared to secondary lymphedema characteristically having more localized symptoms related to the origin of injury. This case presentation describes a patient who presented with bilateral lower extremity swelling, left greater than the right, with imaging results to support the diagnosis of lymphedema. During the time he was followed in our clinic, our team witnessed rapid progression of his lymphedema despite compliance with conservative management. We believe that the primary mechanism of systemic damage to our patient's lymphatic system is the lenalidomide and bortezomib therapy prescribed to treat multiple myeloma. This review explores the relationship between lenalidomide, bortezomib, and lymphedema in efforts of understanding this unique pathology of iatrogenic lymphedema mimicking primary nature.

Stem Cell Autograft Minimal Residual Disease Negativity Improves Outcomes after Autotransplant for Multiple Myeloma

Background: Autologous hematopoietic stem cell transplantation (AHCT) in the up-front setting is the standard-of-care for newly diagnosed multiple myeloma (NDMM). Contemporary induction regimens generate deeper responses, with higher rates of minimal residual disease (MRD) negativity in the bone marrow (BM) leading to improved progression-free survival (PFS) and overall survival (OS). However, it is unclear whether stem cell autograft (AG) contamination with myeloma cells and/or their precursors contributes to relapse after AHCT. To address this, we examined MM contamination of AG by next-generation flow cytometry (NGF) to determine the predictive value of AG MRD status on outcomes after AHCT. Methods: This study included 119 NDMM patients with prospectively collected BM and AG MRD results by NGF who underwent stem cell collection and up-front AHCT at our institution between Sept 2017 and Feb 2020. AG MRD status was assessed in peripheral blood at the time of stem cell collection (SCC). BM MRD status was assessed post-induction/pre-SCC and at 3-months post-AHCT. Additional BM MRD results were also available at 1- and 2-years post-AHCT for most patients. Patients were dichotomized based on AG MRD status (negative vs positive). A Kaplan-Meier model compared median PFS and OS between cohorts. A cox proportional hazards model determined prognostic impact, adjusting for high-risk cytogenetics by FISH and induction therapy. Results: Baseline characteristics were balanced between the MRD-negative and positive groups, with median age at AHCT of 61 (range, 55-67) years in the MRD-negative group and 60 (range, 54-67) years in the MRD-positive group. Patients received a median of 6 (range, 2-12) induction cycles with daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd, n=20), KRd (n=38), bortezomib, lenalidomide, and dexamethasone (VRD, n=51), or other therapy (n=10). Patients with MRD-positive AG were not enriched for high-risk cytogenetics. AG MRD-negativity rates after D-KRd, KRd, VRd, and other therapy were 95.0%, 78.9%, 58.8%, and 50%, respectively. All patients with MRD-positive AG (n=35) also had MRD-positive pre-AHCT BM, whereas 71% of patients with MRD-negative AG had MRD-positive pre-AHCT BM (p <0.001). Sustained or conversion to MRD-negativity in the BM at 3-months and 1-year post-AHCT was observed more for patients with MRD-negative AG than MRD-positive AG (40% vs 9%). At a median follow-up of 40 months (range 33- 46) after AHCT, patients with MRD-negative AG, compared with MRD-positive AG counterparts, had a significantly improved PFS (3-y PFS 78%, CI: 69 ‒ 87, vs. 54%, CI: 39 ‒ 73, p=0.021)(Fig1A) and trend toward better OS (3-y OS 96%, CI: 92 ‒ 100, vs. 82%, CI: 70 ‒ 96)(Fig1B) . The 3-year PFS of the MRD-negative AG group treated with D-KRd, KRd, VRd, and other therapy were 84% (CI: 69 ‒ 100), 79% (CI: 65 ‒ 96), 76% (CI: 71 ‒ 98), and 60% (CI:29 ‒ 100), respectively, while for the MRD-positive AG group treated with KRd, VRd, and other therapy (no D-KRd in this group), 3-year PFS rates were 73% (CI: 47 ‒ 100), 57% (CI: 39 ‒ 83), and 20% (CI:3.5 ‒ 100), respectively (p = 0.4). The 3-year PFS for patients with or without high-risk cytogenetics were 59% (CI: 44 ‒79) and 90% (CI: 81 ‒ 100), respectively, in the MRD-negative AG group, and 40% (CI: 22 ‒ 74) and 67% (CI: 49 ‒ 93), respectively, in the MRD-positive AG group (p = 0.002). The 3-year OS rates were 93% (CI: 85 ‒ 100) and 100% (CI: 100 ‒ 100) for the MRD-negative AG group and 76% (CI: 61 ‒ 100) and 84% (CI: 69 ‒ 100) for the MRD-positive group (p not calculated). On univariate analysis of PFS, the presence of high-risk cytogenetics (HR 3.2, CI: 1.55 ‒ 6.57), R-ISS stage (HR 3.01, CI 1.42 ‒6.41 for R-ISS=3), and AG MRD positive (HR 2.14, CI: 1.10 ‒ 4.16) were significant prognostic factors. Multivariate analysis identified high-risk cytogenetics (HR 3.16, CI: 1.51 ‒ 6.60) as the only significant factor for PFS. Conclusion: Patients with MRD-negative AG have improved PFS and OS following AHCT. These findings support the potential utility of AG MRD status as a prognostic parameter for clinical outcomes, with implications for guiding post-AHCT therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and safety of lenalidomide combined with bortezomib and dexamethasone induction therapy in newly diagnosed patients with multiple myeloma

