Prognostic Factor In Multiple Myeloma Research Articles

Reduction rate of monoclonal protein as a useful prognostic factor in standard-risk group of newly diagnosed multiple myeloma.

Multiple myeloma (MM) is a common hematologic malignancy that originates from a malignant clone of plasma cells. Solitary plasmacytoma, history of diabetes, and platelet count are considered as prognostic factors for MM. But some patients are still associated with much worse outcomes without any prognostic predictors. This study aimed to observe the reduction rate of monoclonal protein (M protein) after the first and fourth chemotherapy cycles, which is considered as a new prognostic factor for progression-free survival (PFS) in standard-risk group of newly diagnosed MM patients. To investigate the reduction rate of M protein after first and fourth cycle chemotherapy as a useful prognostic factor. A total of 316 patients diagnosed with MM for the first time between 2010 and 2019 at the Lishui Municipal Central Hospital were included. All patients were diagnosed according to the National Comprehensive Cancer Network (NCCN) 2020.V1 diagnostic criteria. The risk assessment was performed by the Mayo Stratification for Macroglobulinemia and Risk-Adapted Therapy guidelines. After diagnosis, 164 patients were evaluated and underwent treatment with four to eight courses of continuous induction chemotherapy. The patients with no response after induction treatment were administered additional therapy following the NCCN 2020.V1 criteria. The following baseline data from the patients were collected: Gender, age at diagnosis, Durie-Salmon stage, glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, catabolite activator protein, albumin/globulin ratio, lactate dehydrogenase, translocation (t)(6;14), t(11;14), maintenance regimen, total cholesterol (TC), triglyceride, and phosphorous. All baseline data and the reduction rate of M protein after each chemotherapy cycle from the first to fourth were assessed by univariate analysis. The factors influencing the overall survival and PFS were then assessed by multivariate analysis. We found the first cycle (C1) reduction rate and the fourth cycle (C4) reduction rate as predictors of PFS. Then, PFS was compared between patients with a C1 reduction rate of M protein of ≥ 25% vs < 25% and ≥ 50% vs < 50%, and between patients with a C4 reduction rate of ≥ 25% vs < 25%, ≥ 50% vs < 50%, and ≥ 75% vs < 75%. Multivariate analysis revealed age [hazard ratio (HR): 1.059, 95% confidence interval (95%CI): 1.033-1.085, P ≤ 0.001], International Staging System stage (HR: 2.136, 95%CI: 1.500-3.041, P ≤ 0.001), autotransplantion (HR: 0.201, 95%CI: 0.069-0.583, P = 0.019), TC (HR: 0.689, 95%CI: 0.533-0.891, P = 0.019), C1 reduction rate (HR: 0474, 95%CI: 0.293-0.767, P = 0.019), and C4 reduction rate (HR: 0.254, 95%CI: 0.139-0.463, P = 0.019) as predictors of PFS. The Kaplan-Meier survival analysis and the log-rank tests revealed that a higher reduction rate of M protein after first cycle (≥ 50%) and fourth cycle (≥ 75%) chemotherapy was associated with a longer PFS than the lower one. Higher reduction rates of M protein after the first and fourth chemotherapy cycles can act as advantageous prognostic factors for PFS in standard-risk group of MM patients during initial diagnosis.

The diagnostic and prognostic value of haematologic parameters in multiple myeloma patients

ABSTRACTObjectivesMultiple myeloma (MM) is a malignant disease characterized by a single clonal proliferation of B cell-derived plasma cells in the bone marrow. It is the second most common haematologic malignancy in adults. The objective of this retrospective study is to evaluate the diagnostic and prognostic value of haematologic parameters in MM.MethodsThe difference of NLR/ALB ratio (NAR) and NLR/HDL-C ratio (NHR) between the 151 newly diagnosed MM patients and 153 healthy controls was compared. According to NAR and NHR cutoff values obtained from the ROC curve, MM patients were divided into low group and high group. The differences in hematological parameters and survival time between the two groups were compared. Independent prognostic analysis was performed using Cox proportional hazard regression model.ResultsThe NAR and NHR values in MM group were significantly higher than those in control group (P < 0.001). Higher NAR levels were significantly associated with lower albumin (ALB), higher β2 microglobulin(β2-MG), higher creatinine (Crea), and highe ISS stage (All P<0.05). High NHR group was significantly correlated with age , β2-MG and ISS stage (All P<0.05). In high NAR or NHR groups, OS and DFS was significantly shortened and the prognosis was poor (P < 0.05). Multivariate analysis showed that PLT, ISS stage and NAR were independent prognostic indicators of OS in MM patients, while ALB, PLT and NAR were independent prognostic factors of DFS.ConclusionNAR and NHR are inexpensive, readily available diagnostic indicators for MM, and NAR is an independent prognostic factor for MM.

