Treatment Of Refractory Multiple Myeloma Research Articles

Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma.

B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial. We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes. At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5-100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse. Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.

Treatment of multiple myeloma with selinexor: a review.

Over the last 20 years, breakthroughs in accessible therapies for the treatment of multiple myeloma (MM) have been made. Nevertheless, patients with MM resistant to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have a very poor outcome. Therefore, it is necessary to explore new drugs for the treatment of MM. This review summarizes the mechanism of action of selinexor, relevant primary clinical trials, and recent developments in both patients with relapsed/refractory myeloma and patients with newly diagnosed myeloma. Selinexor may be useful for the treatment of refractory MM.

Targeting the ubiquitin-proteasome system: a novel therapeutic strategy for neuroblastoma.

Neuroblastoma (NB) stands as a common and formidable malignant tumor among children, characterized by marked tumor heterogeneity and resistance to conventional treatments. Central to the regulation of protein stability, localization, and function is the process of ubiquitination-a critical protein modification. The therapeutic potential of drugs that target deubiquitination, demonstrated in the treatment of refractory multiple myeloma, warrants investigation in the context of NB. This review endeavors to demystify the intricate biological implications of ubiquitination within NB pathology, synthesize the current landscape of preclinical studies focused on the inhibition of the ubiquitin-proteasome system in NB, and assess the viability of this strategy as an innovative therapeutic frontier.

The treatments of Carvykti in Multiple myeloma

Multiple myeloma is a severe malignance caused by damaged B cells from bone marrow plasma cells. Multiple treatments have been introduced to release and treat such a disease, but in general, high rate and severity of adverse events and relatively unideal efficacies of those existing treatments necessitate a new therapy achieving a better curative effect. Thus, CARVYKTI, a CAR-T therapy, has been developed for treat patients with multiple myeloma and who have already received several other treatments. By having genetically modified T cells, damaged cancer-causing B cells are targeted and vanished specifically. Recently, the FDA has officially approved CARVYKTI as a treatment for refractory multiple myeloma, and the basic pharmacology and the phase1b-2 clinical trial are summarized in this paper.

Ixazomib-induced Sweet’s syndrome: A case report

Ixazomib, a proteasome inhibitor commonly used for the treatment of multiple myeloma, is a rare cause of Sweet’s syndrome. We present a 62-year-old man who developed drug-induced Sweet’s syndrome during his fifth cycle of ixazomib for treatment of refractory multiple myeloma. Monthly rechallenge led to the recurrence of symptoms. The patient was successfully treated with addition of weekly corticosteroids and resumed his cancer treatment.

Abstract 13446: Predicting Cardiovascular Risk and Preempting Major Cardiovascular Events During CAR T Therapy

Chimeric antigen receptor (CAR) T cell therapy is a breakthrough personalized, genetically engineered therapy that has been proven effective for the treatment of refractory multiple myeloma and large B cell lymphoma. However, significant major adverse cardiovascular events (MACE) have been reported with its application. To further investigate associated risk factors for MACE, we performed a retrospective analysis of a cohort of consecutive patients treated with CAR T therapy at our center. Clinical, laboratory and imaging parameters were collected for 48 patients. Of these, 7 patients (14.6%) had a MACE event. Variables analyzed included age, sex, body mass index, coronary artery calcium, lipid profile, baseline medications, preceding anthracycline or carfilzomib exposure, cancer type, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), tocilizumab, among others (Table). Peak C-reactive protein (CRP, median [IQR]) level was 76.00 (73.1) mg/dL in patients without MACE and 121.30 (133.22) mg/dL in patients with MACE, p = 0.028). CRS and ICANS grades were associated with MACE events ( p = 0.039 and 0.03, respectively). No echocardiographic differences were found. Our results indicate that the degree of inflammatory response, reflected by peak CRP level, is associated with MACE events in patients receiving CAR T therapy. These data suggest that inflammatory markers may be clinically relevant predictors of subsequent MACE complications in patients receiving CAR T therapy. Prospective inflammation monitoring and anti-inflammatory strategies may preempt MACE in this patient population.