Objective: This study aimed to evaluate the efficacy and safety of lenalidomide combined with bortezomib and dexamethasone (VRD) in the treatment of newly diagnosed multiple myeloma (MM) . Methods: A total of 150 newly diagnosed patients with MM diagnosed in The First Affiliated Hospital of Soochow University from November 2018 to February 2021 and received VRD as the induction regimen were included to evaluate the safety and efficacy of VRD induction therapy for newly diagnosed MM. Results: The median follow-up was 22 months, two patients (1.3%) died early after treatment, and 148 patients (98.7%) completed induction therapy. 116 patients (77.3%) were mobilized to collect autologous hematopoietic stem cells, 101 cases (87.1%) were qualified in the collection, of which 48 cases (41.4%) were excellent in the collection. The 3-year progression-free survival (PFS) rate was 59%, and the 3-year overall survival (OS) rate was 83%. After induction, complete remission (CR) /stringent CR rate was 54.4%, ≥ very good partial remission rate was 77.3%, overall response rate was 86.0%, and minimal residual disease negative rate was 46.0%. There was no statistically significant difference in the efficacy of cytogenetic high-risk patients compared with standard risk patients (P=0.456) . The median PFS time of cytogenetic high-risk patients was shorter than that of standard risk patients (not reached vs 33 months, P=0.014) . There was no statistically significant difference in the median OS time (not reached vs not reached, P=0.072) . The highest incidence of hematological adverse events was thrombocytopenia (72%) , followed by neutropenia (42%) and anemia (20%) . The highest incidence of non-hematological adverse events was peripheral neuritis (56.7%) . The main digestive tract symptoms include constipation (30.0%) and diarrhea (17.3%) . Upper respiratory tract infection (23.3%) and lung infection (7.3%) are the main infections. The incidence of adverse thrombocytopenia (90.0% vs 63.7%, P=0.001) , neutropenia (54.2% vs 36.3%, P=0.038) , anemia (33.3% vs 13.7%, P=0.005) , diarrhea (27.1% vs 12.7%, P=0.030) , limb edema (20.8% vs 3.9%, P=0.030) , fever (20.8% vs 4.9%, P=0.006) , thrombosis (8.3% vs 0, P=0.016) , and renal function deterioration (20.8% vs 3.9%, P=0.030) in patients with renal insufficiency was higher than that in patients with normal renal function. Conclusion: The VRD regimen has a significant effect on newly diagnosed MM, does not affect the hematopoietic stem cell collection, and has controllable adverse events; however, the incidence of adverse events was higher in patients with renal insufficiency.