Response-Adapted Therapy for Newly Diagnosed Multiple Myeloma.

The development of potent novel agents has improved outcomes for patients with multiple myeloma (MM). Heterogeneity of response to therapy, an expanding arsenal of treatment options, and cost are however major challenges for physicians making treatment decisions. Response-adapted therapy is hence an attractive strategy for sequencing of therapy in MM. Despite its successful application in other haematologic malignancies, response-adapted therapy is yet to become a standard of care for MM. We provide our perspective on response-adapted therapeutic strategies evaluated thus far and how they may be implemented and improved on in treatment algorithms of the future. While older studies suggested that early response based on International Myeloma Working Group response criteria could impact long-term outcomes, recent data have contradicted these findings. The advent of minimal residual disease (MRD) as a powerful prognostic factor in MM has raised the promise of MRD-adapted treatment strategies. The development of more sensitive techniques for paraprotein quantification as well as imaging modalities to detect extramedullary disease is likely to change response assessment in MM. These techniques combined with MRD assessment may provide sensitive and holistic response assessments which could be evaluated in clinical trials. Response-adapted treatment algorithms have the potential to allow an individualised treatment strategy, maximising efficacy, while minimising toxicities and cost. Standardisation of MRD methodology, incorporation of imaging into response assessment, and the optimal management of MRD positive patients are key questions to be addressed in future trials.

Red cell distribution width, neutrophil lymphocyte ratio and interleukin 10 are good prognostic markers in multiple myeloma.

Multiple myeloma (MM) is still an incurable disease so we need to continue developing new diagnostic and prognostic options for its management. There are multiple prognostic factors for MM, but most of them are costly and time consuming. Hence comes the urge to identify bed side and low cost prognostic tools, that is why this study was aiming to identify in Egyptian MM patients. The study was carried on 60 newly diagnosed multiple myeloma patients and 20 age and sex matched healthy individuals as controls. Studied subjects were subdivided into two groups: Group I: 60 multiple myeloma patients which were subdivided into three subgroups: Stage I: 10 patients, Stage II: 17 patients, Stage III: 33 patients, Group II: 20 healthy controls. A progressive significant increase in IL-10, RDW, NLR, and beta2 microglobulin (β2M) with disease progression from stage I towards stage III as compared to the control group. However, IL-10, RDW, and NLR have the best prognostic efficiency value regarding to sensitivity, specificity and positive predictive value when compared with β2M. IL-10, RDW, and NLR are simple, easy and bedside tests (in the case of RDW, and NLR). They have high sensitivity and specificity when compared to β2M, which is a well-established prognostic factor that highlights the valuable role they play as prognostic markers in MM.

Increased Expression of SRSF1 Predicts Poor Prognosis in Multiple Myeloma.

Multiple myeloma (MM) is a clonal plasma cell disorder which still lacks sufficient prognostic factors. The serine/arginine-rich splicing factor (SRSF) family serves as an important splicing regulator in organ development. Among all members, SRSF1 plays an important role in cell proliferation and renewal. However, the role of SRSF1 in MM is still unknown. SRSF1 was selected from the primary bioinformatics analysis of SRSF family members, and then we integrated 11 independent datasets and analyzed the relationship between SRSF1 expression and MM clinical characteristics. Gene set enrichment analysis (GSEA) was conducted to explore the potential mechanism of SRSF1 in MM progression. ImmuCellAI was used to estimate the abundance of immune infiltrating cells between the SRSF1high and SRSF1low groups. The ESTIMATE algorithm was used to evaluate the tumor microenvironment in MM. The expression of immune-related genes was compared between the groups. Additionally, SRSF1 expression was validated in clinical samples. SRSF1 knockdown was conducted to explore the role of SRSF1 in MM development. SRSF1 expression showed an increasing trend with the progression of myeloma. Besides, SRSF1 expression increased as the age, ISS stage, 1q21 amplification level, and relapse times increased. MM patients with higher SRSF1 expression had worse clinical features and poorer outcomes. Univariate and multivariate analysis indicated that upregulated SRSF1 expression was an independent poor prognostic factor for MM. Enrichment pathway analysis confirmed that SRSF1 takes part in the myeloma progression via tumor-associated and immune-related pathways. Several checkpoints and immune-activating genes were significantly downregulated in the SRSF1high groups. Furthermore, we detected that SRSF1 expression was significantly higher in MM patients than that in control donors. SRSF1 knockdown resulted in proliferation arrest in MM cell lines. The expression value of SRSF1 is positively associated with myeloma progression, and high SRSF1 expression might be a poor prognostic biomarker in MM patients.