ACUTE PULMONARY HYPERTENSION AFTER BORTEZOMIB THERAPY

ACUTE PULMONARY HYPERTENSION AFTER BORTEZOMIB THERAPY

The role of monoclonal antibodies in treatment of refractory multiple myeloma

Multiple myeloma (MM) is a B-cell malignant tumor; its morphological substrate – plasma cells – produces monoclonal immunoglobulin. Primarily, MM is diagnosed in elderly people and is characterized by a variety of clinical manifestations caused by plasma cells infiltration and organ damage. Despite successes in MM therapy, in the majority of cases recurrences of MM or refractory process are observed. In this case, the choice of antitumor drug is usually made depending on its tolerability, toxicity, and availability. Selection of correct treatment can be complicated by such frequent clinical manifestations of MM as osteolytic vertebral lesions leading to development of pathologic compression fractures which in some cases cause spinal cord compression and full immobility in the patients with MM.A clinical case of a 62-year-old female patient with refractory MM is presented. Pathologic compression fractures of the Th12 and L2 vertebral bodies with massive extraosseous component at the Th12 vertebra level posed a threat of spinal cord compression. At the 1st stage, percutaneous vertebroplasty was performed, then antitumor therapy with daratumumab without increased intercycle intervals which significantly increased patient’s quality of life.

Extramedullary Myeloma to the Liver Following Bispecific Antigen T-Cell Treatment for Refractory Multiple Myeloma.

A 70-year-old man diagnosed with refractory multiple myeloma was admitted to hospital for an elevation in his liver enzymes. In the 7 years since diagnosis, he had undergone 8 chemotherapy regimens, an autologous stem cell transplant, and palliative chemotherapy to his T-spine. He was now undergoing bispecific antigen T-cell treatment with the elevation in his liver enzymes occurring 2 days after his initial treatment. He underwent liver imaging as part of his workup. Previous CT scans of his abdomen showed a normal liver in May 2020, and in October 2020, they showed a nonspecific hypoattenuation in the inferior right hepatic lobe.

Targetting CD38 in T Cell Acute Lymphoblastic Leukemia

Targeted immunotherapy has become a promising emerging therapeutic strategy for many cancers. No safe and effective immunotherapies have been developed for T-cell acute lymphoblastic leukemia (T-ALL). CD38 is a transmembrane glycoprotein found on the cell surface of activated T cells, terminally differentiated B cells, but relatively low levels on normal lymphoid and myeloid cells. Daratumumab (Janssen Biotech, Inc.) is a human monoclonal antibody that binds to CD38 and is used in the treatment of refractory multiple myeloma (MM).To ensure CD38 is a relevant target in T-ALL, we evaluated CD38 expression by flow cytometry from 21 patients with T-ALL (10 early T-cell precursor (ETP) and 11 non-ETP) at diagnosis and after induction chemotherapy. CD38 was expressed in all samples and surface expression did not change after induction (mean CD38 mean fluorescence intensity (MFI) at diagnosis vs end-of-induction: 3.27 log vs 3.19 (p = 0.25). Similarly, we evaluated CD38 expression of 15 primary T-ALL xenograft samples (7 ETP and 8 non-ETP T-ALL), and only 1 sample demonstrated low CD38 expression. In contrast, we evaluated CD38 expression in 10 patients with de novo B-ALL at diagnosis and found CD38 expression was significantly decreased after induction therapy (5351 vs. 723, p-0.002). Therefore we hypothesized that targeting CD38 with daratumumab would be effective against T-ALL.We xenografted primary ALL blasts from 15 different patients, including 7 with ETP-ALL and 8 with non-ETP T-ALL. Mice were randomized to daratumumab (200 μg /mouse intraperitoneally weekly) vs isotype control (200 μg/mouse; 5 mice per arm for each sample) after they developed >1% peripheral blood (pb) blasts by FACS. Disease burden was assessed by FACS enumeration of pb blasts weekly and splenic blasts at sacrifice.We demonstrate striking efficacy of daratumumab monotherapy in 6 of 7 ETP-ALL samples with significant reduction of pb and splenic blasts. Mice treated with high disease burden from 5 of the 8 non-ETP T-ALL samples were moribund immediately after daratumumab injection, presumably from tumor lysis. Autopsy performed on moribund compared to isotype-treated animals did not reveal embolism. We repeated the experiments in the 8 non-ETP T-ALL samples and the one ETP sample that did not respond when treated at high disease burden. For these experiments, we treated the mice after injection but before detectable pb blasts (termed low disease burden). Using this approach, daratumumab was effective in 7 of 8 non-ETP ALL samples and the one ETP sample that was non-responsive when treated at high disease burden. In summary, we found dara monotherapy was effective in patient-derived xneograft models developed from 14 of 15 patients with T-ALL.The 1 T-ALL sample that did not respond to daratumumab, was the only sample with low CD38 expression. Therefore we hypothesize that the clinical benefit from daratumumab reflects the level of CD38 expression. In myeloid and MM cells, low dose all-trans retinoic acid (ATRA) significantly upregulates CD38 expression. We have similarly tested T-ALL cell lines across a broad range of ATRA doses, however ATRA has no effect on CD38 expression on T-ALL cells. Experiments are ongoing to evaluate alternative agents such as interferon to upregulate CD38 and CRISPR/Cas9 to knock-out CD38.In summary, we found daratumumab is a highly effective novel monotherapy for T-ALL in preclinical models. Based on this work, we are planning to open a multi-institutional early phase clinical trial for children and young adults with relapsed and refractory T-ALL. DisclosuresMaude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Adaptimmune: Consultancy; Jazz Pharmaceuticals: Consultancy; University of Pennsylvania: Patents & Royalties.

