NDMM Patients Research Articles

Location of the t(4;14) Translocation Breakpoint Identifies a Subset of Newly-Diagnosed Multiple Myeloma Patients with Poor Prognosis

Introduction: The recombination of chromosomes 4 and 14 (t(4;14)) is a primary, predominantly clonal event in newly diagnosed multiple myeloma (ndMM) that is present in ~15% of patients. The translocation results in enhancer regions from the immunoglobulin heavy chain locus upregulating the expression of NSD2 and FGFR3 genes implicated in the disease biology of this subset of MM patients (Chesi et al. Blood. 1998, Keats et al, Leuk Lymph. 2006). The presence of t(4;14) translocation is a considered a biomarker of aggressive disease and is part of the Revised International Staging System (R-ISS) for clinical risk stratification. However, historically only ~40% of t(4;14) patients are high-risk based on the GEP70 gene expression signature. (Weinhold et al. Leukemia. 2016) Our previous analysis of a large cohort of ndMM patients described the genomic features of t(4;14) vs ndMM overall population demonstrating that only ~25% of t(4;14) patients died within 24 months of diagnosis and described biomarkers in this high-risk subset. This analysis identified both known and novel aberrations in ndMM, including some that were associated with high-risk t(4;14) (Ortiz et al Blood. 2019; 134 (Suppl_1):366). In this updated analysis, we provide a more robust analysis of the t(4;14) dataset and demonstrate the prognostic value of the NSD2 breakpoint location.Methods: We generated a large genomic dataset from t(4;14) ndMM patients with whole genome sequencing (WGS) and RNA-seq from a TOUL dataset (t(4;14) N=114) patients treated in routine practice), the IFM2009 trial (N=19), and the Myeloma Genome Project (MGP) (N=34) for discovery and validation. Gene expression, copy number aberration, single nucleotide variant and translocations were derived from RNAseq and WGS profiling of biopsies from patients aged less than 75 years who received transplant, and integrated with clinical information (including age, OS). Cytogenetic assessments from WGS were made by MANTA and used to identify translocation DNA breakpoint location.Results: In all datasets, three DNA breakpoint locations were identified, and based on their position with respect to the NSD2 gene named “no-disruption” (upstream of NSD2 gene), “early-disruption” (in the 5' UTR of NSD2 gene) and “late-disruption” (in the coding region of NSD2 gene). Using paired RNA-seq data, we identified IGH-NSD2 RNA fusion transcripts relative to the breakpoints that corresponded with previously described NSD2 isoforms. “No-disruption” and “early-disruption” breakpoints predominantly produced a fusion transcript (MB4-1) that retained the full coding sequence of the gene, while the “late-disruption” produced truncated fusion transcripts (MB4-2/3). We conducted survival analysis in our datasets based on both DNA breakpoint location and RNA fusion transcripts. This analysis demonstrated a significant difference in outcome between the patient samples with “no-disruption” and the “late-disruption” breakpoints that associated with good and poor OS, respectively (OS pval < 3e-4) in the discovery TOUL dataset. Patients with “late-disruption” had a median OS of 28.64 mo vs 59.18 mo for “early disruption” and 82.26 mo for those with “no disruption” (Figure). This association was replicated in an independent dataset (MGP N=33, replication pval<4.3e-5). The mOS difference of patients based on which fusion transcript they express is less than the difference based on breakpoint (mOS MB4-1 = 47.38 mo. vs. MB4-2/3 = 60.89 mo.). These analyses demonstrate that the breakpoint location has a stronger association with outcome than fusion transcript expression.Conclusion: From a large genomic dataset, we were able to discover and validate a clear association between the translocation breakpoints and survival outcome in t(4:14) ndMM patients. While prospective validation is needed before clinical application of our finding, molecular identification of high-risk t(4;14) patients using DNA breakpoint location may enable proper risk classification for this patient group at diagnosis, and would provide improved opportunities for risk-adjusted therapy and identification of a therapeutic target for this high-risk subpopulation. Ongoing work on mutations, copy number, and differential gene expression analyses between translocation breakpoint sub-groups and will be presented. [Display omitted] DisclosuresStong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ortiz: Bristol Myers Squibb: Current Employment. Towfic: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pierceall: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Flynt: Bristol Myers Squibb: Current Employment. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

Daratumumab Plus Ixazomib, Lenalidomide, and Dexamethasone As Extended Induction and Consolidation Followed By Lenalidomide Maintenance in Standard-Risk Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (IFM 2018-01): A Phase II Study of the Intergroupe Francophone Du Myélome (IFM)

Daratumumab Plus Ixazomib, Lenalidomide, and Dexamethasone As Extended Induction and Consolidation Followed By Lenalidomide Maintenance in Standard-Risk Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (IFM 2018-01): A Phase II Study of the Intergroupe Francophone Du Myélome (IFM)

Deep Immune Profiling in Multiple Myeloma at Diagnosis and Under Lenalidomide Maintenance Therapy