CT-defined body composition as a prognostic factor in multiple myeloma

ABSTRACTObjectivesBody composition assessment is comprised by skeletal muscle mass (SMM) and subcutaneous and visceral adipose tissue (SAT and VAT) and can be quantified by imaging. It can be predictive of several clinically outcomes in patients with hematological diseases. Our aim was to establish the effect of body composition parameters on overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma (MM).Materials and methodsAll patients with MM were retrospectively analyzed between 2009 and 2019. One hundred twenty-three patients were included into the analysis. Whole-body computed tomography (CT) was used to calculate SMM, VAT, and SAT.ResultsOverall, 22 patients (17.9%) of the patient sample died. Forty patients were sarcopenic (32.5%), 79 patients were visceral obese (64.2%), and 18 patients (14.6%) were sarcopenic obese. Parameter of body composition did not influence OS: sarcopenia, hazard ratio (HR) = 1.3 (95% CI 0.50–3.34), p = .59; visceral obesity, HR = 1.6 (95% CI 0.70–3.76), p = .26; sarcopenic obesity, HR = 2.3 (95% CI 0.90–5.63), p = 0.08. Patients with infectious complications showed higher VAT values.ConclusionsCT-defined body composition parameters have no influence on survival in patients with MM undergoing autologous stem-cell therapy. These results corroborate previous smaller studies that body composition might have a limited role in this tumor entity. VAT may predict the occurrence of infectious complications.

The Relationship of CCL5 and CCR1 Variants with Response Rate and Survival Taking into Account Thalidomide/Bortezomib Treatment in Patients with Multiple Myeloma.

(1) Background: Chemokines and chemokine receptors play an important role in tumor development. The aim of this study was to check the significance of CCL5 and CCR1 variants with response rate, survival, and the level of regulated on activation, normal T cells expressed and secreted (RANTES/CCL5) in multiple myeloma (MM) patients; (2) Methods: Genomic DNA from 101 newly diagnosed MM patients and 100 healthy blood donors were analyzed by Real-time PCR method (for CCL5 and CCR1 genotyping). In a subgroup of 70 MM patients, serum samples were collected to determine the level of RANTES; (3) Results: multivariate Cox regression showed increased risk of disease relapse or progression (HR = 4.77; p = 0.01) in MM patients with CG + CC genotypes of CCL5 rs2280788. In contrast, CT + TT genotypes of CCL5 rs2107538 were associated withdecreased risk of death (HR = 0.18; p = 0.028) and disease relapse or progression (HR = 0.26; p = 0.01). In MM patients with major genotypes of rs2280789, rs2280788, and rs2107538, higher survival rates were observed in response to treatment with thalidomide and bortezomib. Statistically significant lower RANTES levels were seen in minor genotypes and heterozygotes of CCL5 and CCR1 variants; (4) Conclusions: Major genotypes of CCL5 variants may be independent positive prognostic factors in MM.

