Advances In Multiple Myeloma Research Articles

Gene Expression Profiling to Predict Prognostic Biomarkers for Relapse in Multiple Myeloma

Background: Multiple myeloma (MM), an incurable malignancy of plasma cells (PCs), is the second most common hematological cancer caused primarily by structural variations (chromosomal aberrations and somatic mutations). The majority of the patients acquired resistance against standard therapeutic approaches for MM and experienced relapse despite the continuous advances in MM therapies.Methods: We performed Differential Gene Expression (DGE), literature mining and SNV analysis of Next Generation Sequencing (NGS) data of Newly Diagnosed MM (NDMM) and Relapsed/Refractory MM (RRMM). The selected Differentially Expressed Genes (DEGs) were subjected to functional enrichment and pathway analysis. Immune cells infiltration analysis was also performed to estimate immune cells variations in the Tumor Microenvironment (TME) of RRMM. Result: CSF1R, VCAN, NRP1, COL22A1, BPI, BIRC5, MNX1, FAT1, ERG, TCL1A, AFF3 were selected after DGE, literature mining and SNV analysis. The functional enrichment of these DEGs showed significant enrichment for positive regulation of cell population proliferation, serene/threonine kinase activity, endothelial cell proliferation, cytokine binding, G protein activity and GDP binding, whereas KEGG pathway analysis revealed vital role of PI3K-Akt signaling pathway along with various cancer pathways. The immune cells infiltration analysis revealed the higher count of neutrophils and lesser level of T cells (CD8+) in TME of RRMM. Conclusion: Our study suggests that neutrophils play an important role in modulation of TME in RRMM. The selected DEGs have previously been identified in progression, drug resistance and relapse of various cancers. The role of these biomarkers in RRMM has not been explored yet. Therefore, neutrophils, selected DEGs and PI3K-Akt signaling pathway are potential targets to investigate in RRMM.Keywords: Multiple Myeloma; Relapse; Differential Expression; Immune Cell Infiltration; Literature Mining

Patient perspectives on BCMA-targeted therapies for multiple myeloma: a survey conducted in a patient advocacy group.

Advances in multiple myeloma (MM) treatment have shifted the therapeutic landscape. Understanding patients' perspectives can assist physicians in helping patients make informed decisions. This study aimed to understand the patient decision-making process and gain insights into patient perspectives on B-cell maturation antigen (BCMA)-targeted therapies for MM. An 18-question survey was completed by patients with MM enrolled in HealthTree® Cure Hub, an online portal helping patients with plasma cell dyscrasias navigate their disease. From October 28, 2022, to January 12, 2023, 325 patients with MM participated in the survey. The mean age (standard deviation) of the respondents was 66 (8) years; 54% were female and 90% were White. Among 218 patients with complete clinical records in the database, the median (min, max) lines of therapy (LOT) was 2 (1,16). Among 61 (28%) patients who had received ≥4 LOTs, 55 (90%) were triple-class exposed. Of the 290 patients who responded to the question about openness to new therapies, 76 (26%) were open to trying a new therapy immediately and 125 (43%) wanted more information on safety and efficacy. Most respondents reported likely or very likely to try a BCMA CAR T-cell therapy (60%) or a bispecific antibody (74%) and some needed more information to decide (16% for CAR T-cell therapy and 13% for bispecific antibody). The most requested information included efficacy, side effects (SEs), eligibility, and administration process for both CAR T-cell and bispecific therapies. When 2 therapies with the same efficacy and duration of response were offered, 69% of respondents would prefer the therapy with a lower risk of severe SEs but requires continuous dosing with no treatment-free interval, and 31% preferred a therapy given once followed by a treatment-free interval but with a potentially higher risk of severe SEs. To receive an effective therapy, the top acceptable trade-offs included frequent monitoring of SEs and initiating a new therapy in a hospital setting, and the least acceptable compromise was caregiver burden. This study found a high level of openness in patients with MM to try BCMA-targeted therapies. Information on efficacy, safety, availability, and eligibility may assist patients on decision-making.

Recent Advances in Multiple myeloma

Multiple myeloma (MM) represents a malignant proliferation of plasma cells originating from a single clone. The tumour causes bone pain, fracture, anaemia, and other infections. Patients present with MM are symptomatic and need cytotoxic chemotherapy. Previously, melphalan and glucocorticoid were accepted as first-line treatments. Recently, immunomodulatory drugs and proteasome inhibitors have become the treatment of choice. There are several new drugs approved for multiple myeloma: monoclonal antibodies, nuclear export inhibitors, B-cell maturation antigen (BCMA)-directed antibody, CAR T-cell therapy, histone-deacetylase inhibitor, and stem cell mobilizer. Drugs like cobemetinib are being evaluated for potential role in the treatment of MM. Pharmacogenomics and precision medicine also play a crucial role in the treatment of multiple myeloma.