IntroductionHere we report the results of one of the secondary endpoints of the Finnish Myeloma Group-MM02 study; composition of bone marrow (BM) immune cell subsets at treatment start and during lenalidomide (Len) maintenance focusing on 2 different response groups: good responders (GRs) and poor responders (PRs) at pre- and post-treatment stages. We evaluated the BM immune profile with CyTOF (cytometry by time-of-flight). Our hypothesis was that there would be distinct differences in immune cell profiles between patients with good and poor response, especially in the T and NK cell subsets.Patients and methodsTwenty-two patients were included in this CyTOF study. Eighteen were NDMM patients from FMG-MM02 study who received 3 RVD cycles followed by ASCT. Len started 3 months after ASCT 10 mg/day in 21/28-day cycles until progression or toxicity. BM samples were collected to the Finnish Hematology Registry Clinical Biobank (FHRB Biobank) at several timepoints; from 18 patients at diagnosis, from 11 patients 1 st sample at good response during Len and 2 nd sample if this good response was maintained and from 5 patients at relapse during Len. The patients in the good response cohort (n=11) had progression-free survival (PFS) > 5 years. For comparison, we included 4 BM samples from the FHRB Biobank, taken at a good response after ASCT from MM patients without exposure to Len.ResultsWith a median follow-up of 81 months (13-97) the median PFS was not reached in the good response (GR) cohort and was 18 months in the poor response (PR) cohort. The 1 st GR samples were collected after a median of 21 (6-46) months of Len. The 2 nd samples in GR cohort were collected after a median of 56 (45-67) months of Len. The PR samples were taken after a median of 6 (2-23) months of Len.CyTOF analysis revealed distinct good and poor responder's immune signatures at baseline level. GR, baseline group has shifted phenotype of T cells toward the CD8 T cells, expressing markers, attributed to the cytotoxicity (CD45RA, CD57), as well as having slightly higher abundance of CD8 TE and lower abundance of CD8 naïve T cells. Total T cells amounts were significantly higher in GR. Increased expression of CD56, CD57, and CD16 were also seen on NK cells in GR at the baseline, indicating both maturation and cytotoxic potential of NKs. In contrast, a significant decrease of CD56 and CD16 expression suggesting reduced cytotoxic potential and increase of CD57 were seen on NKs in PR, baseline indicating senescence status a phenotype associated with exhaustion.By using viSNE we discovered two novel populations - MAC1, and MAC2, - associated with disease pathogenesis. We further investigated the composition of these populations, and it appears that MAC1 expressed CD38+CD56+CD45-CD19- presumably malignant plasma cells and MAC2 expressed CD45- CD14+CD38+CD56+TCRgd+CCR7+CCR6+CXCR4+ CXCR3+CXCR5+CD294+, which might be the novel populations, having the features of myeloid suppressor cells. These two immune cells were higher in PR (9.2% and 8.2%, respectively) at baseline as compared to the GR (2.3% and 1.7%).NKs, T cells, and B cells showed a high expression of monocytic marker CD14 and chemokine receptors (CCR7, CCR6, CXCR4, CXCR3, and CXCR5) in PR both at baseline and relapse. This might be attributed to either biological features of MM environment, or the high level of interaction between these populations and monocytes, which left traces of their membranes on the non-monocytic populations.ConclusionsPatients, responded to the treatment, have higher abundances of effector/cytotoxic cells, expressing higher levels of CD57 and/or CD45RA for T cells, and CD57, CD16, and CD56 for NK cells indicating proper differentiation and maturation of T, and NK cells to effector and cytotoxic subsets. Additionally, those patients have less degree of tumor burden as well as decreased expression of chemokine receptors. During the therapy administration, good responders show the increase in effector memory CD4 and CD8 subsets of T cells abundance, indicating even the higher cytotoxic effect of immune system. DisclosuresSilvennoinen: Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Luoma: Amgen: Honoraria; Janssen: Honoraria; Incyte: Honoraria. Anttila: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Säily: Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Partanen: Takeda: Honoraria; Abbvie: Honoraria; Behring: Honoraria. Heckman: Novartis: Research Funding; Orion Pharma: Research Funding; Celgene/BMS: Research Funding; Oncopeptides: Consultancy, Research Funding; Kronos Bio, Inc.: Research Funding.

Circulating Tumor Cells (CTCs) in Smoldering and Active Multiple Myeloma (MM): Mechanism of Egression, Clinical Significance and Therapeutic Endpoints

Circulating Tumor Cells (CTCs) in Smoldering and Active Multiple Myeloma (MM): Mechanism of Egression, Clinical Significance and Therapeutic Endpoints

Impact of Achieving an Early Complete Response in Multiple Myeloma and Predictors of Subsequent Outcome

Impact of Achieving an Early Complete Response in Multiple Myeloma and Predictors of Subsequent Outcome

Identification of Previously Unrecognized Multiple Myeloma Risk Subgroups with a Novel Biological Disease Stratifier

Background: The prognosis of MM is determined by affected organs, tumor burden as measured by e.g., the international staging system (ISS), disease biology such as cytogenetic abnormalities, and response to therapy. The outcome of high-risk MM patients classified by ISS or adverse risk cytogenetics is not uniform and patients show heterogeneous survival. Recent insights into the pathogenesis of MM highlighted genome/transcriptome editing as well as inflammation as drivers for the onset and progression of MM. We hypothesized that inclusion of molecular features into risk stratification could potentially resolve the challenge of accurately distinguishing between high-risk and low-risk MM patients at initial diagnosis and improve outcome.Aim: We aimed to create a simple molecular risk score to identify unrecognized patient subgroups, who have been previously misclassified by current risk stratifiers.Method: The Multiple Myeloma Research Foundation CoMMpass study genomics dataset, combining mRNA Seq and clinical data from more than 700 MM patients, allowed us to evaluate the prognostic value of demographic and clinical parameters, cytogenetics, and gene expression levels of APOBEC genes as well as inflammation-modulating cytokines in MM patients. We calculated hazard ratios and Kaplan-Meier survival estimates for all extracted features. Combining clinical variables that were significantly associated with PFS and OS, we then applied machine learning approaches to identify the most accurate classification model to define a new risk score that is easy to compute and able to stratify NDMM patients more accurately than cytogenetics-based classifiers. Based on a Kaplan-Meier survival curve analysis, we then evaluated the performance of our newly built EI score in sub-classifying of current multiple myeloma risk stratifiers.Results: Based on machine learning models, we defined a weighted OS/PFS risk score (Editor-Inflammation (EI) score) based on mRNA expression of APOBEC2, APOBEC3B, IL11, TGFB1, TGFB3, as well as ß2-microglobulin and LDH serum levels. We showed that the EI score subclassified patients into high-risk, intermediate-risk, and low-risk prognostic groups and demonstrated superior performance (C-index: 0.76) compared to ISS (C-index: 0.66) and R-ISS (C-index: 0.64). We further showed that EI low-risk patients do not benefit from autograft and maintenance therapy. Re-classification of ISS (Figure 1a, b, c) and R-ISS risk groups further confirmed the superiority of the EI score. In addition, the EI score identified previously unrecognized distinct subgroups of MM patients with adverse risk cytogenetics but good prognosis (Figure 1d, e, f). For example, the EI score excellently subclassified del(17p) MM patients into three main risk subgroups including a super low-risk group (none of them has p53 mut) with 5-year OS of 100%, an intermediate-risk group (30% of these patients also have p53 mut) with 5-year OS rate of 75%, and a very poor prognosis group of patients (40% of these patients also have p53 mut) with 5-year OS rate of 0% (2y OS: 40%) (Figure 1f). In line, we could show that patients with del(17p) and high EI score exhibit an enrichment of APOBEC induced genomic mutations compared to intermediate-risk and low-risk patients supporting the hypothesis that del(17p) along with high APOBEC expression levels activate the APOBEC mutation program and thus create an optimal environment for tumor progression. These findings support the necessity of a prognostic score that more accurately reflects MM disease biology.Conclusion: Although MM is considered as an incurable disease, an improved risk stratification could help to identify previously unrecognized low- and high-risk patient subgroups that are over- or undertreated and lead to improved outcomes. Our EI score is a simple score that is based on recent insights into MM biology and accurately identifies high-risk and low-risk newly diagnosed MM patients as well as misclassified MM patients in different cytogenetic and ISS risk subgroups. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Alternative Splicing Landscape in Multiple Myeloma Is Determined By IGH Translocations and Mutations of RNA Processing Genes