Mutation Profile of Normal and Tumor Cells in a Patient with Multiple Myeloma: A Case Report

This paper is a case report of a patient with newly diagnosed multiple myeloma (MM) who underwent exome sequencing of peripheral blood lymphocytes and CD138+ tumor plasma cells prior to therapy. This patient showed some inherited genetic variants which are associated with underlying risk for MM. This patient’s genotype was reported to have some variants in the DNA repair genes, including inherited mutations in the RFDW3 and TP53 genes. They are involved in the maintenance of genome stability and accumulation rate of somatic mutations, including structural rearrangements and chromosome aberrations. A large number of structural variations&#x0D; and mutational signature ID6 in the tumor genetic material point to the disruption of DNA damage repair. The tumor cell exome analysis yielded a profile of somatic mutations, also the mutations in the genes previously associated with MM, as well as a functional significance of the detected abnormalities. Somatic mutations also included damaging mutations and highly significant mutations in the other tumor-associated genes, such as ASCC3, TET3, and CHD1, as well as in the antimicrobial peptide-coding genes CAMP and HTN3. With the exception of an extra copy of 1q arm in the tumor plasma cell genome, the patient showed no genetic risk factors associated with poor prognosis of the disease. Based on literature, inherited (ABCB1 mutations) and somatic (trisomy 3) variations detected in the patient’s genetic material can be characterized as positive prognostic factors in MM.

BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma.

BRD9 is a defining component of the noncanonical SWI/SNF complex, which regulates gene expression by controlling chromatin dynamics. Although recent studies have found an oncogenic role for BRD9 in multiple cancer types including multiple myeloma, its clinical significance and oncogenic mechanism have not yet been elucidated. Here, we sought to identify the clinical and biological impact of BRD9 in multiple myeloma, which may contribute to the development of novel therapeutic strategies. We performed integrated analyses of BRD9 in vitro and in vivo using multiple myeloma cell lines and primary multiple myeloma cells in established preclinical models, which identified the molecular functions of BRD9 contributing to multiple myeloma cell survival. We found that high BRD9 expression was a poor prognostic factor in multiple myeloma. Depleting BRD9 by genetic (shRNA) and pharmacologic (dBRD9-A; proteolysis-targeting chimera; BRD9 degrader) approaches downregulated ribosome biogenesis genes, decreased the expression of the master regulator MYC, and disrupted the protein-synthesis maintenance machinery, thereby inhibiting multiple myeloma cell growth in vitro and in vivo in preclinical models. Importantly, we identified that the expression of ribosome biogenesis genes was associated with the disease progression and prognosis of patients with multiple myeloma. Our results suggest that BRD9 promotes gene expression by predominantly occupying the promoter regions of ribosome biogenesis genes and cooperating with BRD4 to enhance the transcriptional function of MYC. Our study identifies and validates BRD9 as a novel therapeutic target in preclinical models of multiple myeloma, which provides the framework for the clinical evaluation of BRD9 degraders to improve patient outcome.

Biallelic deletion of 1p32 defines ultra-high-risk myeloma, but monoallelic del(1p32) remains a strong prognostic factor

AbstractCytogenetic abnormalities (CAs) are known to be the preponderant prognostic factor in multiple myeloma. Our team has recently developed a prognostic score based on 6 CAs, with which del(1p32) appears to be the second worst abnormality after del(17p). This study aimed to confirm the adverse effect of 1p32 deletion in patients with newly diagnosed multiple myeloma (NDMM). Among 2551 patients with newly diagnosed multiple myeloma, 11% were harboring del(1p32). Their overall survival (OS) was significantly inferior compared with patients without del(1p32) (median OS: 49 months vs 124 months). Likewise, progression-free survival was significantly shorter. More importantly, biallelic del(1p32) conferred a dramatically poorer prognosis than a monoallelic del(1p32) (median OS: 25 months vs 60 months). As expected, the OS of patients with del(1p32) significantly decreased when this abnormality was associated with other high-risk CAs [del(17p), t(4;14), or gain(1q)]. In the multivariate analysis, del(1p32) appeared as a negative prognostic factor; after adjustment for age and treatment, the risk of progression was 1.3 times higher among patients harboring del(1p32), and the risk of death was 1.9 times higher. At the dawn of risk-adapted treatment strategies, we have confirmed the adverse effect of del(1p32) in multiple myeloma and the relevance of its assessment at diagnosis.