Clinical Outcomes in Real-World Patients (RW) with Triple-Class Exposed (TCE) Relapsed/Refractory Multiple Myeloma (RRMM): A Retrospective Study Using Electronic Health Records from Flatiron Health and COTA Vantage Databases

Introduction: With rapid treatment advances in multiple myeloma (MM), more patients receive the 3 main classes of MM treatments (immunomodulatory imide drug [IMiD] agents, proteasome inhibitors [PIs], and anti-CD38 monoclonal antibodies [mAbs]) in earlier lines of therapy and become TCE. This is a prerequisite for subsequent treatment with some novel therapies eg, anti-B-cell maturation antigen (BCMA) agents. Published evidence of RW clinical outcomes in patients with TCE MM is scarce in the evolving RRMM treatment landscape. The objective of this study was to assess RW clinical outcomes in patients with TCE RRMM who received treatment post-TCE. Methods: In this observational study, we analyzed de-identified patient data derived from electronic health records (EHRs) from 2 key United States (US) MM longitudinal databases (Flatiron Health MM [FHMM] and COTA Vantage MM [CVMM]). We identified patients who became TCE between November 2015 and March 2021 and received a subsequent treatment post-TCE; the earliest available end date of the 3rd treatment class was considered the date patients became TCE. The start date of the 1st treatment post-TCE (index treatment) was defined as the index date. We analyzed patient demographics, disease characteristics, prior treatment exposure, refractory status, and index treatments patterns/classes. Clinical endpoints assessed were response rates (overall and complete), overall survival (OS), progression-free survival (PFS), and time to progression (TTP). Results: The FHMM and CVMM databases included 1,319 and 1,118 TCE patients, respectively, of whom 897 and 795 received an index treatment post-TCE. Median (range) follow-up for patients who received an index treatment was 18.1 (0.1-82.0) and 15.5 (0.03-72.3) months for FHMM and CVMM cohorts, respectively. Median age for both RW cohorts was 68 years, more than half of patients were men and the majority were White. Patients received a median of 3 lines of prior treatment (range, 1-14 and 1-12 for FHMM and CVMM cohorts, respectively). In both RW cohorts, >75% of patients who received an index treatment were triple-class refractory and approximately 10% were penta-refractory, having received treatment with 2 IMiD agents, 2 PIs, and an anti-CD38 mAb. Approximately 67% and 79% of patients in the FHMM and CVMM cohorts, respectively, had ECOG performance status 0 or 1. Approximately 54% and 61% had received prior stem cell transplantation. IMiD agents either alone or in combination with a PI and/or anti-CD38 mAb constituted the main regimens for index-treated patients. In the CVMM cohort, the overall and complete response rates were 15.2% and 1.7%, respectively; response data were not available in the FHMM cohort. Median OS (22.3 and 20.4 months), median PFS (4.8 and 4.9 months), and median TTP (5.9 and 5.9 months) were comparable for both FHMM and CVMM cohorts. Conclusions: In this observational cohort study of 2 US RW EHR databases, patients became TCE with a median of 3 prior lines of therapy. Post-TCE, most patients with RRMM still received the same 3 treatment classes with poor response and survival outcomes on their treatments. Despite advances in MM management, this study highlights the need for more efficacious novel treatments for patients with TCE MM and serves as a RW benchmark in the literature for appraising emerging data from novel agents in patients with RRMM.

Circulating serum microRNAs as biomarkers of drug resistance in multiple myeloma patients treated with bortezomib-based regimens – pilot study

Despite advances in multiple myeloma (MM) treatment, drug resistance remains a clinical challenge. We aimed to develop a prognostic model for bortezomib resistance based on miRNA expression profiling. The study included 40 previously untreated MM patients receiving bortezomib-based regimens (20 treatment-sensitive, 20 resistant). Pretreatment venous blood samples were analyzed for miRNA expression. Differential expression analysis revealed upregulated miR-27b-3p (FC 1.45, p = 0.017) and let-7b-5p (FC 1.44, p = 0.025) in the resistant group. Univariate analysis identified let-7b-5p (OR 3.17, 95%CI: 1.19–11.4, p = 0.04) and miR-27b-3p (OR 4.73, 95%CI: 1.4–26.6, p = 0.036) as risk factors for resistance. The final multivariate model included miR-27b-3p (OR 23.1, 95% CI: 2.8–452, p = 0.015), let-7b-5p (OR 4.38, 95% CI: 1.28–22.2, p = 0.038), and miR-103a-3p (OR 15.3, 95% CI: 1.33–351, p = 0.049). These miRNAs may serve as biomarkers of treatment response in MM. However, external validation is necessary to confirm the clinical utility of our model.