Introduction: Alternative Splicing (AS) plays a key role in regulating numerous cellular processes in both normal and malignant cells. Previous studies have revealed mutations in the spliceosome complex, such as SF3B1, can cause increased AS frequencies in multiple myeloma (MM) patients, and patients with increased levels of AS are associated with a poor prognosis. Other frequently mutated genes involved in RNA processing include DIS3 and FAM46C, thus, systematically investigating other causes of AS abnormalities and pathologies in MM patients is highly necessary.Materials and Methods: RNA-seq data from 598 newly diagnosed MM patients from the MMRF CoMMpass study were utilized to generate AS comparisons. They were previously annotated for cytogenetic, copy number, and mutation data (version IA16). RNA-seq data were aligned to HG38 using STAR and Salmon. SUPPA2 was used for calling AS differences. For each identified AS event, the splicing level was defined by Percentage of Spliced-In (PSI) while the mean difference of splicing levels between two groups was measured by ΔPSI (dPSI) and by the P-value from independent T-tests against PSIs in the two groups. Filtering thresholds were determined to find high-quality differentially spliced events and were filtered for those also present in normal PCs (GSE110486). Geneset enrichment analysis was performed to identify dysregulated pathways caused by differential splicing and differential expression. Survival analysis was performed on clinical annotations of 598 NDMM patients while the Logrank test and Cox regression were used to evaluate the risk of AS and other genomic factors. Kaplan-Meier curves were plotted for various subgroups.Results: We compared 16 major cytogenetic subgroups, including Ig translocations (t(4;14), t(14;16), t(11;14)), hyperdiploidy, mutations in KRAS, NRAS, BRAF, FAM46C, SF3B1, DIS3 and TP53, combined events (t(4;14) plus DIS3 mutation), as well as those with biallelic abnormalities (DIS3, FAM46C, and TP53). Samples with SF3B1 hotspot mutations identified the greatest number of AS events (n=862), and samples with any SF3B1 mutation had approximately half as many. IGH translocations had an equivalent number of AS events to those with SF3B1 mutations, with t(14;16) having the most (n=587) followed by t(11;14) (n=366), and t(4;14) (n=256). We observed an increased number of significant AS events in bi-allelic DIS3 and FAM46C groups (n=404 and 171) compared to their mono-allelic abnormalities (n=114 and 35). As DIS3 mutations are enriched in the t(4;14) subgroup we also examined that interaction and found significantly more AS events (n=481; p<0.01) in the combination compared to either event alone. As expected, KRAS, NRAS and BRAF mutations did not have enrichment for AS events (n=2, 15, 23, respectively).The majority of AS events were unique to each subgroup, exemplifying the AS heterogeneity in these subgroups. Among overlapped events, an alternative first (AF) exon in ACACA was consistently more spliced in t(14;16), t(11;14) and t(4;14) groups (dPSI=0.18, 0.10, 0.12, P=2x10 -5, 2x10 -9, 5x10 -5). ACACA encodes an enzyme that significantly affects MM cell growth and viability, suggesting that similar regulations exist in the three translocation groups. Unique events were also detected including an AF event in MIB2 (E3 Ubiquitin Protein Ligase 2) in the t(11;14) group (dPSI=0.17, P=7x10 -14), and a skipped exon in UBXN4 (related to ER stress) in t(14;16) group (dPSI=0.1, P=3x10 -4). AS heterogeneity also leads to functional heterogeneity in the three groups. Besides commonly downregulated RNA catabolic processes, cell adhesion, migration and mobility related pathways are enriched pathways in t(14;16); cell growth related pathways in t(11;14); and ERK related pathways in t(4;14). High-risk events were identified through survival analysis and included a retained intron in RPS16 in the t(14;16) (Hazard Ratio (HR)=18.81, p=0.004). Similarly, high risk was associated with an AF event in DDX39B in t(11;14) (HR=2.62, p=0.001) and an AF event in COPA in t(4;14) (HR=6.29, p=0.001).Conclusion: AS is defined by multiple genomic events, including primary translocations and mutations in RNA processing genes, DIS3 and FAM46C, and interactions between genomic markers can increase AS. AS events contribute to outcome and some high risk AS events may serve as prognostic marker or potentially novel targets. DisclosuresWalker: Sanofi: Speakers Bureau; Bristol Myers Squibb: Research Funding.

Multiomic Mapping of Copy Number and Structural Variation on Chromosome 1 (Chr1) Highlights Multiple Recurrent Disease Drivers

Multiomic Mapping of Copy Number and Structural Variation on Chromosome 1 (Chr1) Highlights Multiple Recurrent Disease Drivers

Outcomes of Single Versus Tandem Hematopoietic Stem Cell Autologous Transplant in High-Risk Myeloma Patients: A Single-Center Experience