Clonotypic Mass Spectrometry with Easym Assay for Detection of Measurable Residual Disease in Multiple Myeloma

The presence of measurable residual disease (MRD) is an important prognostic factor for multiple myeloma. However, MRD tests in current clinical use require bone marrow (BM) samples that are uncomfortable, expensive, and time-consuming for patients. BM-based assays are also limited by sampling of a single location within the marrow, which may not accurately represent overall disease burden. Consequently, there is an urgent unmet need for peripheral blood-based MRD testing that would allow for convenient, repeated assessment of MRD. M-protein quantification using mass spectrometry (MS) is promising candidate methodology for peripheral blood MRD monitoring due to its exceptional analytical sensitivity. Specifically, "clonotypic" MS techniques can identify and track a specific M-protein "peptide fingerprint", allowing sensitive and specific measurement of MRD that may exceed BM-based techniques. However, clinical data regarding this approach is limited and no clonotypic MS assays are currently in clinical practice. Consequently, we performed a pilot study to assess the use of clonotypic MS-based MRD testing using the EasyM system (Rapid Novor, Kitchener, ON). We retrospectively identified a subset of patients in our institutional tissue bank who met the following criteria: 1) IgG multiple myeloma, 2) M-protein ≥0.5 g/dL by serum protein electrophoresis (SPEP) at diagnosis, and 3) adequate samples for analysis. Baseline and follow up serum samples were analyzed by the study sponsor in a blinded fashion. EasyM results were subsequently compared to SPEP and, when available, next generation sequencing MRD testing with the clonoSeq assay (Adaptive, Seattle, WA). We used receiver-operator curve analysis to identify cutoffs for percent reduction in EasyM to predict BM-based MRD using the R package "cutpointr". 19 patients were identified for analysis. Median age was 62 and 52% were male. All patients received proteasome inhibitor-based induction and 17 patients received lenalidomide. All underwent autologous stem cell transplant (ASCT) in first remission. A clonotypic signature was identified in all 19 patients from the baseline sample. 54 follow up samples were analyzed. Percent change in EasyM and SPEP were well correlated (Pearson R = 0.808; p < 0.01). 37 timepoints had MRD testing available. Of these, 14 and 9 timepoints were negative at 10-5 and 10-6, respectively; only 3 (8%) had undetectable M-protein by EasyM, all MRD negative at 10-6. Using receiver-operator curve analysis, we identified optimal cutoffs for percent reduction in EasyM by area under the curve for BM-based MRD at 10-5 (99.0%) and 10-6 (99.3%) thresholds. The PPV and NPV for EasyM at 10-5 were 91% and 80%. The PPV and NPV for EasyM at 10-6 were 92% and 58%. Given the half-life of IgG (2 - 3 weeks), we also performed an exploratory analysis for MRD at 10-5 separating day 100 samples (n = 18) from later samples (n = 18). This analysis yielded slightly different optimal cutoffs for percent reduction by EasyM for day 100 (98.2%) versus later timepoints (99.4%), with similar PPV (91% and 92%) and improved NPV (100% for both), suggesting time of sample collection may impact the predictive value of EasyM. At day 100 after ASCT, 7 patients were in CR, 9 in VGPR and 3 in PR. 7 patients progressed during the follow up period. One patient had undetectable EasyM at day 100 after ASCT and received only 4 months of post-ASCT lenalidomide, but remains in CR over 3 years after transplant. Two patients achieved undetectable EasyM at 9 and 55 months, respectively, post-ASCT and remain in CR at 52 and 64 months. Our study provides initial data regarding clonotypic MS with the EasyM assay for peripheral blood MRD testing. We demonstrated excellent correlation between percent reduction in M-protein by SPEP and EasyM. Interestingly, 79% of samples that were MRD negative at 10-5 by clonoSeq had detectable M-protein by clonotypic MS, suggesting EasyM may be a more sensitive test for residual disease. After optimization, EasyM showed excellent PPV and NPV for BM-based MRD negativity, suggesting clonotypic MS be able to identify patients who can forego a bone marrow biopsy for MRD monitoring. We are currently validating this assay in non-IgG isotypes and light chain disease. Overall, clonotypic MS represents a promising new tool for myeloma monitoring and should be performed in larger retrospective cohorts and integrated into prospective trials for further validation.

