High-risk Myeloma Research Articles

The Top Concerns at and Since Diagnosis: Standard v. High Risk Myeloma Patients

Background: Learning about a new diagnosis, such as multiple myeloma (MM), is an important step of the disease journey. However, the education process can be overwhelming especially when factoring in disease progression, predicted by risk stratification. Unfortunately, recent research documents that excessive information can be confusing, frustrating, and negatively impact cancer treatment decision-making. The primary purpose of this survey was to capture the common questions and concerns of newly diagnosed SMM and MM patients dealing and during the years since diagnosis and evaluate the potential impact of risk classification (standard v. high risk). Methods: Using HealthTree® Cure Hub, a comprehensive platform for managing personal health for chronic illnesses, participants were recruited to take an 18 question online survey. Participants were asked to report their risk level and select the concerns experienced at and since diagnosis. A secondary aim was to identify common topics MM patients may have for a HealthTree Myeloma Coach, one-on-one mentoring help from an experienced caregiver or MM patient. Results: Of the 419 myeloma patients who responded, 167 had standard risk and 107 were high risk. Of standard risk patients 73% had MM and 26% had SMM, 80% were diagnosed before 2020, 79% saw a specialist, mean age of 66±7 years, 45% male, 30% reported currently working, 56% retired, and 69% had health insurance. While, of the high risk patients 83% had MM and 17% had SMM, 78% were diagnosed before 2020, 81% saw a specialist, mean age of 65±9 years, 38% male, 49% retired, 35% reported currently working, and 78% had health insurance. The top 6 questions at diagnosis were identical between groups: What are the myeloma treatment options?, What is my life expectancy?, What is myeloma?, Can myeloma be treated?, What can I expect during treatment?, and What side effects would I experience? Since diagnosis 3 additional concerns entered the top 6 for standard risk and 2 for high risk, one of which was shared: Is a clinical trial right for me? The standard risk group also added: What can I do to prevent further spread of the disease?, and Does my doctor have sufficient experience? While the high risk group added: How do I deal with anxiety? Intriguingly, the common topics MM patients identified that a HealthTree Myeloma Coach can help address complemented those identified in the other questions: nutrition and exercise, clinical trials, help with a specific treatment, plus, working and living with myeloma. Of note the standard risk patients also included the topic of kidney issues and retiring with myeloma, while the high risk patients requested additional help with resources available at HealthTree and orthopedic issues. Discussion & Conclusion: These results identified the major concerns of standard and high risk MM and SMM patients at and since diagnosis. The concerns begin with domains involving learning about treatment options, life expectancy and the disease of myeloma to concerns of how to manage side effects, while managing the disease, and, critical to finding a cure, a desire to learn more about joining clinical trials. Moreover, this study revealed additional topic areas a Myeloma Coach can address to help MM patients, who commonly achieve long and durable MM remission, remain current with novel treatments, learn more about clinical trials, and receive insight on living, working and retiring with myeloma. Critically, this study also highlights the mental challenges associated with being a high risk myeloma patient, with concerns of dealing with anxiety, becoming a prevalent concern since diagnosis. Taken together, this study highlights the importance of assisting high risk patients in learning how to live with their disease and manage their mental health and programs, like HealthTree Myeloma Coach, where someone who has experience with MM could provide key guidance, while supporting and sharing relevant resources.

Are we ready to look beyond plasma cells in assessing high-risk smoldering myeloma?

Sklavenitis-Pistofidis etal. report clinical and correlative results of a single-arm phase II trial of elotuzumab, lenalidomide, and dexamethasone in patients with high-risk smoldering myeloma. The authors explore the interactions between the genetics of the plasma cell clone and the immune microenvironment as potential biomarkers of treatment susceptibility and efficacy.

Immune biomarkers of response to immunotherapy in patients with high-risk smoldering myeloma.

Patients with smoldering multiple myeloma (SMM) are observed until progression, but early treatment may improve outcomes. We conducted a phase II trial of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM and performed single-cell RNA and Tcell receptor (TCR) sequencing on 149 bone marrow (BM) and peripheral blood (PB) samples from patients and healthy donors (HDs). We find that early treatment with EloLenDex is safe and effective and provide a comprehensive characterization of alterations in immune cell composition and TCR repertoire diversity in patients. We show that the similarity of a patient's immune cell composition to that of HDs may have prognostic relevance at diagnosis and after treatment and that the abundance of granzyme K (GZMK)+ CD8+ effector memory T(TEM) cells may be associated with treatment response. Last, we uncover similarities between immune alterations observed in the BM and PB, suggesting that PB-based immune profiling may have diagnostic and prognostic utility.