Therapeutic Targeting of Interferon Regulatory Factor 4 with Next Generation Antisense Oligonucleotides Produces Robust In Vivo Antitumor Activity in Preclinical Models of Multiple Myeloma

Despite significant recent advances in therapeutic options, multiple myeloma (MM) remains an incurable disease, and novel agents targeting novel molecular pathways with activity in advanced patients are urgently needed. Interferon Regulatory Factor 4 (IRF4) is a transcription factor involved in immune responses in normal B and T cells, and is strongly implicated in the development of hematological malignancies, especially MM. Although recent publications have pointed to IRF4 as a driver oncogene in the progression of MM, it is considered an intractable target by conventional therapeutic approaches.Here we describe an antisense oligonucleotide (ASO) approach to selectively target IRF4. Administration of next generation human IRF4 ASOs via ‘free-uptake’ (without transfection) to a large panel of human MM cell lines resulted in a dose-dependent IRF4 reduction with concomitant induction of apoptosis. ASO-mediated IRF4 depletion also decreased the levels of c-Myc, another key oncogene in MM. MM cells were sensitive to even modest depletion of IRF4 (<50%), suggesting the strong dependence of MM cells on IRF4 for their survival. IRF4 ASOs also enhanced the sensitivity of the tumor cells to the treatment of IMiD (lenalidomide), proteasome inhibitor (Bortezomib) and BTK inhibitor (Ibrutinib) in MM cell, including KMS-11, JJN3 and MM1.R. In addition, Bortezomib-resistant clones of KMS-11 cells established from a long-term exposure to the drug remained sensitive to IRF4 inhibition. Importantly, in two different subcutaneously implanted MM tumor models, systemic administration of 2 independent human IRF4 ASOs depleted IRF4 protein levels in tumors and inhibited the growth of tumors compared to control treatment. Moreover, in a clinically relevant MM mouse model where human MM cells accumulate in the mouse bone marrow, treatment with human IRF4 ASOs substantially prolonged the survival of the tumor-bearing animals along with specific downregulation of human IRF4 and its downstream gene c-Myc. Finally, systematic treatment of mice with mouse-selective IRF4 ASOs at 50 mg/kg, twice a week for 4 weeks was well tolerated in normal mice, which is consistent with the lack of phenotypes observed in IRF4 heterozygous animals. Taken together, these results suggest that MM cells rely heavily on the survival pathway mediated by IRF4 and that selective knockdown of IRF4 by next generation ASOs is an attractive therapeutic strategy for the treatment of patients with advanced treatment-refractory MM. DisclosuresZhou:Ionis Pharmaceuticals: Employment, Equity Ownership. Schmidt:Ionis Pharmaceuticals: Employment. Kim:Ionis Pharmaceuticals: Employment. MacLeod:Ionis Pharmaceuticals: Employment.

PCN20 Efficacy and Safety of Selinexor for Patients with Relapsed and Refractory Multiple Myeloma: A Meta-Analysis