Pomalidomide in relapsed and refractory multiple myeloma: multicenter retrospective study

Background. The treatment options for patients with multiple myeloma who refractory to previous bortezomib and lenalidomide therapy are limited. Pomalidomide is ап immunomodulatory agent that was registered for the treatment of patients with double refractory multiple myeloma.Aim. To evaluate efficacy, safety and optimal course of the therapy with pomalidomide in routine practice in patients with double refractory multiple myeloma.Materials and methods. Overall, 71 patients with double refractory multiple myeloma were included in the retrospective analysis. There were 36 males and 35 females. The median age was 61 years (range 35-79). According to Durie-Salmon staging system, there were 53 (79.1 %) patients in stage III, 13 (19.4 %) - stage II, and 1 (1.5 %) - stage I.The stage was unknown in 4 patients. Kidney impairment at the onset was in 10 (15 %) patients, the normal function was in 57 (85 %) patients and 4 patients had no data. Most patients (n = 68, 95.8 %) received pomalidomide in one therapy line, in 3 (4.2 %) patients - drug was given in two lines, totally 74 episodes of use. Median number of drugs prescribed prior to pomalidomide were 4 (2-9) drugs, including target ones - 2 (2-5). In the first remission 31 (43.6 %) patients received high-dose therapy with autologous stem cell transplantation. pomalidomide was administered in combination with low doses of dexamethasone (PomDex, n = 44; 59.4 %) and as a part of triple regimens (n = 30; 40.6 %). previously exposed (n = 22; 73.3 %) and new drugs (n = 8; 26.7 %) were used in the combination treatment. In 44 (61.9 %) patients pomalidomide was administered more than 3 years after the onset of the disease, median 63.5 (37-184) months. In 27 (38.1 %) patients it was given within less than 3 years after the onset, median 21 (6-36) months. The primary endpoint was progression-free survival. Secondary endpoints - pomalidomide tolerability, response rate and optimal third drug in the triple regimen. The dependence of progression-free survival, frequency of response and adverse events from the pretreatment, the choice of the third drug, gender, age, immunochemical variant, stage according to the International Staging System and to Durie-Salmon classification was studied.Results. The median time from the diagnosis to the start of pomalidomide therapy was 44.5 (6-184) months. The median of cycles with pomalidomide was 3 (1-30). The response was achieved in 52 (70 %) patients. The median progression-free survival was 4 (1-30) months, overall survival - 6 (0.5-42) months. Adverse effects were noted in 34 (46.5 %) patients. The most frequent adverse events were neutropenia grade III-IV (n = 14; 41.3 %), infection (n = 7; 20.7 %) and fatigue with limitation of daily activity (n = 6; 20.6 %). The rate of adverse events was higher in patients with triplets than doublets regimens of therapy: 43.3 % (n = 13) and 27.2 % (n = 12) respectively (p = 0.008). There were no statistically significant differences in progression-free survival between pomalidomide treatment options (two- or three-component regimen).Conclusion. Compared to the three-component therapy consisting of drugs to which refractoriness was previously diagnosed the PomDex scheme is less toxic and equally effective. Therapy with pomalidomide is effective in the majority of patients with double refractory multiple myeloma even in heavily pretreated. The toxicity is acceptable.

Lenalidomide, bortezomib and dexamethasone induction therapy for the treatment of newly diagnosed multiple myeloma: a practical review.

For patients with newly diagnosed multiple myeloma, survival outcomes continue to improve significantly: however, nearly all patients will relapse following induction treatment. Optimisation of induction therapy is essential to provide longer term disease control and the current standard of care for most patients incorporates an immunomodulatory agent and proteasome inhibitor, most commonly lenalidomide and bortezomib in combination with dexamethasone (RVD), with maintenance until progression. Historically there has been limited access to RVD as an induction strategy outside of the United States; fortunately, there is now increasing access worldwide. This review discusses the rationale for use of RVD as induction therapy and aims to provide guidance in prescribing this regimen in order to optimise efficacy while minimising the toxicities of treatment. We also highlight the increasing evidence for the utility of addition of a monoclonal antibody to the RVD backbone to deepen responses and potentially provide longer disease control.

Updated survival with extended follow-up on patients with newly diagnosed multiple myeloma treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy and a risk-stratified maintenance approach.