Lenalidomide-dexamethasone versus observation in high-risk smoldering myeloma after 12 years of median follow-up time: A randomized, open-label study

BackgroundSmoldering multiple myeloma (SMM) is a heterogeneous disease in terms of progression to myeloma (MM), but its standard of care continues to be observation. MethodsThe QuiRedex phase 3 trial initiated in 2007 included 119 high-risk patients with SMM randomized to treatment or observation. Treatment consisted of nine 4-week induction cycles (lenalidomide [Rd], 25 mg on days 1–21 plus dexamethasone, 20 mg on days 1–4 and 12–15), followed by maintenance (R, 10 mg on days 1–21) for up to 2 years. The primary end-point was time to progression (TTP) to myeloma based on per protocol population. Secondary end-points were overall survival (OS), response rate, and safety. An update of the trial after a long-term follow-up is presented here. This trial was registered with ClinicalTrials.gov (NCT00480363). FindingsAfter a median follow-up time of 12.5 years (range: 10.4–13.6), the median TTP to MM was 2.1 years in the observation arm and 9.5 years in the Rd arm (HR: 0.28, 95% CI: 0.18–0.44, p < 0.0001). The median OS was 8.5 years in the abstention arm and not reached in the Rd group (HR: 0.57, 95% CI: 0.34–0.95, p = 0.032). Patients who progressed received optimized treatments according to the standards of care, and the OS from progression was comparable in both arms (p = 0.96). InterpretationThis analysis confirms that early treatment with Rd for high-risk SMM translates into a sustained benefit in both TTP and OS. FundingPethema (Spanish Program for the Treatment of Hematologic Diseases), Spain.

FOXM1 regulates glycolysis and energy production in multiple myeloma

The transcription factor, forkhead box M1 (FOXM1), has been implicated in the natural history and outcome of newly diagnosed high-risk myeloma (HRMM) and relapsed/refractory myeloma (RRMM), but the mechanism with which FOXM1 promotes the growth of neoplastic plasma cells is poorly understood. Here we show that FOXM1 is a positive regulator of myeloma metabolism that greatly impacts the bioenergetic pathways of glycolysis and oxidative phosphorylation (OxPhos). Using FOXM1-deficient myeloma cells as principal experimental model system, we find that FOXM1 increases glucose uptake, lactate output, and oxygen consumption in myeloma. We demonstrate that the novel 1,1-diarylethylene small-compound FOXM1 inhibitor, NB73, suppresses myeloma in cell culture and human-in-mouse xenografts using a mechanism that includes enhanced proteasomal FOXM1 degradation. Consistent with the FOXM1-stabilizing chaperone function of heat shock protein 90 (HSP90), the HSP90 inhibitor, geldanamycin, collaborates with NB73 in slowing down myeloma. These findings define FOXM1 as a key driver of myeloma metabolism and underscore the feasibility of targeting FOXM1 for new approaches to myeloma therapy and prevention.