Although the outcomes of multiple myeloma (MM) have improved, relapsed and refractory MM (RRMM) remains a major challenge (RRMM). Selinexor is a very recent first-in-class, oral selective-inhibitor-of-nuclear-export (SINE) compound that impedes Exportin 1. This is the first meta-analysis to determine the efficacy and safety of selinexor, including in combination, for RRMM. We conducted a comprehensive literature search until September 10, 2020, to identify literature related to the efficacy and safety of selinexor alone or in combination with corticosteroids and proteasome inhibitors for the treatment of RRMM. Independent reviewers performed study selection, data extraction, and the risk of bias assessment based on Cochrane criteria. The primary outcome measures of interest were efficacy outcomes, with safety outcomes being of secondary interest. Statistical analyses using a fixed/random effects model were performed, at a statistical significance of p<0.05. The RevMan software was used for analysis. A total of five phases I-II clinical trials were included, including a total of 348 RRMM patients. Most of the patients were scored between 0-2 based on Eastern Cooperative Oncology Group (ECOG) performance-status scoring. Meta-analysis of all the studies found significant overall clinical benefit rate (47.5, 95% confidence interval [CI] 23.9-71.0, P<0.0001), overall response rate (35.3, 95% CI 17.1-53.6, P=0.0001), and complete response (2.6, 95% CI 0.3-4.9, P=0.03). For safety outcomes, only the rate of discontinuations was significant with selinexor (19.4, 95% CI 13.4-25.5; P<0.00001). Subgroup analyses demonstrated that the efficacy is higher with selinexor combinations compared to selinexor alone, and suggested that outcomes may vary based on the refractory status of the MM. Based on the type of included studies, this is a pilot analysis that demonstrated that selinexor produces significantly better responses with an acceptable safety profile in RRMM patients. Combination with other drugs produces a better response with no additional safety concerns.

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

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

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy.

Multiple myeloma (MM) is an incurable malignancy of plasma cells with a clinical course characterized by multiple relapses and treatment refractoriness. While recent treatment advancements have extended overall survival (OS), refractory MM has a poor prognosis, with a median OS of between 4 and 6 months. Nuclear export inhibition, specifically inhibition of CRM1/XPO1, is an emerging novel treatment modality that has shown promise in treatment-refractory MM. Initially discovered in yeast in 1983, early clinical applications were met with significant toxicities that limited their utility. The creation of small molecule inhibitors of nuclear export (SINE) has improved on toxicity limitations and has led to investigation in a number of malignancies at the preclinical and clinical stages. Preclinical studies of SINEs in MM have shown that these molecules are cytotoxic to myeloma cells, play a role in therapy resensitization, and suggest a role in limiting bone disease progression. In July 2019, selinexor became the first nuclear export inhibitor approved for use in relapsed/refractory MM based on the STORM trial. As of May 2020, there were eight ongoing trials combining selinexor with standard treatment regimens in relapsed/refractory MM. Eltanexor, a second-generation SINE, is also under investigation and has shown preliminary signs of efficacy in an early clinical trial while potentially having an improved toxicity profile compared with selinexor. Results in ongoing trials will help further define the role of SINEs in MM.

S2649 A Rare Case of Carfilzomib Causing Drug-Induced Liver Injury

INTRODUCTION: Drug induced liver injury (DILI), can be caused by a variety of medications and/or herbal supplements. Carfilzomib, a chemotherapy agent used in the treatment of refractory multiple myeloma, has rarely been shown to cause DILI. We found only one other published case report of DILI by Carfilzomib leading to acute hepatic failure. We present a 70 year old male who we diagnosed with DILI from Carfilzomib use. CASE DESCRIPTION/METHODS: A 70 year old male with a history of multiple myeloma presented for further evaluation of a headache and scleral icterus for two weeks. He denied having any other symptoms. His oncologist started him on Carfilzomib 5 months ago given his refractory multiple myeloma. He did not report any alcohol use. Physical exam showed scleral icterus. Laboratory findings on admission: ALT 964 AST 848 Total Bilirubin 7.3 Direct Bilirubin 5.88 and ALP 855. PT was 12.7 and INR 1.11. Tylenol level was less than 2. Ethanol level was undetectable. Hepatitis panel was unremarkable. Serum IgG, IgM, AMA, ANA, ACE level, HSV/EBV/CMV PCRs were negative. MRCP did not show any lesions, obstruction, pancreatic and/or biliary duct dilation. Liver biopsy displayed interface hepatitis, lobular inflammation, portal eosinophils and neutrophils consistent with DILI. He was monitored off Carfilzomib, liver function tests improved and he was discharged home. He followed up in the hepatology clinic at 24 days and 78 days post discharge with essentially resolution of his jaundice and LFTs improved to normal levels (Table 1). DISCUSSION: DILI can be caused by many toxins, herbal supplements or drugs. DILI is typically classified into intrinsic/direct versus idiosyncratic. Intrinsic/direct DILI is dose dependent with symptoms presenting acutely, usually hours to days after initiation of the offending agent. Idiosyncratic DILI is not dose dependent and symptoms occur within days to weeks of drug exposure. We found only one other published case report of DILI by Carfilzomib leading to acute hepatic failure. To date, there has not been literature published on patients taking Carfilzomib with the severity of drug induced liver injury as seen in our patient. Our goal is to highlight the importance of DILI as a potential side effect of taking Carfilzomib in addition to reviewing reported acute liver failure from this drug as cited in prior literature. As in our patient, it is our hope to stress the importance of recognizing DILI early on and thus preventing acute liver failure from developing.Table 1.: LFT Trend During Hospital Admission and Post Discharge Follow Up