Introduction: Over the past decade, significant advances in the treatment strategy of newly diagnosed multiple myeloma patients (NDMM) have challenged the initial management strategy in transplant-eligible (TE) patients. The value of a single autologous stem cell transplant (ASCT) is established in standard-risk myeloma; however, the role for tandem ASCT reveals conflicting results, especially in patients with high-risk cytogenetic (HR) features. HR changes include at least one of the cytogenetic lesions: t(4;14), t(14;16), t(14;20), del17p, 1q amp +, 1q amp + del 1p. Subgroup analyses of HR patients in the EMN02 study suggest benefits with tandem ASCT.Methods: We retrospectively reviewed our single centre ASCT experience in TE NDMM patients with HR from London, Canada, from January 1, 2007, to April 30, 2021 with the primary objective to compare single versus tandem ASCT for patients with high-risk MM. Secondary objectives include progression-free survival (PFS), overall survival (OS) and the effect of maintenance therapy on survival. OS and PFS were estimated using the Kaplan-Meier method. We also applied univariate and multivariate cox regression to assess the effects of age, hemoglobin, and creatinine on survival.Results: 155 NDMM received at least one ASCT between January 1, 2007 to April 30, 2021. 61/155 (39.3%) patients had HR disease. T(4:14) was seen in 19/61 (31.1%) patients; t(14:16) in 9/61 (9.8%) patients; del 17p in 20/61 (32.7%) patients, 1q amp in 36/61 (59.0%) patients and 1p del + 1q amp in 8/61 (13.1%). Patients with more than one abnormality was seen in 22/61 (36.0%) patients. In this high-risk group, the most common induction regimen consisted of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in 58/61 patients (95.0%). 34 (55.7%) patients received single ASCT and 27 (44.2%) patients received tandem ASCT. 18/34 (52.9%) single ASCT patients and 15/27 (55.5%) tandem ASCT patients received maintenance therapy. Maintenance therapy included single-agent lenalidomide (imid) in 14/61 (22.9%); single-agent bortezomib or ixazomib (proteasome inhibitor (PI)) in 8/61 (13.1%), and; imid + PI combination in 11/61(18.0%). Baseline characteristics are summarized in Table 1.Single versus tandem ASCT in HR patients revealed no statistically significant PFS difference at 60 months (p=0.3). Maintenance therapy demonstrated a substantial improvement in PFS regardless of the number of ASCT (single ASCT HR=0.1687, 95% CI range 0.05-0.52, p<0.001) tandem ASCT (HR=0.1319, 95% CI range 0.01-0.96, p=0.019). PFS was similar in patients who did not receive maintenance in tandem ASCT (20 months) or single ASCT (19 months) (p=0.57).At the 60-month follow-up, the median PFS for high-risk patients without maintenance was 18.8 months. In contrast, the PFS for patients on maintenance was not reached (HR=0.1446, 95% CI range 0.05-0.38, p<0.001). There was no difference in OS (p=0.38) with or without maintenance therapy. When comparing single-agent vs. combination strategy with maintenance, there was no PFS (p=0.47) or OS (p=0.68) difference between strategies. All patients were progression-free in those who received any maintenance at 60 months.Conclusion: In our single centre experience, single vs. tandem ASCT in TE NDMM with HR disease did not contribute to long-term survival outcomes, but the presence of any maintenance therapy had a more considerable impact on PFS. Our data does show a longer progression-free survival compared to previous published data, which is likely due to our sample size. [Display omitted] DisclosuresLam: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Phua: Amgen: Honoraria; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Louzada: Amgen: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

Lenalidomide Dosing and Outcomes in Transplant-Ineligible Patients with Newly-Diagnosed Multiple Myeloma: A Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

Lenalidomide Dosing and Outcomes in Transplant-Ineligible Patients with Newly-Diagnosed Multiple Myeloma: A Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

Progression Free Survival (PFS) Analysis of Daratumumab (Dara), Cyclophosphamide, Thalidomide and Dexamethasone: A Quadruplet Intensified Treatment for Transplant Eligible Newly Diagnosed Multiple Myeloma (TE NDMM) Patients

Background: Newly drugs access for MM treatment still a challenge in some countries. One of the most available inductions for TE NDMM patients (pts) worldwide is cyclophosphamide (C), thalidomide (T) and dexamethasone (d)-(CTd). Dara the first anti- CD38, had been combined with VCd, VTd and VRd and markedly increased the depth and duration of the response. We hypothesized that Dara and CTd combination could be safe and allow deeper activity as an alternative protocol.Aims: The aims of this analysis were to evaluate Progression Free Survival (PFS) of Dara-CTd treatment and minimal residual disease (MRD) after one year of Dara maintenance. Primary endpoint of the study was to evaluate the VGPR after two consolidation cycles post-autologous stem cell transplantation (ASCT).Methods: This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, creatinine clearance > 30 ml/min, normal cardiac, renal and liver function and the Easter Cooperative Oncology Group (ECOG) performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg oral (PO) on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 - 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16mg/Kg and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara at 16mg/Kg was used monthly as maintenance until progression or limiting toxicity. G-CSF was used for stem cell (SC) mobilization and plerixafor had been allowed whenever the pts need. The MRD was evaluated by next-generation flow (NGF) based and PET-CT was performed when the patient obtained NGF negativity or finished consolidation. PFS outcome was estimated using Kaplan-Meier method. All pts received antiviral, anti-pneumocystis and anti-thrombotic prophylaxis. Data cut-off was June 15, 2021.Results: The first pts was enrolled in November 2018. A total of 24 pts were included, the median age being 60 (range 37- 67 years), 23 (92%) were non-white, 5 (21%) had an R-ISS = 1, 12 (54%) had an R-ISS = 2 and 4 (16%), an R-ISS = 3. Six (25%) pts had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. To date, all pts have completed induction, 20 have received transplant and 17 have completed D+90 post-transplant assessment. No SC mobilization failure was observed, and six (30%) pts needed plerixafor use. By ITT analysis after a median follow up of 20 months the PFS at 12 and 18 months was 86%. No PFS difference was observed between different subgroups.Regarding response rates, after the end of induction (cycle 4), 19 (90%) of the pts obtained > PR and 8 (38%) obtained >VGPR, including three MRD negativity by NGF. 17 pts have completed two consolidation cycles after transplant and 94% obtained > VGPR as best response, 13 (76%) obtained MRD negativity by NGF and 10 (58%) had negative PET-CT. Seven (41%) pts had both flow and PET-CT negativity. Six pts completed one year of maintenance and five of them (83%) still MRD negativity by NGF. Four pts died from infection, two of them related with covid infection (one before transplant and one during maintenance). Another case post-transplant, considered not related to the investigational agent and one after consolidation, related to the investigational agent. Two pts have discontinued treatment due to progression - 1 before ASCT e 1 during maintenance.The most common adverse events (AEs) grades 3 and 4 were neutropenia (n = 12), infusion reaction (n = 7), neuropathy (n = 6), lymphopenia (n = 4), infection (n = 3), hypertension (n = 1) and rash (n = 1).Summary/Conclusion: The Daratumumab - CTd protocol is an active regimen capable of producing deep and sustainable responses and improve the PFS of NDMM TE pts with a favorable safety profile. Clinical trial information: NCT03792620. DisclosuresDe Queiroz Crusoe: Janssen: Research Funding. Hungria: Sanofi: Honoraria, Other: Support for attending meetings/travel ; Takeda: Honoraria; Abbvie: Honoraria; Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel .

Is Symptom Burden Associated with Health Care Utilization: A Longitudinal Population-Based Cohort Study of Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma

IntroductionTransplant ineligible patients with newly-diagnosed multiple myeloma (TI NDMM) have high rates of health care utilization [emergency department visits and/or unplanned hospitalization (ED/hosp)] due to a combination of co-morbidities/frailty, disease manifestations and toxicities of anti-MM treatment. Understanding and optimizing unplanned health care utilization represents an important step in delivering person-centred care in MM.Patient reported outcomes (PROs) may represent one opportunity for predicting health care utilization. Databases within Ontario, Canada represent a unique opportunity to evaluate this association due to the implementation of a standardized population-wide PRO tool (the Edmonton Symptoms Assessment System [ESAS]). ESAS scores have been completed by patients during all outpatient cancer clinic visits since 2007. The ESAS is a validated and reliable tool that assesses the severity of nine common symptoms: well-being, pain, tiredness, anxiety, depression, drowsiness, lack of appetite, nausea and shortness of breath. Patients score these on a rating scale from 0 (no symptom) to 10 (worse possible symptom).The objective of our study was to evaluate the association between PROs (ESAS score) and the subsequent 14-day risk of ED/hosp among TI NDMM patients in the first year following diagnosis.MethodsWe conducted a retrospective population-based study using administrative data from ICES (previously known as the Institute of Clinical Evaluative Sciences), which maintains databases of health records for all patients in the publicly funded health care system in Ontario, Canada. All patients with NDMM identified using the ICD-O-3 code 9732 (MM), who received treatment without transplant in the first year between Jan 2007-Dec 2018 were included. Patients with no documented ESAS score within one year following diagnosis were excluded. The main outcome of interest was the occurrence of at least one ED/hosp within 14 days of an ESAS assessment in the first year following diagnosis. The main exposure variable was ESAS score (individual score for each of the nine symptoms and total score of all the nine symptoms [t-ESAS]) at each index date. A logistic regression model was used to assess the association of ESAS score and subsequent 14-day ED/hosp. A generalized estimating equations approach was used to account for patient level clustering, arising from multiple ESAS assessments taken on the same patient (over the first year after diagnosis).ResultsThere were 2876 TI NDMM patients identified completing a total of 17,353 ESAS assessments. Baseline characteristics of the cohort are shown in Table 1. Tiredness, poor well-being and pain were the three most common severe symptoms present in 19.6%, 12.4% and 12.2% of the assessments, respectively. With regards to health care utilization, there were a total of 1755 ED/hosp visits in 1172/2876 (40.8%) TI NDMM patients within one year following diagnosis in our cohort.The proportion of patients with ED/hosp within 14 days of the ESAS assessment are outlined in Figure 1. There was an incremental increase in ED/hosp with increasing ESAS scores (higher score indicative of worse symptoms) for each individual symptom. A similar trend was noted for those with increasing t-ESAS scores with a 14-day ED/hosp event rate of 31.3% for those with a maximum score of 90 compared with 5.5% for those with a score of 0.Univariable and multivariate odds for ED/hosp are presented in Table 2. All nine symptom scores and t-ESAS were associated with an increased risk of ED/hosp visits. After controlling for confounders, individual symptoms (pain, tiredness, lack of appetite, shortness of breath and impaired well-being) and t-ESAS remained positively associated with ED/hosp. Conversely, self-reported depression was associated with decreased risk of ED/hosp (odds ratio 0.96 per unit increase, 95% Cl 0.93-0.99, p=0.01).ConclusionOur findings represent the largest study to date demonstrating that a PRO measure of symptom burden is associated with health care utilization in TI NDMM. Even after controlling for baseline factors, ED/hosp remained positively associated with higher ESAS symptom scores. The results of this study may help clinicians identify patients at high risk for ED/hosp. Further studies are required to understand whether targeted intervention aimed at reducing this symptom burden may help decrease ED/hosp usage. [Display omitted] DisclosuresMian: BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Pond: Takeda: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca, Merck, Profound Medical: Consultancy; Roche Canada: Current holder of individual stocks in a privately-held company. D'Souza: Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Janssen, Prothena: Consultancy; Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees. Wildes: Carevive: Consultancy; Seattle Genetics: Consultancy; Sanofi: Consultancy; Janssen: Consultancy.

Results of an International, Multi-Centre, Retrospective Study to Describe Treatment Pathways, Outcomes and Resource Use in Patients with Multiple Myeloma in Emerging Markets (INTEGRATE)

Results of an International, Multi-Centre, Retrospective Study to Describe Treatment Pathways, Outcomes and Resource Use in Patients with Multiple Myeloma in Emerging Markets (INTEGRATE)

Randomized Trial Comparing Pomalidomide, Bortezomib, and Dexamethasone (PVd) Versus Bortezomib and Dexamethasone（Vd） in NDMM with Renal Impairment（RI）