8061 Background: Lenalidomide, bortezomib, and dexamethasone (RVD) has been established as an effective and well-tolerated induction regimen in patients with newly diagnosed myeloma (NDMM). We have previously published a retrospective analysis of 1000 patients treated with RVD and risk-stratified maintenance therapy showing a median PFS of 65 months and median OS of 126 months for the entire cohort (Joseph et al, JCO 2020). This data has served as an important benchmark for evaluating upfront treatment strategies in NDMM. Here, we present updated survival data with extended follow up on this patient population treated at the Winship Cancer Institute of Emory University. Methods: From January 2007 to August 2016, 1000 consecutive newly diagnosed myeloma patients treated with RVD induction therapy (R-25 mg/day on days 1-14, V-1.3 mg/m2 on days 1,4,8,11 and D-40 mg once/twice weekly as tolerated) were identified. Demographics, clinical characteristics, and outcomes data for the patients were obtained from our institutional review board-approved myeloma database. Responses were evaluated per IMWG Uniform Response Criteria. Results: The median age of this cohort was 61 (range 16-83). Other notable patient characteristics include: M/F 54.6%/45.4%, W/AA 61.8%/35.9%; ISS I/II/III 45.8%/30.8%/23.4%. R-ISS I/II/III 39.9%/48.7%/11.5%; Isotype IgG/IgA/FLC 59.2%/19.0%/15.7%; standard risk(SR)/high risk (HR) 71.2%/15.8%.. High risk disease was defined as the presence of t(4;14), t(14;16), del(17p), and/or complex karyotype by conventional metaphase cytogenetics. 81.8% of patients underwent ASCT, with 16.8% having deferred ASCT. 75.3% of patients were initiated on maintenance therapy. With a median follow up of 88.4 months, the median PFS for the entire cohort was 68.7 months (95% CI 61.8-75.5) and the median OS was 128.9 months. The median PFS for HR patients was 42.4 months (95% CI 35.7-48.9), and the median PFS for SR patients was 80.3 months (95% CI 72.8-87.8). The median OS for SR patients was not reached, and for HR patients was 86.6 months (95% CI 70.1-103.1). Conclusions: Updated analysis with long-term follow up of this database of 1000 NDMM patients treated with RVD continues to demonstrate that, in combination with a risk-stratified maintenance strategy, RVD delivers durable remissions and impressive long-term outcomes. This study remains the largest cohort of patients treated with RVD reported to date, and continues to show the efficacy of this upfront treatment approach in newly diagnosed myeloma.

P226 Bortezomib-induced muscle toxicity mimicking myositis

Abstract Background/Aims Novel drugs such as bortezomib are proteasome inhibitors that are used to treat multiple myeloma. Bortezomib induces apoptosis of rapidly dividing, metabolically active cells with extensive protein synthesis. Literature review shows two case reports of bortezomib-induced reversible muscle toxicity and motor neuropathy, used to treat multiple myeloma (MM) with persistently normal creatine kinase. In a single-centre prospective study, 14 out of 24 patients with symptomatic MM were treated with bortezomib and, among these, seven developed proximal lower limb weakness with complete resolution of symptoms after discontinuation of bortezomib as depicted in our case. We present a case of myositis mimic which was triggered by the use of immunotherapy Bortezomib to treat multiple myeloma. Methods An 81-year-old Caucasian gentleman was admitted with proximal lower limb weakness. He had a background history of multiple myeloma, treated with melphalan, prednisolone and bortezomib commenced in September 2019. Following his fourth cycle in January 2020, he noted proximal lower limb weakness and was referred to Rheumatology. He had MRI of the spine which did not reveal any cord compression. His prednisolone was stopped. On further questioning, there were no features to suggest connective tissue disease, inflammatory arthritis or vasculitis. On examination power was reduced to 4/5 in the proximal muscles of lower limb affecting his mobility. Rest of the examination was unremarkable. Results All bloods including creatinine kinase, autoimmune profile and inflammatory markers were normal. Magnetic resonance imaging (MRI) of the thighs showed diffuse fatty atrophy within all muscle groups of the thighs with low grade oedema within the vastus lateralis and intermedius particularly of the left thigh when compared to the right. The appearances were in keeping with inflammatory myositis, without any abscess formation. Electromyography showed abnormal signals with neurogenic and myopathic changes. Nerve conduction studies showed moderate length-dependent axonal peripheral neuropathy. Following his review, investigations and discussion between Rheumatology and Haematology, it was believed that his lower limb weakness was likely related to his bortezomib and the decision was made to stop bortezomib therapy. He was followed up in Rheumatology and Haematology clinic after stopping bortezomib with improvement of lower limb weakness and mobility. His creatinine kinase and inflammatory markers remained persistently normal. Muscle biopsy was not considered as there was enough evidence to suggest it was bortezomib induced muscle toxicity. Conclusion We present a case of myositis mimic whose symptoms completely resolved on stopping bortezomib. As this is one of the rare and early complications of bortezomib we suggest that patients treated with bortezomib should be monitored for muscle weakness. Disclosure G. Ansari: None. Z. Alkutobi: None. A. Nandagudi: None.