P923: TANDEM AUTOLOGOUS STEM CELL TRANSPLANTATIONS STILL BENEFIT FOR MYELOMA PATIENTS: A POOLING META-ANALYSIS

Background: Although high-dose therapy and autologous stem cell transplant combined with novel agents continues to be the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma patients, disease progression remains an issue. To deepen the treatment response and prolong disease free survival, tandem autologous stem cell transplant is one of treatment choice. Compared to toxicity of sub-sequent pharmacotherapy or allogeneic transplant, tandem ASCT is well-tolerated. However, the efficacy of tandem ASCT is not fully defined yet. Thus, we aimed to assess effectiveness of tandem ASCT. Aims: To evaluate the true effect of tandem autologous/autologous stem cell transplantation for myeloma patients in current era. Methods: Eligible randomized controlled trials published before Dec 2021 were retrieved from databases. Myeloma patients received tandem autologous stem cell transplantation was included. Systematic review and pairwise meta-analysis were performed. We calculated the hazard ratio (HR) with 95% confidence intervals (CIs). Results: Ten articles, involving 3,123 patients, met the selection criteria. All studies demonstrated acceptable quality. The mean age was 58.2 year-old with mean 36.2% high risk cytogenetics feature. Eight trials were international multi-centers phase III RCTs. Tandem autologous stem cell transplantation compared to single ASCT was associated with a significantly superior progression free survival (random-effect HR 0.89; 95% CI 0.82-0.97; I2 = 0.0%), but no significance difference regard to overall survival (random-effect HR 0.98; 95% CI 0.94–1.03; I2 = 0%). For high risk myeloma subgroup, 4 trials compared tandem ASCT versus lenalidomide, tandem ASCT demonstrated superior progression free survival (random-effect HR 0.87; 95% CI 0.82–0.91; I2 = 0%) Image:Summary/Conclusion: In conclusion, tandem ASCT are still to be considered as an acceptable treatment options in general myeloma patients. High-risk cytogenetics is frequently observed in newly diagnosed myeloma with worsens outcome after single autologous, whereas a tandem autologous transplant strategy may overcome onset poor prognosis.

Inhibition of the Protein Arginine Methyltransferase PRMT5 in High-Risk Multiple Myeloma as a Novel Treatment Approach.

Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. Subsets of patients have high-risk features linked with dismal outcome. Therefore, the need for effective therapeutic options remains high. Here, we used bio-informatic tools to identify novel targets involved in DNA repair and epigenetics and which are associated with high-risk myeloma. The prognostic significance of the target genes was analyzed using publicly available gene expression data of MM patients (TT2/3 and HM cohorts). Hence, protein arginine methyltransferase 5 (PRMT5) was identified as a promising target. Druggability was assessed in OPM2, JJN3, AMO1 and XG7 human myeloma cell lines using the PRMT5-inhibitor EPZ015938. EPZ015938 strongly reduced the total symmetric-dimethyl arginine levels in all cell lines and lead to decreased cellular growth, supported by cell line dependent changes in cell cycle distribution. At later time points, apoptosis occurred, as evidenced by increased AnnexinV-positivity and cleavage of PARP and caspases. Transcriptome analysis revealed a role for PRMT5 in regulating alternative splicing, nonsense-mediated decay, DNA repair and PI3K/mTOR-signaling, irrespective of the cell line type. PRMT5 inhibition reduced the expression of upstream DNA repair kinases ATM and ATR, which may in part explain our observation that EPZ015938 and the DNA-alkylating agent, melphalan, have combinatory effects. Of interest, using a low-dose of mTOR-inhibitor, we observed that cell viability was partially rescued from the effects of EPZ015938, indicating a role for mTOR-related pathways in the anti-myeloma activity of EPZ015938. Moreover, PRMT5 was shown to be involved in splicing regulation of MMSET and SLAMF7, known genes of importance in MM disease. As such, we broaden the understanding of the exact role of PRMT5 in MM disease and further underline its use as a possible therapeutic target.

What Is Genomic High-Risk Myeloma?

Although treatment of multiple myeloma has changed dramatically over time, there is still a subpopulation of patients who do not respond to treatments and are labeled as high risk. A combination of serum and genomic markers can be used to identify and stratify these patients according to associations with outcome. The most common method of identifying the genomic markers of high-risk multiple myeloma is using fluorescence in situ hybridization using probes to identify IgH translocations or copy number changes including the t(4;14), t(14;16), t(14;20), gain 1q, and del(17p). However, as research studies utilize newer technologies, such as whole genome sequencing, more high-risk factors are being identified including mutations of TP53, DIS3, BRAF, and complex structural events. Integration of comprehensive genomic studies into clinical trials will aid in defining the genomic high-risk landscape of multiple myeloma, which in turn can be transferred to individual patient diagnostics and treatment management.

Safety and efficacy of apixaban as thromboprophylaxis in myeloma patients receiving chemotherapy: A prospective cohort study

•We report an amended thromboprophylactic strategy using apixaban rather than low-molecular-weight heparin for high thrombotic risk myeloma patients. •No thrombotic events are reported in patients receiving prophylactic apixaban. •Major bleeding occurred in 1.2% patients on prophylactic apixaban. •Apixaban appears to be an effective and safe alternative to low-molecular-weight-heparin as thromboprophylaxis in myeloma.