Background:RI is one of the most common complications of multiple myeloma (MM). The incidence of RI at diagnosis ranges from 20% to 50%, Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI, and the addition of a third drug to Vd seems to be beneficial，but not for sure. Pomalidomide is extensively metabolized by liver, with only approximately 2% of active substance eliminated in the urine, which suggests that RI may not affect pomalidomide exposure in a clinically relevant manner. The MM013(phase 2, NCT02045017) trial confirmed that Pomalidomide could be safely used in RRMM with RI and achieved good response in MM and Renal function. The OPTIMISMM (phase 3, NCT01734928) trial Subgroup analysis reported efficacy and safety of PVd vs Vd at first relapse by renal function (creatinine clearance [CrCl] < 60 vs ≥ 60 mL/min) before. The ORR significantly improved with PVd vs Vd regardless of renal status (P < .001 for both renal groups): 91.4% vs 53.6% (≥ VGPR,54.3% vs 21.4%) in the CrCl < 60 mL/min group and 89.5% vs 55.2% (≥ VGPR, 64.5% vs 23.0%) in the CrCl ≥ 60 mL/min group. Since RVd is the standard treatment for NDMM patients, We believe that standard dose Pomalidomide plus Vd will be very promising for NDMM patients with RIStudy Design/ Methods:This is a multicenter, prospective, randomized phase 2 study designed to evaluate the efficacy and safety of PVd Versus Vd in Patients With NDMM and Renal Impairment（RI）.Eligible patients were aged ≥18 years and had a diagnosis of multiple myeloma, measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were required to have had no prior antimyeloma regimen. The definition of RI is based on reduced creatinine clearance (15 mL/min≤CrCl＜60 mL/min) without indication for hemodialysis, which have to be the result of myeloma. Key exclusion criteria included previous course of chemotherapy; uncontrolled malignant disorder, infection, or peripheral neuropathy, patients on dialysis will be excluded too.Approximately 79 patients will be randomized 2:1(Figure 1) to Arm A (PVd) or Arm B (Vd), both Arms will have induction therapy for 4 cycles. In Arm A, patients will receive pomalidomide 4 mg on days 1-14 of each cycle. Bortezomib 1.3 mg/m 2 on days 1, 4, 8, and 11 of each cycle. Dexamethasone 20mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle (21-day cycles); In Arm B, patients will receive the same bortezomib and dexamethasone as Arm A.The primary endpoint is ≥VGPR, the secondary endpoints are MRD(-) rate,renal response,Immune function,Renal tubular function, and safety. Myeloma response and renal response will be assessed by the International Myeloma Working Group criteria after each cycle. Eficacy analyses will be performed on the intent-to-treat population; Safety analysis will be conducted in the safety population, which are composed of all patients who received ≥1 dose of study medication. The trial is currently enrolling and will be open in 8 sites in China.Disclosure：Research Sponsor : CHIATAI TIANQING PHARMACEUTICAL GROUP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Pomalidomide which was approved in RRMM will be used in NDMM with RI

OAB-029: Bone marrow adipocytes induce metabolic reprogramming of multiple myeloma cells

<h3>Background</h3> Obesity-induced increases in bone marrow adipocyte (BMAd) numbers and volume are associated with an increased risk of MM. However, the associated molecular mechanisms have remained largely unknown. We hypothesize that BMAd support MM cells through metabolic reprogramming. <h3>Methods</h3> BM aspirates of MGUS, SMM, and NDMM patients were used to obtain mature BMAd or stromal cells (BMSCs). Murine BMSC cell-line OP9, MM cell-line 5TGM1, and human-origin MM cell-lines MM.1S, OPM2 were obtained from ATCC. Cell proliferation was assessed by CyQUANT Assay; lipolysis by Lipolysis Assay (Sigma); lipid uptake by flow cytometry (FCM) of fluorescent fatty acids (FA) BODIPY-C12 and -C16, or LipidTox. In-vivo efficacy of FA treatment was assessed in a MM CB17 SCID mouse plasmacytoma model. <h3>Results</h3> In-vitro co-culture revealed that BMSC-derived adipocytes (Ad) from MGUS/SMM and NDMM donors significantly increased the proliferation of MM.1S MM cells. Similarly, mature murine OP9 Ad cells also increased the proliferation of 5TGM1 murine MM cells. Interestingly, co-cultures showed dramatic decrease in LipidTox-stained lipid-droplet size distribution, suggesting increased lipolysis in Ad, further confirmed by increased glycerol content in conditioned media in the presence of MM cells. Moreover, BMAd from MGUS, SMM, and NDMM patients showed increased expression of genes responsible for lipolysis (NR1H3) and increased FA desaturation (SCD1, FASD2). Although MM cells lacked intracellular lipid storage, OPM2 and 5TGM1 MM cells rapidly took up BODIPY-C12 and -C16 FAs. The FA secreted from Ad were directly taken up by MM cells as shown by transfer of LipidTox-labeled lipids from OP9 Ad to unstained 5TGM1 or OPM2 MM cells as assessed by FCM. The addition of acipomox, a small-molecule inhibitor of lipolysis, decreased LipidTox signal in MM cells compared to untreated OP9 cells. FA are transported into cells through FATP (1-6) or CD36 receptors. Bioinformatics analysis of public Oncomine database showed that FATP1 and FATP4 were highly expressed in 21 human MM cell lines. MM cells from NDMM patients expressed high levels of FATP1 and FATP4. The uptake of BODIPY-C12 and -C16 by 5TGM1 or OPM2 MM cells was significantly reduced in the presence of Lipofermata, a pharmacological small-molecule inhibitor of FATP. Lipidomic analysis of BM aspirates from MM patients showed altered expression of various FA, including arachidonic acid (AA). Low doses of AA (0.125 - 2 µM) increased the proliferation and viability of MM cells whereas high doses (25- 100µM) dramatically decreased it, indicating a bimodal cellular effect of AA. Peritumoral AA treatment in a plasmacytoma model decreased tumor volume significantly. <h3>Conclusion</h3> We show that MM cells induce lipolysis in BMAd and that the released FFA are then taken up by MM cells through FATPs. Inhibition of either BMAd lipolysis or FFA transporter into MM cells could be a potential novel strategy to prevent MM progression.

DARATUMUMAB (DARA), CYCLOPHOSPHAMIDE, THALIDOMIDE AND DEXAMETHASONE: A QUADRUPLET INTENSIFIED TREATMENT FOR TRANSPLANT ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA (TE NDMM) PATIENTS