Meibomian Gland Dysfunction Associated with Bortezomib in a Multiple Myeloma Patient

Purpose: This study reports a case of meibomian gland dysfunction associated with bortezomib, which is a treatment of choice for multiple myeloma.Case summary: A 59‐year‐old female patient presented to our hospital with a complaint of dryness that had worsened for 2 months and eye discharges that were difficult to remove even after washing her face. The patient had been diagnosed with multiple myeloma 5 months prior and had undergone four cycles of bortezomib therapy. Slit‐lamp microscopy revealed a number of pouting of the meibomian gland (MG) orifices in both eyes. Meibography revealed that more than one‐third and less than twothirds of the total MG area of both upper lids were lost and more than two‐thirds of the total MG area of both lower lids were lost. No clinically significant improvements were noted at 8 months despite thorough eyelid hygiene therapy, including warm compresses, topical antibiotics, steroids, and artificial tears. However, when the patient revisited our clinic 2 months after completing bortezomib treatment, the subjective symptoms had improved and all of the pouting of MG orifices had disappeared. There was no significant difference in the MG dropout area for either eye compared with the observations from a previous visit during bortezomib treatment.Conclusions: Clinicians should be aware that MG dysfunction may occur or worsen in patients receiving bortezomib treatment and should consider this when establishing a treatment plan for meibomian dysfunction or when educating patients.

Real-world evidence of levofloxacin prophylaxis in elderly patients with newly diagnosed multiple myeloma who received bortezomib, melphalan, and prednisone regimen.

BackgroundAlthough survival outcomes of multiple myeloma (MM) have improved with the development of new and effective agents, infection remains the major cause of morbidity and mortality. Here, we evaluated the efficacy of levofloxacin prophylaxis (in a real-world setting) during bortezomib, melphalan, and prednisone (VMP) therapy in elderly patients with newly diagnosed MM.MethodsThis study retrospectively analyzed the records of patients with newly diagnosed MM treated with the VMP regimen between February 2011 and September 2020 at three institutes of the Republic of Korea.ResultsOf a total of 258 patients, 204 (79.1%) received levofloxacin prophylaxis during VMP therapy. The median number of levofloxacin prophylaxis cycles was 4 (range, 1‒9), but 10 patients did not complete the planned prophylaxis because of side effects. Sixty-six patients (25.5%) experienced severe infections during VMP therapy, most of which (74.7%) occurred within the first four cycles of VMP therapy regardless of levofloxacin prophylaxis status. Early severe infection was significantly associated with poor survival. In multivariate analysis, levofloxacin prophylaxis was significantly associated with a lower risk in early severe infection.ConclusionOur findings suggest that levofloxacin prophylaxis should be considered at least during the first four cycles of VMP therapy in elderly patients with newly diagnosed MM.

Efficacy of Intermittent, Oral Famciclovir Prophylaxis for Bortezomib-Induced Herpes Zoster in Multiple Myeloma Patients.