Gabarap Loss Mediates Immune Escape in High Risk Multiple Myeloma

Gabarap Loss Mediates Immune Escape in High Risk Multiple Myeloma

Single Cell Multi-Omic Profiling of Multiple Myeloma with t(4;14) Finds an Immune Microenvironment Gene Signature That Correlates with Clinical Outcomes

BackgroundMultiple Myeloma (MM) is an incurable plasma cell (PC) malignancy and high risk MM remains an unmet clinical need. Translocation 4;14 occurs in 15% of MM and is associated with an adverse prognosis. A deeper understanding of the biology and immune micro-environment of t(4;14) MM is necessary for the development of effective targeted therapies. Single Cell multi-omics provides a new tool for phenotypic characterization of MM. Here we used Proteona's ESCAPE™ single cell multi-omics platform to study a cohort of patients with t(4;14) MM.MethodsDiagnostic bone marrow (BM) samples from 13 patients with t(4;14) MM (one of whom had samples at diagnosis and relapse) were analysed using the ESCAPE™ platform from Proteona which simultaneously measures gene and cell surface protein expression of 65 proteins in single cells. Cryopreserved BM samples were stained with antibodies and subsequently sorted on CD138 expression. The CD138 positive and negative fractions were recombined at a 1:1 ratio for analysis using the 10x Genomics 3' RNAseq kit. Resulting data were analyzed with Proteona's MapSuite™ single cell analytics platform. In particular, Mapcell was used to annotate the cells and MapBatch was used for batch normalization in order to preserve rare cell populations.ResultsPatients had a median age of 63 years and received novel agent-based induction. Median progression free and overall survival (PFS and OS) were 22 and 34 months respectively.We first analyzed serial BM samples from an individual patient that were taken at diagnosis and relapse following bortezomib based treatment. The PCs in this patient showed variations in gene expression between diagnosis and relapse (Fig 1A), including the reduction of HIST1H2BG expression, which has previously been correlated with resistance to bortezomib. Subsequent analysis of the immune cells identified a shift in the ratio of T cells to CD14 monocytes from 5.7 at diagnosis to 0.6 at relapse suggesting a major change in the BM immune micro-environment in response to therapy.Next, we analyzed the malignant PCs of the diagnostic samples. As expected, MMSET (NSD2) was overexpressed in all PCs compared to normal PCs, while FGFR3 expression could be categorized into no expression of FGFR3, low expression (<10% of cells expressing FGFR3) or high expression (>80% of cells expressing FGFR3) (Fig 1B). No gene or protein expression patterns within the PCs were identified that correlated with PFS or OS in this cohort.Finally, we analyzed the immune micro-environment in the diagnostic samples (Fig 1C). While there was no overall discernable pattern of cell types present, one cluster of cells, annotated as 'unknown' cell type, suggested a small population of cells that had not been previously annotated in published single cell RNA-seq data. The cells were CD45+ and CD138 - both at the protein and RNA level, suggesting they are not plasma cells.We tested if the number of the ‘unknown’ cells in each sample correlated with PFS, but there was no significant correlation. We then used these cells to derive a gene signature profile which was expressed in most of the cells in the ‘unknown’ cluster as well as a minor fraction of cells in other clusters including some PCs. The number of cells expressing the gene signature negatively correlated with PFS, with samples containing more cells expressing the signature having a lower PFS than samples with fewer signature positive cells (Fig 2). The correlation remained significant whether we included PCs in the analysis or not, but was not significant amongst only the PC population, suggesting that the cells responsible for the correlation are from the immune micro-environment.ConclusionsWe present the first application of single cell multi-omic immune profiling in high-risk MM and demonstrate that t(4;14) is a phenotypically heterogenous disease. While no consistent gene or protein expression patterns were identified within the malignant cell population, we did identify gene expression changes in a relapsed patient sample that may reflect key alterations in the PCs responsible for therapy resistance. In addition, we identified a gene signature expressed in a rare population of non-plasma cells that significantly correlated with PFS in this patient cohort. These data highlight the potential of single cell multi-omic analysis to identify immune micro-environmental signatures that correlate with response to therapy in t(4;14) MM. [Display omitted] DisclosuresScolnick: Proteona Pte Ltd: Current holder of individual stocks in a privately-held company. Huo: Proteona Pte Ltd: Ended employment in the past 24 months. Xu: Proteona Pte Ltd: Current Employment. Chng: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria.

A Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

A Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Single-Cell RNA-Sequencing Identifies Immune Biomarkers of Response to Immunotherapy in Patients with High-Risk Smoldering Myeloma

Single-Cell RNA-Sequencing Identifies Immune Biomarkers of Response to Immunotherapy in Patients with High-Risk Smoldering Myeloma

Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd

Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd

Circulating Plasma Cells Are the Most Powerful Prognostic Marker in Transplant Ineligible Multiple Myeloma with 2% As a New Cut-Off for Primary Plasma Cell Leukemia

Background:Tumor burden in multiple myeloma (MM) is routinely evaluated in the bone marrow, though its prognostic value is not proven. There is an increasing interest in liquid biopsies due to its minimally invasive nature and more comprehensive evaluation of tumor burden. Growing evidence supports the quantification of circulating plasma cells (cPCs) measured by multiparameter flow cytometry (MFC) as a powerful diagnostic biomarker suitable for risk stratification of newly diagnosed transplant eligible MM (Garces et al, EHA 2021). Nevertheless, there are virtually no data regarding prognostic impact of cPCs in MM patients ineligible for transplantation. Primary plasma cell leukemia (pPCL) is a rare and most aggressive monoclonal gammopathy with dismal outcomes defined by more than 20% of cPCs and/or absolute cPCs count of ≥2 x10 9/L. Recently, there have been many efforts to redefine these criteria as lower number of cPCs probably portends equally poor prognosis.Aims:To evaluate prognostic significance of cPCs in a large cohort of transplant ineligible (Tx-ineligible) newly diagnosed MM patients and to define cut-offs for risk stratification. Moreover, to establish cut-off identifying ultra high risk MM patients mimicking the prognosis of pPCL and propose new definition of pPCL.Methods:Circulating PCs were measured by 8 color flow cytometry in 402 Tx-ineligible MM patients (including n=7 pPCL) diagnosed between 2012 and 2019 at University Hospitals Brno and Ostrava, Czech Republic. Patients were treated in real-world setting and the clinical analysis was performed retrospectively based on data from the Czech Registry of Monoclonal Gammopathies. Median follow-up was 20.5 months. The intermediate cutoff was identified using ROC analysis considering overall survival (OS). Moreover, data from the large published cohort of pPCL patients treated in real-world setting were used to find a new cut-off identifying these ultra-high-risk pPCL-like patients (Jurczyszyn et al. BJH,2018).Results:Circulating PCs were detected in peripheral blood (PB) of 303/402 (75%) patients. In 303 patients with detectable cPCs the median percentage was 0.06% with range 0.0008% - 79%. The median limit of detection of MFC technique was 0.006 (sensitivity 10e-5). Patients stratification into 3 subgroups according to quantification of cPCs (low: ≤ 0.2%; intermediate: 0.2 - 2% and high: >2.0%) resulted in significantly different OS (36.5 vs. 28.1 and 13.6 months; p < 0.0001) and progression free survival (PFS) (17.9 vs. 14.7 and 3.4 months; p < 0.0001). Patients with no detected cPCs (0%) did not separate from subgroup >0% to <0.2% (p >0.05) suggesting that next-generation flow cytometry (NGF) with sensitivity 10e-6 is needed for the identification of this favorable prognostic group. In order to demonstrate that patients with more than 2% of cPCs have similarly poor outcome as pPCL patients, we compared those with 2% - 20% (n=15) vs. those with >20% (n=7) of cPCs. The outcomes were practically identical with median PFS of 3.1 vs. 4.2 months (p = 0.23) and median OS of 13.6 vs. 14.6 months (p=0.23).Next, we analyzed patient´s characteristics in association with the level of cPCs (low, intermediate and high) and we demonstrated that there was significantly higher proportion of patients with ISS III stage (38%, 52% and 82%), elevated LDH level (8%, 19% and 55%) and high risk cytogenetics (12%, 21% and 36%) hand in hand with increasing number of cPCs. CPCs were identified as the most powerful prognostic marker in univariate (HR=2.7 for OS and HR=6.3 for PFS; p=0.001) and multivariate analysis (HR=4.2 for OS and HR=5.8 for PFS; p<0.001), including ISS, LDH and FISH cytogenetics.Conclusion:The quantification of cPCs in PB of newly diagnosed MM is the most powerful prognostic factor as we demonstrated on a large cohort of transplant ineligible patients. We defined 2% of cPCs as a new cut-off for ultra high risk myeloma resembling behavior of primary PCL. We propose this 2% cut-off for redefinition of pPCL criteria that warrants further investigation in prospective setting. To identify subgroup with especially favorable outcome with no detectable cPCs, NGF with high sensitivity of 10e-6 is needed. Quantification of cPCs by MFC is easy, fast, affordable and worldwide available procedure providing highly relevant prognostic information that might be implemented into routine clinical practice. [Display omitted] DisclosuresJurczyszyn: Janssen-Cilag, Amgen: Honoraria, Speakers Bureau. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Hajek: Janssen: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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.