SDC2 Expression Is Increased in Myeloma Cells in Response to Loss of Pro-Survival Surface Proteins, CD28 and CD86

Introduction: While recent advances in multiple myeloma (MM) have improved overall survival, most patients will succumb to late-stage and drug resistant disease. Plasma cell (PC) survival outside of the bone marrow is characteristic of late-stage myeloma and pivotal to disease progression. PCs are typically restricted to the bone marrow microenvironment, as they are dependent on stromal interactions for survival. One such interaction is the engagement of CD28 and its ligand CD86, proteins which are best understood for their roles in T-cell activation by antigen presenting cells. However, myeloma cells can express both CD28 and CD86 on the cell surface. Notably, high CD28 expression is seen in 59% of medullary recurrences, and over 90% of extramedullary relapses. Moreover, high CD86 expression is more common in malignant plasma cells as compared to precursor stages and has a reported role in driving expression of IRF4. We have previously shown that expression of CD28 and CD86 is associated with worse outcomes than that observed in patients with low expression in the MMRF CoMMpass study (NCT01454297). We have also shown that silencing of CD28 or CD86 results in cell death and loss of IRF4 protein expression in human myeloma cell lines (HMCL). We confirmed these studies using CRISPR/Cas9 editing and demonstrated loss of proliferation and induction of cell death in HMCLs. However, the mechanism(s) by which CD28 and CD86 contribute to MM cell survival is not fully understood. Methods: To shed light on the mechanistic basis of CD28 and CD86 in the survival of MM, we used CRISPR/Cas9 editing to disrupt expression from RPMI8226 myeloma cells. We then passaged transduced cells to select for populations that can survive loss of CD28 or CD86. These passaged cells were sorted into populations that either retained CD28 or CD86 expression as transduction controls (High), or populations that underwent CRISPR/Cas9 depletion (Low). Surface expression of CD28 High/Low and CD86 High/Low populations was confirmed via flow cytometry and were then processed for RNA isolation and cDNA library preparation. RNA-sequencing was performed using paired-end sequencing, and data were aligned using the STAR aligner. Differentially expressed genes were determined using edgeR with an FDR ≤ 0.05 and a fold-change ≥ 2.0. Validation of RNA-sequencing results was further assessed via western blot and flow cytometry. Results: Analysis of RNA-sequencing results indicated that 57 genes were differentially expressed between High and Low cells, with 23 genes common to both CD28 and CD86 High/Low comparisons. (FDR<0.05). Notably, our results reveal that loss of CD28 or CD86 is associated with an increase in mRNA expression of Syndecan-2 (SDC2). In addition, our preliminary experiments evaluating SDC2 surface expression via flow cytometry suggest that both CD28 Low and CD86 Low populations have increased expression of SDC2. Additionally, in the RNA-seq analysis we also observed that CD28 Low and CD86 Low cells were also able to sustain mRNA expression of IRF4. This result was later confirmed via western blot, demonstrating CD28 Low and CD86 Low cells sustain protein expression of IRF4. Conclusions: Our results demonstrate that RPMI8226 cells that lack CD28 or CD86 expression have increased mRNA and protein expression of SDC2, a member the heparan sulfate proteoglycan family. Since SDC2 expression has also been associated with a number of cancers including colorectal, lung, and pancreatic cancers, these results provide insight to potential alternative pathways that contribute to myeloma survival independent of CD28 and CD86 signaling. We also confirmed that CD28- and CD86-depleted populations were able to maintain IRF4 mRNA/protein levels. This indicates myeloma cells have mechanisms to sustain IRF4 expression in addition to CD28 and CD86 signaling. These results are also consistent with previous findings illustrating importance of IRF4 in myeloma. Finally, we have developed CRISPR/Cas9-depleted CD28 and CD86 populations in additional HMCLs. We are currently in the process of isolating CD28 High/Low and CD86 High/Low populations for additional analysis and will present these upcoming results.

Differential Diagnosis and Therapeutic Advances in Multiple Myeloma: A Review Article.

Multiple myeloma (MM) is a hematologic malignancy characterized by the abnormal clonal proliferation of plasma cells that may result in focal bone lesions, renal failure, anemia, and/or hypercalcemia. Recently, the diagnosis and treatment of MM have evolved due to a better understanding of disease pathophysiology, improved risk stratification, and new treatments. The incorporation of new drugs, including proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies and high-dose chemotherapy followed by hematopoietic stem cell transplantation, has resulted in a significant improvement in patient outcomes and QoL. In this review, we summarize differential diagnoses and therapeutic advances in MM.