Long-term continuous treatment as a new strategy for relapsed or refractory multiple myeloma

The prognosis for patients with multiple myeloma has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens, and improved management of toxicities. Treatment of relapsed or refractory multiple myeloma represents a vital aspect of the overall care for patients with multiple myeloma and a critical area of ongoing biologic and clinical research. The choice of regimen at relapse is usually based on the prior response, toxicities, assessment of prognostic factors, age and comorbidities of individual patients, their somatic condition and expected effectiveness and tolerability. The new drugs, such as ixazomib, carfilzomib, pomalidomide, daratumumab and elotuzumab in combinations in doublet or triplet regimens, have greatly increased the treatment armory against myeloma. Long-term continuous therapies as a new strategy for relapsed or refractory multiple myeloma have been shown to provide an eradicating of minimal residual disease and deep prolong responses, with the goal of improving progression-free survival and overall survival. The integration of novel agents into the treatment paradigm has shifted the perception of multiple myeloma from an incurable fatal disease to a manageable chronic one. This review discusses the most recent and effective regimens for the relapsed or refractory multiple myeloma treatment, based on the results of recently published phase II and III clinical trials. Analyses the current clinical trial data discussed with a focus on lenalidomide or bortezomib as a basis of new treatment regimens.

Infusion of chimeric antigen receptor T cells against dual targets of CD19 and B-cell maturation antigen for the treatment of refractory multiple myeloma.

ObjectiveTo investigate the safety and efficacy of chimeric antigen receptor T (CAR-T) cell infusion in patients with refractory multiple myeloma (MM).MethodsSixteen patients diagnosed with refractory MM were included in this study. Patients received initial infusions of T-derived CD19/B-cell maturation antigen (BCMA) CAR-T cells with 100% CD19, followed by second infusions with 40% BCMA and third infusions with 60% BCMA. The total doses were 0.5–1 × 107/kg CD19 and 1.2 − 6.2 × 107/kg BCMA. Patients were monitored after infusion. Levels of interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor-α, and C-reactive protein were determined by enzyme-linked immunosorbent assay.ResultsCytokine release syndrome (CRS) was observed in all 16 patients. Thirteen patients with CRS stage II−IV had persistent hyperthermia from 5−14 days after infusion, while most patients developed hyperthermia from 1 day after infusion and their temperatures returned to normal within 2−10 days. Levels of all factors were significantly elevated 2 days after infusion, peaked at 5 days, and then gradually decreased to normal levels. All inflammatory factors showed normal levels by 10 days after infusion.ConclusionBody temperature and levels of inflammatory factors all increased dramatically after infusion of CD19/BCMA CAR-T cells, but recovered to normal levels after appropriate treatment and nursing.

Dissecting Heterogeneity of Tumor Cells and Their Microenvironment in Refractory Multiple Myeloma