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

Introduction: Studies have demonstrated that multiple myeloma (MM) is a clinically, genetically complex and heterogeneous disease. Cytogenetic alterations identify high-risk patients in MM and are associated with a poor prognosis. They include at least one of the following at diagnosis: t(4;14), t(14;16), t(14;20), del(17p), 1q amp and 1q amp + del(1p). Autologous stem cell transplantation (ASCT) and the development of novel agents have considerably increased the median survival of MM patients. Patients with high-risk cytogenetics are associated with worse survival, and studies have shown improvement in progression-free survival with tandem ASCT when compared to single ASCT.Methods: This is a retrospective single-center study evaluating MM patients with high-risk cytogenetics at our center who have undergone a tandem autologous transplant from January 1, 2017, to December 31, 2020. Primary objective was overall response rates (ORR) and relapse rates. Secondary objectives looked at progression-free survival (PFS), overall survival (OS) using the Kaplan-Meier method.Results: From January 1, 2017, to December 31, 2020, 25 high-risk patients underwent tandem ASCT. Key patient characteristics are shown in table 1. Translocation (4:14) was seen in 8/25 (32%) patients; t(14:16) in 5/25 (20%) patients; del17p in 7/25 (28%), 1q amp in 8/25 (32%) patients, del1p + 1q amp in 5/25 (20%) patients. In terms of double hit and triple hit disease, 9/25 (36%) patients had two high risk changes and 3/25 (12%) with had three high risk changes. ISS staging wise, 5/25 (20%) patients were ISS stage I, 5/25 (20%) patients ISS stage 2 and 9/25 (36%) patients were ISS stage 3. The most common induction regimen consisted of cyclophosphamide, bortezomib, and dexamethasone (CyBorD). One patient each transitioned to daratumumab, lenalidomide and dexamethasone and PAD/CVD due to poor response. Maintenance therapy was given to 21/25 (84%) tandem ASCT patients with 5 (20%) patients receiving lenalidomide, 4 (16%) patients receiving proteasome inhibitor and 12 (48%) patients received dual maintenance.In terms of response, we recorded CR (complete response) vs VGPR (very good partial response) vs PR (partial response) after induction, 2-3 months after ASCT #1, 2-3 months after ASCT #2, 12 months after ASCT #2, and 12 months after maintenance. Following induction, 16 patients had achieved VGPR, and 9 of patients had achieved PR. After ASCT #1, 5 (55.5%) PR patients deepened their response to a VGPR. 1-3 months post ASCT #2, 3 (33.3%) PR patients deepened to a VGPR, and 2 (12.5%) VGPR patients achieved CR. 12 months after ASCT #2, 2 of the previous VGPR patients (12.5%) achieved CR, and 1 PR (11.1%) patient achieved VGPR.At the median follow-up time of 60 months, 44% of patients had relapsed. 1 patient relapsed within 1-3 months post ASCT#1. Nine other patients relapsed post ASCT #2 and maintenance except one patient who relapsed at time of ASCT #2. Univariable analysis identified hemoglobin as a statistically significant association with risk of progression or death. All patients who received any maintenance after tandem transplant were progression-free at 60 months (p<0.001).Conclusion: In our retrospective study, results suggest that tandem ASCT allows for deepening of responses. Together with maintenance therapy, this contributes to the durability of further PFS prolongation in high-risk MM patients. [Display omitted] DisclosuresLam: Novartis: 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; Servier: 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; Amgen: 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; Beigene: 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; AstraZeneca: 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; SeaGen: 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; Pfizer: 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. Phua: 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; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Amgen: Honoraria. Louzada: Amgen: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