Impact of primary language on health inequities in multiple myeloma.

e18640 Background: Limited English proficiency (LEP) has been shown to exacerbate health inequities in the US due to difficulties navigating a complex health system and assimilating complicated information regarding diagnosis, and treatment. Advances in multiple myeloma (MM) care have improved clinical outcomes but added complexity to diagnosis and treatment. However, there is limited data on whether LEP impacts health inequities in MM care. We sought to assess the impact of primary language on MM care and outcomes at our safety net hospital, serving a culturally and linguistically diverse population where patients have equal access to novel agents and autologous stem cell transplant (SCT). Methods: We retrospectively studied 213 patients with newly diagnosed MM between January 1st, 2000, and December 31st, 2021. Data were extracted from electronic medical records. Patients were classified as LEP or EP based on self-reported language at the time of diagnosis. Patients were subsequently propensity matched based on age, sex, type of insurance, Charlson comorbidity index, creatinine, LDH, year of MM diagnosis, ISS stage, presence of high-risk cytogenetics, and receipt of SCT. Type of insurance was used as a surrogate for socioeconomic status. Kaplan Meier estimate and log rank tests were used to assess overall (OS) and progression free survival (PFS). Results: Of 213 patients, 75 (35.2%) had LEP, 135 (63.4%) were black, 49 (23.0%) were white, 22 (10.3%) patients were of another race, and 7 (3.3%) did not self-identify. Mean age was 63.6 (SD ± 11.4), and 114 (53.5%) patients were male. Median follow-up of the entire cohort was 56.9 months. At baseline, there were no statistically significant differences in the covariates above between LEP and EP patients except for increased incidence of diabetes mellitus in EP patients (84.0% vs. 89.1%, p 0.02). More LEP patients were inpatients at the time of diagnosis compared to EP patients (36.0% [27/ 75] versus 23.9% [33/138]). Median number of hospitalizations and ED visits in the first 6 months of diagnosis were 4 and 3 versus 1 and 2 in LEP versus EP patients, respectively. There were no differences in adjusted PFS or OS between propensity matched LEP and EP patients. Conclusions: In our cohort, there were no significant differences in demographics, clinical parameters, socioeconomic status, or transplant utilization between LEP and EP patients, which allowed us to assess the association of primary language with any observed health inequities. In a setting where all patients have access to novel treatments, SCT, patient navigators, interpreters, and social workers, there were no differences in PFS or OS. However, language barriers may explain health inequities related to later diagnosis and increased healthcare utilization. LEP patients with MM may benefit from additional language-concordant resources to improve disparities.

Partnering With All Patients: Ensuring Shared Decision Making and Evidence-Based Management for Underrepresented Groups With Multiple Myeloma.

Several landmark therapeutic advances in multiple myeloma (MM) have led to an unprecedented number of options available to patients and their physicians as shared decision making is attempted. A myriad of factors need to be considered to ensure that patient-, disease-, and treatment-related factors are addressed to arrive at the most appropriate choice for patients at that time in their journey with myeloma. Some of these factors have traditionally remained underaddressed but have a clear association with patient outcomes, leading to underrepresented groups of patients with MM, including the elderly patients, racial-ethnic minorities, and those with specific advanced comorbidities, for example, renal insufficiency. Some of these factors may not be modifiable, but data suggest that they may give rise to implicit or explicit bias and affect treatment decisions. A growing body of literature is bringing these factors to light. However, their incorporation in day-to-day decision making for patients needs to be universal. It is imperative that prospective data are generated for all these and other underrepresented groups such that evidence-based medicine is applicable universally to all patients with MM, irrespective of clinical and sociodemographic factors.

Lenalidomide Maintenance and Measurable Residual Disease in a Real-World Multiple Myeloma Transplanted Population Receiving Different Treatment Strategies Guided by Access to Novel Drugs in Brazil

Despite recent advances in multiple myeloma (MM), the incorporation of novel agents and measurable residual disease (MRD) monitoring in low-income countries remains a challenge. Although lenalidomide maintenance (M-Len) after autologous stem cell transplantation (ASCT) has been associated with improved outcomes and MRD has refined the prognosis of complete response (CR) cases, until now, there have been no data on the benefits of these approaches in Latin America. Here, we evaluate the benefits of M-Len and MRD using next-generation flow cytometry (NGF-MRD) at Day + 100 post-ASCT (n = 53). After ASCT, responses were evaluated based on the International Myeloma Working Group criteria and NGF-MRD. MRD was positive in 60% of patients with a median progression-free survival (PFS) of 31 months vs. not reached (NR) for MRD-negative cases (p = 0.05). The patients who received M-Len continuously had a significantly better PFS and overall survival (OS) than those without M-Len (median PFS: NR vs. 29 months, p = 0.007), with progression in 11% vs. 54% of cases after a median follow-up of 34 months, respectively. In a multivariate analysis, MRD status and M-Len therapy emerged as independent predictors of PFS (median PFS of M-Len/MRD- vs. no M-Len/MRD+ of NR vs. 35 months, respectively; p = 0.01). In summary, M-Len was associated with improved survival outcomes in our real-world MM cohort in Brazil, with MRD emerging as a useful reproducible tool to identify patients at an earlier risk of relapse. The inequity in drug access remains a hurdle in countries with financial constraints, with a negative impact on MM survival.