Introduction: Despite significant improvements in therapy during the last decade, most multiple myeloma (MM) patients develop refractory disease over time. Treatment of refractory MM is a major challenge, likely due to the still poorly characterized inter- and intratumor heterogeneity at this stage of the disease, and the complex interplay of MM cells with the microenvironment (ME). In particular, there is an urgent need to unravel how these features of MM are linked to molecular mechanisms of drug resistance. Methods: We resolved the cellular composition, underlying transcriptional inter- and intra-patient heterogeneity and molecular treatment response of relapsed/refractory MM by single cell RNA sequencing (scRNA-seq). Using droplet-based microfluidics, ~230,000 single cell gene expression profiles from bone marrow (BM) aspirates of 21 patients sorted into CD138+and CD138- fractions were acquired, allowing for a comprehensive analysis of both MM cells as well as their ME. Patients had a median of 4 prior lines of therapy including both a proteasome inhibitor and an immunomodulator and were refractory to their immediate prior line of therapy at time of sampling. In addition, paired samples before either pomalidomide- or carfilzomib-based therapies were analyzed for 16/21 patients. Genomic aberrations in individual patients were mapped by interphase fluorescence in situ hybridization. Cells were clustered and CD138+ MM subtypes as well as immune cell-types of the ME were identified from their single cell transcriptomes and a copy number variation (CNV) analysis. As a reference for non-malignant cells and to construct a developmental B-cell trajectory the Human Cell Atlas BM scRNA-seq reference dataset was used. To characterize interactions of MM cells with their ME, the correlated expression of ligand-receptor pairs was exploited. Results: The analysis of inter- and intra-tumor heterogeneity of molecular MM subgroups revealed distinct transcriptome signatures with contributions that could be assigned to differences in heavy and light chain immunoglobulin expression as well as known genomic alterations, including t(11;14), t(4;14) and hyperdiploidy. MM cells from individual patients largely maintained a plasma cell specific gene expression profile but a partial loss of plasma cell identity was detected based on mapping to a developmental B-cell trajectory. It was characterized by the upregulation of subgroup transcriptome signatures associated with earlier stages of B-cell development in almost 50% of patients, such as a pre-B or mature B cell-like phenotype. Within individual samples, subclonal MM cell populations with specific gene expression programs were resolved based on the CNV analysis and included those characterized by expression of the immune-activator CD27 and the modulator of WNT signaling FRZB. The analysis of longitudinally collected samples revealed both changes in the cell subtype cluster structure as well as drug-specific adaptation of gene expression programs in distinct subpopulations persisting or emerging at relapse. These profile changes were characterized by e.g. downregulation of Myc target genes upon pomalidomide treatment or induction of heat shock proteins under carfilzomib. Within the ME of refractory MM patients, we observed that the fraction of B cells and CD4+ T cells was strongly reduced while CD14+ and CD16+ monocytes as well as dendritic cells expanded. Notably, the immune checkpoint protein PD-1H (aka VISTA) that inhibits T cell activation was highly expressed in cell types from the myeloid compartment in contrast to healthy donors. Further, a ligand-receptor analysis revealed that MM cells displayed the strongest interactions with monocytes, which were mediated by MIF, BAFF and other cytokines. Conclusions: Our study demonstrates the value of scRNA-seq analysis for identifying crucial transcriptome features that classify refractory MM subtypes and their evolution in response to treatment including regulation of drug resistance associated signaling pathways. Our data suggest that refractory MM cells shape the myeloid compartment in the BM to generate an immune suppressive ME. Understanding the evolution of MM cell heterogeneity and the bone marrow milieu in refractory disease will lead to novel treatment approaches and eventually improve patient outcome. Disclosures Müller-Tidow: MSD: Membership on an entity's Board of Directors or advisory committees. Goldschmidt:John-Hopkins University: Research Funding; Molecular Partners: Research Funding; Amgen: Consultancy, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; John-Hopkins University: Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Research Funding.

New proteasome inhibitors in the management of multiple myeloma

The landscape of multiple myeloma treatment transformed at the last 15 years by the introduction of novel agents (bortezomib, lenalidomide) and wide application of autologous hematopoietic stem cell transplantation, which have prolonged the survival of multiple myeloma patients. Despite the fact that multiple myeloma remains an incurable disease due to the new options, the median overall survival of patients with multiple myeloma in Russia in 2006–2016 was about 55–68 months. Drug resistance and clonal evolution remain a problem. The novel proteasome inhibitors (carfilzomib, ixazomib) differ in chemical structure and pharmacological characteristics. Thereby the next-generation proteasome inhibitor (IPs)-based regimens (KRd (carfilzomib, lenalidomide, dexamethasone), IRd (ixazomib, lenalidomide, dexamethasone), and Kd (carfilzomib, dexamethasone)) are emerging as new standards for the treatment of patients with relapsed and/or refractory multiple myeloma. In a randomized trial phase 3 ENDEAVOR, carfilzomib demonstrated improved survival in direct comparison to bortezomib. The dose-dependent activity of carfilzomib demonstrated in the study of A.R.R.O.W. Аctivity of ixazomib is comparable to that of bortezomib, the oral method of administration and the absence of neurological toxicity, allow for long-term control of the disease. The new PIs are an important advance in relapsed and/or refractory multiple myeloma treatment, increasing survival, response rate and quality of life, even in subgroups of patients with poor prognosis. This review summarizes the main pharmacological properties, mechanisms of action and clinical outcomes of major clinical studies with these agents. A separate issue discusses the problem of overcoming new proteasome inhibitors of drug resistance to bortezomib.

FDA approves new treatment for refractory multiple myeloma

FDA grants accelerated approval to Xpovio (selinexor) tablets in combination with the corticosteroid dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is resistant to several other form