Newly drugs access for MM treatment still a challenge in some countries. One of the most availableinductions for TE NDMM patients (pts) worldwide is cyclophosphamide (C), thalidomide (T) and dexamethasone (d)-(CTd). Dara the first anti- CD38, had been combined with VCd, VTd and VRd and markedly increased the depth andduration of the response. We hypothesized that the combination of Dara and CTd could be safe and allow deeper activityas an alternative protocol. The primary endpoint was to evaluate the VGPR after two consolidation cycles post-autologousstem cell transplantation (ASCT). Secondary endpoints were the overall response rate during alltreatment phases and minimal residual disease (MRD), based on the International Myeloma WorkingGroup (IMWG) criteria that includes the next-generation flow (NGF) by the EuroFlow®and PET-CTand the safety profile. This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TENDMM, creatinine clearance > 30 mL/min, normal cardiac, renal and liver function and the EasterCooperative Oncology Group (ECOG) performance status = 0 - 2. The protocol was Dara-CTd for upto four 28-day induction cycles: C-500 mg oral (PO) on days 1,8 and 15, T at 100-200 mg PO on days1 to 28, (d) at 40 mg PO on days 1,8,15 and 22 and Dara at 16 mg/kg/dose intravenous (IV) on days1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 – 4, followed by ASCT. All ptsreceived up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16 mg/kg and (d) at 40 mg every other week, associated with T at 100 mg PO on days 1 - 28. Dara at 16 mg/kg was used monthly as maintenance until progression or limiting toxicity. G-CSF was used forstem cell (SC) mobilization and plerixafor had been allowed whenever the pts need. All pts receivedantiviral, anti-pneumocystis and anti-thrombotic prophylaxis. The first pts was enrolled in November 2018. A total of 21 pts were included, the median age being 56 (range 37– 67 years), 19 (90%) were non-white, 3 (14%) had an R-ISS = 1, 12 (57%) had an R-ISS = 2 and 3 (14%), an R-ISS = 3. Five (24%) pts had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. To date, all pts have completedinduction, 19 have received transplant and 17 have completed D+90 post-transplant assessment. No SC mobilizationfailure was observed, and five (26%) pts needed plerixafor use. In an intention to treatment analysis, after the end ofinduction (cycle 4), 19 (90%) of the pts obtained > PR and 8 (38%) obtained >VGPR, including three MRD negativity byNGF. 17 pts have completed two consolidation cycles after transplant and 94% obtained > VGPR as best response, 12(70%) obtained MRD negativity by NGF and nine (53%) had negative PET-CT. Seven (41%) pts had both flow and PETCTnegativity. Three pts died from infection, one before transplant because of Covid infection, on post-transplant, considered not related to the investigational agent, and another after consolidation, related to the investigational agent. The most common nonhematological adverse events (AEs) grades 3 and 4 before ASCT were neuropathy (n = 6), infusion reaction (n = 7), infection (n = 2), hypertension (n = 1) and rash (n = 1). This is the first study that combined Dara with CTd as induction for TE NDMM pts. This presentdata has shown that the association of Dara-CTd achieved the primary end point once > 90% of the pts achieved VGPRafter two consolidations cycles, and safety profile was acceptable. NCT03792620.

P-176: Effect of induction regimen in survival in newly diagnosed multiple myeloma patients receiving consolidation with autologous stem cell transplantation

<h3>Background</h3> Novel therapies improved the survival of newly diagnosed multiple myeloma patients (NDMM) during the last decades. Nevertheless, autologous stem cell transplantation (ASCT) remains a standard consolidation strategy. How induction therapy affects the outcomes in NDMM patients receiving consolidation with ASCT has not been explored in our region <h3>Objective</h3> To analyze the impact of different induction therapies in NDMM patients receiving consolidation with ASCT in overall survival (OS) and progression-free survival (PFS) <h3>Method</h3> This is a retrospective survival analysis study based on the Grupo de Estudio Latinoamericano de Mieloma Múltiple (GELAMM) registry. We included adults patients with NDMM who received ASCT as frontline consolidation therapy from 6 countries. The induction regimens compared were VCD (Bortezomib, cyclophosphamide, dexamethasone), VTD (Bortezomib, thalidomide, dexamethasone), CTD (Cyclophosphamide, thalidomide, dexamethasone), or VRD (Bortezomib, lenalidomide, dexamethasone). OS and PFS were defined as the time from MM diagnosis until the death/last control or disease progression, respectively. We used SPSSv.25 for statistical analysis. Survival was analyzed using the Kaplan-Meier model with Log-rank test. <h3>Results</h3> Five hundred eighty-five patients were included, with a median age at diagnosis of 55 years (IQR 10), 54% males, 58.6% IgG, 17.8% IgA, 17.8% Light Chain, and 5.8% other subtype. Risk stratification at diagnosis (n=534) showed 30.7% ISS-I, 34.3% ISS-II, and 35% ISS-III. Two-thirds (66.8%) received maintenance therapy. Induction regimen were 55% VCD, 25% VTD, 16.1% CTD, and 3.9% VRD. The proportion of patients by ISS group was similar among all the regimens (p=0.97). Also, the median age was equivalent among the groups included (p=0.23). At end of induction, the rate of very good partial response or better was 51.3% VCD, 56.7% VTD, 48.9% CTD, and 85% VRD. The 5-year OS for the whole group was 82.7%, and the 5-year OS per induction regimen were 82.9% VCD, 83.6% VTD, 80.1% CTD, and 89.5% VRD (Log-Rank, p=0.70). The median OS was not reached in any of the induction regimens. The 5-year PFS (n=368) for the whole group was 27%, and the 5-year PFS per induction regimen were 27.4% VCD, 20.3% VTD, 30% CTD, and 74% VRD (Log-Rank, p=0.23). The median PFS was 42 months for both VCD and VTD, 48 months for CTD, and not reached for VRD. Maintenance therapy was associated with a 5-year OS of 86.60% vs. 80.60% (p>0.05) for patients not receiving maintenance. The 5-years PFS was 30.3% for maintenance vs. 21.2% (p>0.05) in non maintenance. <h3>Conclusions</h3> in this real-world cohort, VRD as induction therapy was associated with deeper response rates and longer PFS and OS. Regardless of the frontline therapy, ASCT achieves a long PFS and OS in NDMM. There is a trend for longer PFS and OS in patients receiving maintenance. Larger number of patients may be needed to allow more robust conclusions.

P-172: Daratumumab (Dara), Cyclophosphamide, Thalidomide and Dexamethasone: a quadruplet intensified treatment for transplant eligible newly diagnosed Multiple Myeloma (TE NDMM) patients final results