ObjectiveTo explore the efficacy and safety of intermittent, oral famciclovir prophylaxis for bortezomib-induced herpes zoster in multiple myeloma patients.MethodWe retrospectively analyzed the incidence of bortezomib treatment-related varicella-zoster virus reactivation in 719 newly-diagnosed multiple myeloma patients receiving intermittent oral famciclovir prophylaxis, continuous oral acyclovir prophylaxis or no prophylaxis. The definition of intermittent oral famciclovir prophylaxis was oral famciclovir at a dose of 250mg twice daily for 9 days after finishing the last dose of bortezomib therapy every cycle. Age, gender, stage per the International Staging System, type of M protein, baseline of absolute lymphocyte count, absolute neutrophil count, and absolute monocyte count were analyzed to find the potential factors that could predispose to herpes zoster infections.ResultsVaricella-zoster virus infection occurred in 96 patients (13.4%) during bortezomib treatment. The incidence of herpes zoster was significantly higher in the non-prophylaxis group compared with the prophylaxis group (22.9% vs 8.2% P<0.001), while the rate was similar between the intermittent oral famciclovir group and the continuous oral acyclovir group (8.4% vs 7.9% P=0.835). Hepatic and renal toxicity were observed in 12% and 2.8% of the patient respectively in the intermittent famciclovir group, which was similar in the continuous acyclovir group (18.1% and 4.2%). The prophylactic use of antiviral agents is a predictive factor for varicella-zoster virus reactivation.ConclusionIntermittent famciclovir prophylaxis is effective and safe in preventing herpes zoster development and can markedly reduce the duration of oral medicine treatment compared with continuous acyclovir prophylaxis.

Cellular membrane-based vesicles displaying a reconstructed B cell maturation antigen for multiple myeloma therapy by dual targeting APRIL and BAFF

Excessive secretion of cytokines (such as APRIL and BAFF) in the bone marrow microenvironment (BMM) plays an essential role in the formation of relapsed or refractory multiple myeloma (MM). Blocking the binding of excessive cytokines to their receptors is becoming a promising approach for MM therapy. Here, we proposed a strategy of engineering cell membrane-based nanovesicles (NVs) to reconstruct B cell maturation antigen (BCMA), a receptor of APRIL and BAFF, to capture excess APRIL/BAFF in BMM as a bait protein. Our results showed that reconstructed BCMA expressed on the membrane of NVs (Re-BCMA-NVs) retained the ability of binding to soluble and surface-bound APRIL/BAFF in BMM. Consequently, Re-BCMA-NVs blocked the activation of the NF-κB pathway, downregulating the expression of anti-apoptosis genes and cell cycle-related genes, and hence inhibiting MM cell survival. Importantly, Re-BCMA-NVs showed a synergistic anti-MM effect when administrated together with bortezomib (BTZ) in vitro and in vivo. Our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to BTZ-based therapy. Statement of significanceExcessive APRIL and BAFF is reported to promote the survival of MM cell and facilitate the formation of resistance to bortezomib therapy. In this study, we bioengineered cell membrane derived reconstructed BCMA nanovesicles (Re-BCMA-NVs) to capture both soluble and cell-surface APRIL and BAFF. These NVs inhibited the activation of NF-κB pathway and thus inhibit the survival of MM cells in 2D, 3D and subcutaneous mouse tumor models. Importantly, Re-BCMA-NVs showed a synergistic anti-MM effect when administrated together with bortezomib in vitro and in vivo. Taken together, our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to bortezomib-based therapy.

Efficacy of bortezomib in reduction of systemic lupus erythematosus disease activity index score: A meta-analysis

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by the production of auto-antibodies against nuclear and cytoplasmic antigens, which can affect multiple organs. To date, no meta-analysis has reported the efficacy of bortezomib in SLE. We performed a meta-analysis to investigate the efficacy of bortezomib in patients with SLE. Methods: We searched the PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Chinese BioMedical databases for articles published before 18 August 2021 to identify all studies relevant to SLE. The following were our inclusion criteria: (1) written in all languages, (2) bortezomib administration in patients with SLE and, (3) a clear description of SLE Disease Activity Index (SLEDAI) scores. Following were the exclusion criteria: (1) duplicate publications (the most recent article was included for analysis)and, (2) animal experiments, case reports, meeting reports, and reviews. The pooled data were analysed using a fixed- or random-effects model, depending on heterogeneity (determined using the I2 index). Results: Three articles that described 29 patients were included in this study. The forest plot showed a positive association between bortezomib therapy and SLE based on analysis of SLEDAI scores, with an odds ratio of 11.30 (95% confidence interval 7.03–15.56, p &lt; .00001). Conclusion: Bortezomib treatment can reduce the SLEDAI scores in patients with SLE, which suggests the usefulness of this therapeutic approach for SLE.

Addition of bortezomib to high-dose cyclophosphamide therapy as a conditioning regimen for autologous peripheral blood stem cell harvest leads to an increased yield of hematopoietic stem cells.