P-096: Tackling pyrimidine biosynthesis - CTP Synthase 1 is a novel target in the treatment of multiple myeloma

<h3>Background</h3> Clinical progress in patients with high-risk multiple myeloma (MM) is limited and median survival remains at less than two years. Overexpression of cell cycle and proliferation-related genes is frequently observed in high-risk MM and novel treatment strategies for these patients are urgently needed. While the demand for pyrimidines is saturated via salvage pathways in resting cells, proliferating cells depend on the de novo synthesis of pyrimidines to meet the high demand for nucleotides. We therefore speculated that this pathway represents an attractive target in proliferation-associated high-risk myeloma. <h3>Methods</h3> In silico analysis of publicly available gene expression data sets was used to analyze CTP Synthase 1 (CTPS1) expression in different MM subgroups. In vitro, CTPS1 was evaluated as a target via generation of CRISPR/Cas9 CTPS1 knock-out cell lines. Apoptosis induction, cell cycle analysis and membrane potential of the cells were analyzed by flow cytometry. Additionally, the CTPS1 inhibitor STP938 (Step Pharma) was tested in 12 MM cell lines for its anti-myeloma properties. Uridine and cytidine rescue experiments were used to confirm the specificity of the compound. Previously established resistance models to pomalidomide and carfilzomib were used to demonstrate the efficacy of STP938 in advanced disease stages. <h3>Results</h3> In silico gene expression analysis revealed an upregulation of CTPS1 in MM and plasma cell leukemia patients compared to healthy-donor bone marrow plasma cells. Additionally, CTPS1 was found to be upregulated in patients with a proliferative gene expression pattern and high expression levels were linked to poor patient outcome. In vitro, stable CTPS1 knock-out clones failed to proliferate in the absence of exogenous cytidine which can be recycled via the nucleotide salvage pathway. Proliferation inhibition was accompanied by induction of an S-phase cell cycle arrest and apoptosis. The highly specific CTPS1 inhibitor STP938 showed potent inhibition of cell viability in 6 out of 12 cell lines. In accordance with the results obtained in genetic perturbation experiments we observed apoptosis induction, S phase arrest, and loss of mitochondrial membrane potential upon treatment with STP938. Addition of mM concentrations of exogenous cytidine, but not uridine, protected MM cell lines from apoptosis underlining the specificity of STP938. Importantly, the compound remained effective in models resistant to carfilzomib and pomalidomide. <h3>Conclusions</h3> Our in silico data establish CTPS1 as a potential novel target for proliferation associated high-risk disease. In vitro, the essential role of CTPS1 was confirmed by CRISPR/Cas9 deletion and the CTPS1 inhibitor STP938 was found to be highly efficacious in inducing apoptosis in several myeloma cell lines. Pre-clinical experiments have thus confirmed the drugability of CTPS1 and therefore strongly support the further evaluation of STP938.

OAB-022: Monoallelic deletion of BCMA locus is a frequent feature in MM and is associated with increased genomic loss