The evolving diagnosis and treatment paradigms of multiple myeloma in China: 15 years' experience of 1256 patients in a national medical center.

Significant advances in multiple myeloma (MM) over the past 15 years led to exciting changes in the management of MM patients in China, which in turn brought about the early diagnoses, precise risk stratifications, and improved prognoses. We summarized the dynamic changes in the management of newly diagnosed (ND) MM in a national medical center, crossing the old and novel drug era. Demographics, clinical characteristics, first-line treatment, response rate, and survival were retrospectively collected among NDMMs diagnosed in Zhongshan Hospital Fudan University from January 2007 to October 2021. Of the 1256 individuals, median age was 64 (range 31-89) with 45.1% patients >65 years. About 63.5% were male, 43.1% were at ISS stage III and 9.9% had light-chain amyloidosis. Patients with abnormal ratio of free light chain (80.4%), extramedullary disease (EMD, 22.0%), and high-risk cytogenetic abnormalities (HRCA, 26.8%) were detected by novel detection techniques. The best confirmed ORR was 86.5%, including 39.4% with CR. Short- and long-term PFS and OS rates persistently increased each year along with increasing novel drug applications. Median PFS and OS were 30.9 and 64.7months. Advanced ISS stage, HRCA, light-chain amyloidosis and EMD independently predicted an inferior PFS. First-line ASCT indicated a superior PFS. Advanced ISS stage, elevated serum LDH, HRCA, light-chain amyloidosis, and receiving PI/IMiD-based regimen versus PI+IMiD-based regimen independently indicated a poorer OS. In brief, we illustrated a dynamic landscape of MM patients in a national medical center. Chinese MM patients evidently benefited from newly introduced techniques and drugs in this field.

Delineating CDK9- Regulated Molecular Events for the Development of Rationally Derived Multiple Myeloma Treatment Strategies

Abstract Background: Despite major advances in multiple myeloma (MM) therapy over the last 2 decades, most patients relapse. The identification of novel targets and the development of derived treatment approaches are therefore urgently needed. Aberrant expression of various cyclin-dependent kinases (CDKs) in solid and hematologic malignancies including MM, results in the loss of proliferative control and enhanced survival. The serine-threonine kinase CDK9, a subunit of pTEFb, in particular, is a major transcriptional regulator of numerous oncogenes. Past studies have suggested CDK9 as a potential therapeutic target in MM. However, CDK9-regulated molecular events in MM are only partly understood. By delineating CDK9-dependent pathophysiologic effects, the present study proposes rationally derived anti-CDK9-containing novel MM treatment strategies to improve patient outcome. Methods: Following expression profiling, CRISPR loss-of-function screens and correlation analyses in MM cell line and patient cells, the regulatory impact of CDK9 on downstream target genes was outlined using genomic as well as pharmacological approaches in 2D/3D MM models of the tumor microenvironment. Functionally, CDK9-regulated molecular effects as well as anti-MM activity of anti-CDK9-containing rationally derived treatment combinations were determined by gene arrays, qPCR, flow cytometry, and western blot, proliferation and survival analyses. Results: Strongly suggested by a significant induction of CDK9 mRNA expression levels progressing from normal plasma cells to cells from patients with MGUS, SMM and MM; siRNA and CRISP loss-of-function screens across various MM cell lines verified their dependency on CDK9. Correlative expression levels indicated a functional role of CDK9 (but not for CDK2 and CDK7) on Mcl-1, cMyc, Mdm2, and RNA Pol II, but not other genes (e.g., Bcl-2) in the CCLE as well as CoMMpass and GSE5900/GSE2658 MM patient datasets. Indeed, siRNA-mediated CDK9 silencing decreased protein levels of Mcl-1, cMyc, Mdm2, and RNA Pol II, and consequently tumor cell survival. Similarly, the novel, selective CDK9-directed proteolysis-targeting chimera Thal-sns-032 reduced mRNA/ protein levels of CDK9 as well as of Mcl-1, cMyc, RNA Pol II, and Mdm2, and increased p53 levels in a dose- and time-dependent manner, both in MM cell line and primary cells. In contrast, Thal-sns-032 did not inhibit survival of peripheral blood mononuclear cells (PBMCs) from healthy donors. Furthermore, Thal-sns-032 induced downregulation of CDK9, Mcl-1 and cMyc in MM.1S co-cultured with BMSCs cells. Of note, Thal-sns-032- mediated anti-MM effects were abrogated upon its wash-out. Moreover, knockdown CDK9 by shRNA inhibited proliferation and survival, both in MM tumor cell- and tumor cell/BMSC co-cultures. Rationally derived combination strategies of Thal-sns-032 with venetoclax, navitoclax, Selinexor or Carfilzomib as well as other investigational and established MM therapies induced synergistic anti-MM effects in MM cells or BMSC co-cultures. Conclusion: In summary, by delineating CDK9-regulated molecular events in MM, our studies strongly support the therapeutic role of targeted CDK9-therapy and rationally derived MM combination treatment strategies.