Peripheral blood stem cell harvest (PBSCH) is a crucial procedure for autologous stem cell transplantation in patients with multiple myeloma. We herein report a retrospective study to verify the usefulness of bortezomib and high-dose cyclophosphamide therapy (Bor-HDCY) as a conditioning regimen for PBSCH. Thirty-three patients were evaluated. The median age at the first apheresis was 61 (interquartile range, 53-64) years old, and 18 (54.5%) patients were male. Bor-HDCY was performed in 15 patients, and HDCY was performed in 18. In the patients who underwent Bor-HDCY, the CD34+ cell count at the first apheresis was significantly higher than in the others (P<0.01), and the total CD34+ cell count also tended to be high (P=0.0933). In terms of apheresis days, two-thirds of the patients who underwent HDCY had two-day apheresis, whereas most who underwent Bor-HDCY had one-day apheresis. According to univariate analysis, Bor-HDCY (P<0.01), VRd (Bor, lenalidomide, and dexamethasone) as induction therapy (P=0.0529), and ≥VGPR before PBSCH (P=0.0767) were factors associated with a higher CD34+ cell count at first apheresis. Although multivariate analysis showed that there were no independently significant factors influencing the CD34+ cell count at the first apheresis, the stepwise selection method revealed that only the Bor-HDCY regimen remained in the final model (P<0.005). Bor-HDCY may be a useful conditioning regimen for increasing the CD34+ cell yield.

A Novel Model of Tumor-Infiltrating B Lymphocyte Specific RNA-Binding Protein-Related Genes With Potential Prognostic Value and Therapeutic Targets in Multiple Myeloma.

Background: RNA-binding proteins (RBPs) act as important regulators in the progression of tumors. However, their role in the tumorigenesis and prognostic assessment in multiple myeloma (MM), a B-cell hematological cancer, remains elusive. Thus, the current study was designed to explore a novel prognostic B-cell-specific RBP signature and the underlying molecular mechanisms. Methods: Data used in the current study were obtained from the Gene Expression Omnibus (GEO) database. Significantly upregulated RBPs in B cells were defined as B cell-specific RBPs. The biological functions of B-cell-specific RBPs were analyzed by the cluster Profiler package. Univariate and multivariate regressions were performed to identify robust prognostic B-cell specific RBP signatures, followed by the construction of the risk classification model. Gene set enrichment analysis (GSEA)-identified pathways were enriched in stratified groups. The microenvironment of the low- and high-risk groups was analyzed by single-sample GSEA (ssGSEA). Moreover, the correlations among the risk score and differentially expressed immune checkpoints or differentially distributed immune cells were calculated. The drug sensitivity of the low- and high-risk groups was assessed via Genomics of Drug Sensitivity in Cancer by the pRRophetic algorithm. In addition, we utilized a GEO dataset involving patients with MM receiving bortezomib therapy to estimate the treatment response between different groups. Results: A total of 56 B-cell-specific RBPs were identified, which were mainly enriched in ribonucleoprotein complex biogenesis and the ribosome pathway. ADAR, FASTKD1 and SNRPD3 were identified as prognostic B-cell specific RBP signatures in MM. The risk model was constructed based on ADAR, FASTKD1 and SNRPD3. Receiver operating characteristic (ROC) curves revealed the good predictive capacity of the risk model. A nomogram based on the risk score and other independent prognostic factors exhibited excellent performance in predicting the overall survival of MM patients. GSEA showed enrichment of the Notch signaling pathway and mRNA cis-splicing via spliceosomes in the high-risk group. Moreover, we found that the infiltration of diverse immune cell subtypes and the expression of CD274, CD276, CTLA4 and VTCN1 were significantly different between the two groups. In addition, the IC50 values of 11 drugs were higher in the low-risk group. Patients in the low-risk group exhibited a higher complete response rate to bortezomib therapy. Conclusion: Our study identified novel prognostic B-cell-specific RBP biomarkers in MM and constructed a unique risk model for predicting MM outcomes. Moreover, we explored the immune-related mechanisms of B cell-specific RBPs in regulating MM. Our findings could pave the way for developing novel therapeutic strategies to improve the prognosis of MM patients.