<h3>Background</h3> Newly drugs access for MM treatment still a challenge. One of the available inductions for TE NDMM patients (pts) worldwide is cyclophosphamide (C), thalidomide (T) and dexamethasone (d)- (CTd). We hypothesized that the Daratumumab and CTd combo could be safe and allow deeper activity as an alternative protocol. Primary endpoint was to evaluate the VGPR after two consolidation cycles post-ASCT. Secondary endpoints were the ORR during all treatment phases and MRD, based on the IMWG criteria that includes the NGF by the EuroFlow® and PET-CT and the safety profile <h3>Method</h3> This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, CrCl > 30 ml/min, normal cardiac, renal and liver function and the ECOG performance status=0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg PO on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose IV- QW during cycles 1 - 2 and every other week in cycles 3 – 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara was used monthly as maintenance until progression or limiting toxicity. G-CSF was used for stem cell (SC) mobilization and plerixafor if needed. All pts received anti(viral, pneumocystis and thrombotic) prophylaxis. <h3>Results</h3> A total of 21 pts were included, the median age being 56 (range 37 – 67 years), 19 (90%) were non-white, 3 (14%) had an R-ISS = 1, 12 (57%) had an R-ISS = 2 and 3 (14%), an R-ISS = 3. Five (24%) pts had HR [del17p, t(4;14) or t(14;16)]. To date, all pts have completed induction, 19 have received transplant and 17 have completed D+90 post-transplant assessment. No SC mobilization failure was observed, and five (26%) pts needed plerixafor use. In an ITT analysis, after the end of induction (cycle 4), 19 (90%) of the pts obtained > PR and 8 (38%) obtained >VGPR, including three MRD negativity by NGF. 17 pts have completed two consolidation cycles after transplant and 94% obtained > VGPR, 12 (70%) obtained MRD negativity by NGF and nine (53%) had negative PET-CT. Seven (41%) pts had both flow and PET-CT negativity. Three pts died from infection, one before transplant because of Covid, one on post-transplant, considered not related to the investigational agent, and another after consolidation, related to the investigational agent. The most common nonhematological AEs grades 3 and 4 before ASCT were neuropathy (n = 6), infusion reaction (n = 7), infection (n = 2), hypertension (n = 1) and rash (n = 1). <h3>Conclusion</h3> This is the first study that combined Dara with CTd as induction for TE NDMM pts. This present data has shown that the association of Dara-CTd achieved the primary end point once > 90% of the pts achieved VGPR after two consolidations cycles, and safety profile was acceptable. <h3>Clinical trial information</h3> NCT03792620.

PSMB7 Is a Key Gene Involved in the Development of Multiple Myeloma and Resistance to Bortezomib.

Multiple myeloma (MM), the second most commonly diagnosed hematologic neoplasm, is the most significant clinical manifestation in a series of plasma cell (PC) dyscrasia. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), approximately 1% or 10% of which, respectively, can progress to MM per year, are the premalignant stages of MM. The overall survival (OS) of MM is significantly improved by the introduction of proteasome inhibitors (PIs), but almost all MM patients eventually relapse and resist anti-MM drugs. Therefore, it is crucial to explore the progression of MM and the mechanisms related to MM drug resistance. In this study, we used weighted gene co-expression network analysis (WGCNA) to analyze the gene expression of the dynamic process from normal plasma cells (NPC) to malignant profiling PC, and found that the abnormal gene expression was mainly concentrated in the proteasome. We also found that the expression of one of the proteasomal subunits PSMB7 was capable of distinguishing the different stages of PC dyscrasia and was the highest in ISS III. In the bortezomib (BTZ) treated NDMM patients, higher PSMB7 expression was associated with shorter survival time, and the expression of PSMB7 in the BTZ treatment group was significantly higher than in the thalidomide (Thai) treatment group. In summary, we found that PSMB7 is the key gene associated with MM disease progression and drug resistance.

Glutamine-Dependence Targeting By Asparaginase Significantly Increases Anti-Myeloma Activity of Proteasome Inhibitors

Human tumors exhibit high dependence on Glutamine (Gln) for their metabolic processes and macromolecule synthesis, condition that has been defined as “Gln-addiction”. The role of such vulnerability has been recently investigated also in Multiple Myeloma (MM) cells, with Gln uptake exploited as novel therapeutic target. Indeed, MM cells by exhibiting significant lack of Gln synthetase become highly sensitive to Gln depletion. L-asparaginase (ASNase), a bacteric enzyme that by degradating circulating asparagine and glutamine leads to intracellular aminoacids depletion, has been reported to exert a certain degree of activity on human myeloma cell lines (HMLC).Based on these data, here we explored the anti-MM activity of Erwinia chrysantemi -derived L. Asparaginase (ASNase; 10-folder higher glutaminase activity than Escherichia Coli -derived formulation) in combination with the proteasome inhibitor (PI) carfilzomib (KAR), since PIs represent the backbone of current induction therapy for most MM patients.The IC50 value of both E. chrysantemi ASNase and KAR was evaluated in a panel of HMCL carrying a different genetic background. Next, by using Chou-Talalay method we found that low doses of KAR significantly enhances the anti-MM activity of ASNase. The effect of such combination was also tested in presence of IL6 and IGF-1, which mimics Bone Marrow Stromal Cells (BMSCs) milieu. Cell death analysis was measured with Annexin V/Propidium Iodide (AV/PI) staining followed by flow-cytometric analysis. The efficacy of co-treatment was confirmed by treating freshly isolated CD138 positive cells obtained from newly diagnosed MM patients (NDMM). Finally, western blot analysis was employed to fully elucidate mechanisms causing the observed synergism.ASNase treatment showed potent cytotoxic activity in all HMCL lines tested with an IC50 value ranging from 0,03 U/mL to 0.3 U/mL. High sensitivity was also observed on primary CD138+ MM cells obtained from NDMM (IC50 =0.3 U/mL). Importantly, anti-MM activity of ASNase was further increased by adding low doses of the irreversible proteasome inhibitor KAR with a Combination Index value less than 1 in almost all tested drug-concentrations. Similar data were observed in tumors cells obtained from NDMM patients. Of note, the combination ASNase plus KAR resulted more potent than single agent treatment also in culture condition of Gln deprivation, suggesting that ASNase toxicity is not only related to its glutaminase activity. IL6 or IGF-1 addition did not reduce anti-MM activity of ASNase plus KAR, indicating that BMSCs microenvironment may not influence its activity. A time and dose-dependent activity of co-treatment was also observed, with higher efficacy measured at 48 h compared with 24h of drugs exposure. The caspase-3 and PARP cleavage observed in co-treated cells, revealed the crucial role of apoptosis in the synergistic effect observed. Also authophagic features, including LC3II cleavage, were observed in tumor cells treated with KAR plus ASNase compared with single agent treatment.The effect of ASNase treatment on neoplastic cells metabolism has already showed potent antineoplastic activity in a wide range of hematologic malignancies including acute lymphoblastic leukemia and aggressive lymphomas. As result, the Gln dependence represents an attractive therapeutic target to be exploited also in plasma cells disorders. Our preliminary data show that E. chrysantemy derived asparaginase exerts a potent anti-MM activity, which is further increased by addition of the irreversible proteasome inhibitor carfilzomib through a mixed apoptotic/authophagic-mediated mechanism. DisclosuresNo relevant conflicts of interest to declare.