Trends over Time in Overall Survival of Patients with Multiple Myeloma By Race/Ethnicity and By Comorbidity Status: A Surveillance, Epidemiology, and End Results (SEER)-Medicare Analysis

Introduction: New advances in multiple myeloma (MM) treatments have improved overall survival (OS), though there is uncertainty regarding the benefits of these treatments for all patients (pts) with MM. This study assessed OS trends over time in subgroups of pts with MM defined by race/ethnicity and comorbidity status. Methods: Newly diagnosed pts with MM (2007-16) in the US were identified from the SEER-Medicare database. Medicare enrollment on initial diagnosis date was required and pts with other cancers were excluded. Pt characteristics at initial diagnosis and comorbidities during the 6-month baseline period were described for pts with continuous enrollment in the baseline period. OS was described using Kaplan-Meier analysis from initial MM diagnosis to death. Trends in OS over time were evaluated by creating cohorts based on year of diagnosis (2007-09, 2010-12, and 2013-16), and log-rank tests compared OS between the cohorts. All outcomes were described separately for the following race/ethnicity subgroups: non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic (HIS) and for subgroups defined by the presence of diabetes mellitus (DM) or hypertension (HTN), two of the most common comorbidities in pts with MM, in the baseline period. Results: The study included 21,757 pts with MM. Median age at diagnosis was 75 years (range 27-101), 51% of pts were male, and mean Charlson Comorbidity Index (CCI) was 1.2. Overall, 14,077 (64.7%) were NHW, 4078 (18.7%) were NHB, and 2371 (10.9%) were HIS. At baseline, HTN (44.9%), DM (20.4%), renal disease (14.0%), lung disease (13.6%), and heart failure (11.4%) were common comorbidities not related to MM. Monoclonal gammopathy of undetermined significance was identified in 10.0% of pts overall, and in 7.6%, 9.8%, and 11.2% of the NHW, NHB, and HIS cohorts, respectively; 5.5% of pts overall were obese. Median OS was 3.26 years, OS improved significantly over time (P < 0.001 for 2007-09 vs 2010-12, 2007-09 vs 2013-16, 2010-12 vs 2013-16), and median OS increased with each time period (2007-09, 2.78 years; 2010-12, 3.16 years; 2013-16, 3.64 years) (Table 1). The NHW subgroup had a median age of 75 years, 53% male pts, and a mean CCI of 1.1. Trends over time in OS were similar to the overall sample, with P < 0.001 for all-year cohort comparisons and increasing median OS over time. The NHB subgroup had a median age of 73 years, 43% male pts, and a mean CCI of 1.5. Improvements in OS were observed relative to the oldest subgroup (2007-09 vs 2010-12, P < 0.05; 2007-09 vs 2013-16, P < 0.001), but not in the most recent year subgroups (2010-12 vs 2013-16, P = 0.125). The HIS subgroup had a median age of 74 years, 50% male pts, and a mean CCI of 1.4. There was no significant improvement in OS across year cohorts (2007-09 vs 2010-12, P = 0.163; 2007-09 vs 2013-16, P = 0.053; 2010-12 vs 2013-16, P = 0.850), although median OS increased over time (2007-09, 2.92 years; 2010-12, 3.48 years; 2013-16, 3.53 years). Among pts with MM and DM (N = 4410, 20.3%), OS improved over time relative to the oldest cohort (2007-09 vs 2010-12 and 2007-09 vs 2013-16, P < 0.01). No improvement was observed between the most recent cohorts (2010-12 vs 2013-16, P = 0.844) (Table 2). Median OS showed a similar trend (2007-09, 2.44 years; 2010-12, 2.90 years; 2013-16, 2.80 years) and was shorter than the overall population. In the HTN cohort (N = 9646, 44.3%), median OS increased over time (2007-09, 2.58 years; 2010-12: 2.79 years; 2013-16: 3.07 years), but OS showed statistically significant improvements only when comparing the oldest to the most recent cohort (2007-09 vs 2010-12, P = 0.058; 2007-09 vs 2013-16, P < 0.001; 2010-12 vs 2013-16, P = 0.081). Conclusions: Variation in OS trends over time in pts with MM was observed across subgroups. While OS improved significantly across cohorts for NHW and NHB pts, significant improvement was not seen for HIS pts. Comorbidities were common and for pts with HTN and DM, no significant improvement in OS was observed in recent years. Median OS was lower in both comorbidity cohorts compared with the total MM population. Reasons for racial disparities need to be explored further; these differences in outcomes confirm the need for equitable access to effective treatments and tailored treatments for pts with comorbidities. Additional analyses are underway assessing trends over time in gaps in survival between pts with MM and the general population for these subgroups. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A survey on the patient perspective on cure in multiple myeloma