<h3>Background</h3> Immunotherapies in MM targeting BCMA, have shown remarkable clinical benefits. However, two recent reports highlighted that biallelic loss of BCMA cause resistance to anti-BCMA therapy. In both studies BCMA locus was deleted bringing in focus importance of del16p. We have evaluated 2883 MM patients at diagnosis and relapse to understand frequency of BCMA targeting events and characteristics of MM patients with BCMA deletion. <h3>Methods</h3> We observed del16p in 8.58% (7.6% to14.6% in individual studies) of newly-diagnosed patients (n=2458).Frequency of 16p loss in both HMM and NHMM were similar, suggesting its independence from MM subtypes. Overall CN loss was significantly higher in patients with BCMA loss compared to rest of the MM patients. High risk deletion events such as del1p and del17p were more likely to be observed in patients with loss of BCMA locus (OR [95% CI] 19.3(13.1-25.8), FDR=1.5e-65; and 8.8(6.3-12.1), FDR=5.5E-39, respectively)]. MM patients with loss of BCMA locus have increased mutational load (8202 with 95% HDI 6921 and 9535) compared to those without BCMA locus loss (6975 with 95% HDI 6626 – 7343); probability of difference greater than 0 was 96.8% and difference of the means were 1222 [95% CI 112-2589]. To understand the risk profile of patients with loss of BCMA locus, we next focused on the observation that BCMA loss frequently co-occurs with other deletions. <h3>Results</h3> We observed that when BCMA and TP53 or BCMA and del1p loss are present in the same patient, they are likely to have same clonality. These data suggested a possibility of co-occurrence of these events in same cell. To further investigate this observation, we used single cell DNA sequencing data from patients with sub clonal and clonal BCMA locus loss. Interestingly, almost all cells with BCMA loss also had p53 loss, while not all p53 loss cells had BCMA loss suggesting that the chronology of this copy number alternation may suggest first p53 loss followed by BCMA loss. Our data from a patient with BCMA targeting therapy also indicated that BCMA loss tend to co-occur with TP53 deletions (OR=5.67 [95% CI 4.12-7.84], p value < 0.0001).Moreover, we found that TP53 mutations were more frequent for patients with del16p and del17p, compared to patients who only had del16p. <h3>Conclusions</h3> Our data from large scale copy number profiles showed that even without treatment pressure, monoallelic BCMA deletions are frequent events. Moreover, patients with these events show increased genomic loss. Such behavior potentially make these cells vulnerable for biallelic loss of other genes. Our results highlight that by looking at mRNA or protein expressions at bulk sample would not directly indicate the presence or absence of cells with target loss and therefore evaluating single cell level data are necessary. These results suggest the need to study del16p in patients being targeted for BCMA-directed therapy and its association with del17p raises question about the role of BCMA targeted therapy in high-risk myeloma.

OAB-054: Single-cell RNA-sequencing identifies immune biomarkers of response to immunotherapy in patients with high-risk Smoldering Myeloma

<h3>Background</h3> Patients with Smoldering Multiple Myeloma (SMM) are typically observed until progression, but early treatment of high-risk patients may improve outcomes. Clinical and genomic biomarkers can be used to identify SMM patients at high risk of progression, however parallel profiling of the tumor immune microenvironment (TIME) may further improve prediction models. <h3>Methods</h3> Here, we performed single-cell RNA-sequencing on CD138- immune cells from 40 samples of 14 patients enrolled in a Phase II trial of Elotuzumab, Lenalidomide, and Dexamethasone, in patients with high-risk SMM (E-PRISM) to develop biomarkers for optimal patient selection and monitoring of response to treatment. Specifically, we profiled 33 bone marrow (BM) samples collected at baseline (n=11), cycle 9, Day 1 (C9D1, n=13) and EOT (n=9), and 7 peripheral blood mononuclear cell (PBMC) samples collected at baseline (n=4) and C9D1 (n=3). <h3>Results</h3> We found that higher abundance of mature B-cells, Th17 cells and GZMK+ T and NK cells and lower abundance of hematopoietic progenitor cells and plasmacytoid dendritic cells are associated with significantly longer progression-free survival (PFS) in SMM patients under treatment. This signal can be summarized by how normal-like the patients' immune composition is at baseline, whereby patients whose immune composition is normal-like have significantly shorter PFS (p=0.031). This model suggests that at least some of the compositional changes observed in disease reflect the immune system's capacity to react successfully to the immune challenge posed by the tumor, which we termed immune reactivity. Baseline immune reactivity may help to identify patients who will benefit the most from early treatment. Furthermore, we found that the expansion of tissue-resident NK cells and exhausted GZMK+ CD8+ T-cells at C9D1 of treatment is associated with significantly shorter PFS (p=0.039), suggesting that these immune biomarkers may help to monitor response to immunotherapy. Lastly, we found that patients would be classified the same way in terms of our immune biomarkers, had we assayed their peripheral blood instead of their bone marrow, suggesting that minimally invasive immune profiling for prognostication and monitoring may be feasible. <h3>Conclusion</h3> We used single-cell RNA-sequencing to profile the immune microenvironment of patients with high-risk SMM in a Phase II trial of Elotuzumab, Lenalidomide and Dexamethasone and developed immune biomarkers of response to treatment. Our study may usher in a next generation of clinical assays that assess both tumor biology and immune state, as well as common clinical biomarkers, in the marrow or blood, to accurately predict who may benefit from early treatment, monitor response and improve patient outcomes.