Despite great treatment advances in multiple myeloma, relapses are frequent and the disease remains a considerable source of morbidity and mortality.1 As treatments advance and remission is prolonged, the definition of a cure becomes increasingly relevant. In patients with chronic myeloid leukaemia, the concept of a functional cure was described as patients who had no evidence of disease but remained on therapy indefinitely;2 however, a similar unified definition does not exist for patients with multiple myeloma.

Value in Myeloma Care: Myth or Reality.

Despite tremendous advances in multiple myeloma (MM) care, the disease maintains considerable morbidity and requires long-term treatment associated with significant financial toxicity to patients and high costs to society. In this review, we explore why - despite treatment advances - value in MM treatment is largely a myth, then explain some ways the myth might become a reality. We discuss how value-based care in MM should include patient-centered outcomes such as financial toxicity and quality of life, which are heavily impacted by cost of drugs and the indefinite duration of therapy that is standard in MM treatment. We propose multiple paths to work toward reducing cost and augmenting value of care for patients with MM, including improving access to generic drugs, increasing federal funding for clinical trials, designing more patient-centric clinical trials, and exploring the utilization of minimal residual disease (MRD)-driven treatment de-escalation, among others. We remain optimistic that despite the challenges, we can work toward making progress in the realm of value-based care for patients with MM and make it a reality.

Global Myeloma Trial Participation and Drug Access in the Era of Novel Therapies.

PURPOSEThe globalization of clinical trials has accelerated recent advances in multiple myeloma (MM). However, it is unclear whether trial enrollment locations are reflective of the global burden of MM and whether access to novel therapies is timely and equitable for countries that participate in those trials.METHODSTo assess this, we characterized where MM trials that led to US Food and Drug Administration (FDA) approvals were conducted and determined how often and quickly these drug regimens received approval in their participating trial countries on the basis of country income level and geographic region.RESULTSA systematic review was conducted to identify all MM clinical trials that met their primary endpoint, enrolled patients outside the United States, and resulted in FDA approval from 2005 to 2019. A total of 18 pivotal MM clinical trials were identified. High-income countries enrolled patients in 100% (18/18) of the trials identified, whereas upper-middle and lower-middle-income countries were represented in 61% (11/18) and 28% (5/18) of trials, respectively. No patients from low-income countries were enrolled. One trial enrolled patients in sub-Saharan Africa, and no trials enrolled patients in South Asia/Caribbean. For drugs/regimens that were approved in their participating countries, the median time from FDA approval to approval was 10.9 months. There were no drugs approved in lower-middle-income trial countries. MM trials leading to FDA approval are generally run in high-income, European, and Central Asian countries.CONCLUSIONThere are substantial disparities in where novel therapies are evaluated and where they are ultimately approved for use on the basis of income level and geography.

Research Advances in Multiple Myeloma with Chromosome 1q21 Amplification

Multiple myeloma (MM) is a kind of hematologic malignancy occurring in plasma cells. Cytogenetic technique plays an important role in risk stratification of MM. 1q21 amplification is one of the common chromosomal abnormalities in MM. Studies have shown that 1q21 amplification is associated with poor prognosis in MM patients. At present, with the development of new drugs, cellular immunotherapy, and improvement of hematopoietic stem cell transplantation technology, the remission depth and survival time of MM significantly increased. Rapid and accurate identification of high-risk patients and individualized treatment according to the patient's condition is the key to improve the therapeutic effect of MM. This article reviews the mechanism of 1q21 amplification in MM and the efficacy of new drugs in the treatment of MM with 1q21 chromosome amplification.

Plasma cell leukemia: Retrospective review of cases at Monter Cancer Center/Northwell Health Cancer Institute, 2014-2019

Plasma cell leukemia (PCL) is an aggressive malignancy and an area of unmet need. The diagnostic criteria for PCL are in flux and the molecular basis of disease is complex. Due to its fulminant course and lack of prospective clinical trials in PCL, the optimal therapeutic approach remains controversial. “Novel therapy” in this manuscript refers to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). “Newer agents” refers to currently approved and investigational targeted therapies such as monoclonal antibodies (mAbs), example daratumumab (Dara), bi- or tri-specific antibodies, and antibody-drug conjugate therapies (ADCs). Novel therapy and use of newer agents borrowed from treatment advances in multiple myeloma (MM), is impacting PCL outcomes. Therefore, it is crucial to analyze effects of newer agents on PCL survival with respect to disease characteristics and specific treatment regimens used. In this retrospective study, we report outcomes of eight cases of PCL, primary and secondary, the prognostic factors in each case and the impact of different treatment regimens on overall survival (OS).

POSB392 Understanding the Secondary Care Characteristics and Pathways of Multiple Myeloma Patients Who Reach Second-Line Therapy Using the Hospital Episode Statistics (HES) Database

Despite recent advances in Multiple Myeloma (MM) treatment there is little data describing pathway and resource impact. The Objectives: of this study were to understand the demographics, clinical characteristics, and secondary care burden for MM patients up to and including second-line (2L) therapy.

Delineating CDK9 Regulated Molecular Events for the Development of Rationally Derived Multiple Myeloma Treatment Strategies

Background: Despite major advances in multiple myeloma (MM) therapy over the last 2 decades, most patients relapse. The identification of novel targets and the development of derived treatment approaches are therefore urgently needed. Aberrant expression of various cyclin-dependent kinases (CDKs) in solid and hematologic malignancies including MM, results in the loss of proliferative control and enhanced survival. The serine-threonine kinase CDK9, a subunit of pTEFb, in particular, is a major transcriptional regulator of numerous oncogenes. Past studies have suggested CDK9 as a potential therapeutic target in MM. However, CDK9-regulated molecular events in MM are only partly understood. By delineating CDK9-dependent pathophysiologic effects, the present study proposes rationally derived anti-CDK9-containing novel MM treatment strategies to improve patient outcome.Methods: Following expression profiling, CRISPR loss-of-function screens and correlation analyses in MM cell line and patient cells, the regulatory impact of CDK9 on downstream target genes was outlined using genomic as well as pharmacological approaches in 2D/3D MM models of the tumor microenvironment. Functionally, CDK9-regulated molecular effects as well as anti-MM activity of anti-CDK9-containing rationally derived treatment combinations were determined by gene arrays, qPCR, flow cytometry, and western blot, proliferation and survival analyses.Results: Strongly suggested by a significant induction of CDK9 mRNA expression levels progressing from normal plasma cells to cells from patients with MGUS, SMM and MM; siRNA and CRISP loss-of-function screens across various MM cell lines verified their dependency on CDK9. Correlative expression levels indicated a functional role of CDK9 (but not for CDK2 and CDK7) on Mcl-1, cMyc, Mdm2, RNA Pol II, and IRF4, but not other genes (e.g. Bcl-2) in the CCLE as well as CoMMpass and GSE5900/GSE2658 MM patient datasets. Indeed, siRNA-mediated CDK9 silencing decreased protein levels of Mcl-1, cMyc, Mdm2, RNA Pol II, and IRF4, and consequently tumor cell survival. Similarly, the novel, selective CDK9-directed proteolysis-targeting chimera Thal-sns-032 induced a reduction of mRNA/ protein levels of Mcl-1, cMyc, RNA Pol II, but not of other potential targets (e.g. Bcl-2) in a dose- and time-dependent manner. Moreover, Thal-sns-032 reduced Mdm2 and thereby increased p53 protein levels. Consequently, Thal-sns-032 inhibited tumor cell proliferation and survival both in tumor cell- and tumor cell:BMSC co- cultures. Rationally, derived combination strategies of Thal-sns-032 for example with venetoclax, but also other investigational and established MM therapies induced synergistic anti-MM effects within the tumor microenvironment.Conclusion: In summary, by delineating CDK9-regulated molecular events in MM, our studies strongly support the therapeutic role of targeted CDK9-therapy and rationally derive MM combination treatment strategies. DisclosuresVallet: Pfizer: Honoraria; MSD: Honoraria; Roche Pharmaceuticals: Consultancy. Podar: Celgene: Consultancy, Honoraria; Amgen Inc.: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Roche Pharmaceuticals: Research Funding.