Recovery of Uninvolved Heavy/Light Chain Pair Immunoparesis during Maintenance Is an Independent Prognostic Factor for Multiple Myeloma and Could Complement Prognosis Value of Minimal Residual Disease

Recovery of Uninvolved Heavy/Light Chain Pair Immunoparesis during Maintenance Is an Independent Prognostic Factor for Multiple Myeloma and Could Complement Prognosis Value of Minimal Residual Disease

Time to first treatment is an independent prognostic factor for Multiple Myeloma (MM)

IntroductionMultiple myeloma (MM) is an incurable plasma cell neoplasm. In this study, we aimed to analyze the impact of time to initiation of systemic therapy for MM on overall survival (OS). MethodsWe identified cases diagnosed with MM from the National Cancer Database from 2004 to 2013. ResultsA total of 38,178 MM patients were included in the analysis. The median time to systemic therapy in our cohort was 17 days (range 0–120). The median OS for patients who initiated therapy > 30-days after diagnosis was longer than those who received it ≤ 7 days (46 vs. 27-month, p < 0.001). On multivariable analysis, patients who received treatment ≤ 7 days from diagnosis had worse mortality compared with those receiving treatment > 30 days (HR 1.5; 95% CI 1.4–1.6). ConclusionsIn our study, time to initiation of systemic therapy was an independent prognostic factor in MM. Similar to other lymphoid malignancies, this metric may be a surrogate for high-risk disease in MM, and future trials may need to investigate time-to-treatment as a factor to allow enrollment of potentially sick patients.

Minimal residual disease detection by next-generation sequencing in multiple myeloma: Promise and challenges for response-adapted therapy.

Assessment of minimal residual disease (MRD) is becoming a standard diagnostic tool for curable hematological malignancies such as chronic and acute myeloid leukemia. Multiple myeloma (MM) remains an incurable disease, as a major portion of patients even in complete response eventually relapse, suggesting that residual disease remains. Over the past decade, the treatment landscape of MM has radically changed with the introduction of new effective drugs and the availability of immunotherapy, including targeted antibodies and adoptive cell therapy. Therefore, conventional serological and morphological techniques have become suboptimal for the evaluation of depth of response. Recently, the International Myeloma Working Group (IMWG) introduced the definition of MRD negativity as the absence of clonal Plasma cells (PC) with a minimum sensitivity of <10−5 either by next-generation sequencing (NGS) using the LymphoSIGHT platform (Sequenta/Adaptative) or by next-generation flow cytometry (NGF) using EuroFlow approaches as the reference methods. While the definition of the LymphoSIGHT platform (Sequenta/Adaptive) as the standard method derives from its large use and validation in clinical studies on the prognostic value of NGS-based MRD, other commercially available options exist. Recently, the LymphoTrack assay has been evaluated in MM, demonstrating a sensitivity level of 10−5, hence qualifying as an alternative effective tool for MRD monitoring in MM. Here, we will review state-of-the-art methods for MRD assessment by NGS. We will summarize how MRD testing supports clinical trials as a useful tool in dynamic risk-adapted therapy. Finally, we will also discuss future promise and challenges of NGS-based MRD determination for clinical decision-making. In addition, we will present our real-life single-center experience with the commercially available NGS strategy LymphoTrack-MiSeq. Even with the limitation of a limited number of patients, our results confirm the LymphoTrack-MiSeq platform as a cost-effective, readily available, and standardized workflow with a sensitivity of 10−5. Our real-life data also confirm that achieving MRD negativity is an important prognostic factor in MM.

CD43 is an adverse prognostic factor in newly diagnosed multiple myeloma

Currently, the expression pattern and prognostic value of CD43 expression in multiple myeloma (MM) remain unknown. 109 newly diagnosed MM patients were recruited and CD43 expression was determined by multiparameter flow cytometry, of which 77 (70.6%) were CD43 positive. Patients with positive CD43 expression were more likely to present with, hemoglobin < 85 g/L (p = 0.008), International Staging System (ISS) stage III (p = 0.044), 13q14 deletion (p = 0.034) and more monoclonal plasma cells (p = 0.003). Patients with CD43 positive had significantly poor treatment response (p = 0.021), progression-free survival (PFS) (p = 0.012), and overall survival (OS) (p = 0.023) than those without CD43. The poorer prognosis of CD43-positive patients was retained in multivariate analysis (p = 0.005 for PFS; p = 0.013 for OS). Our study indicated that CD43 was an independent adverse prognostic factor in multiple myeloma.

The association between minimal residual disease status and survival outcomes in transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM) patients: Systematic review.

e20009 Background: Despite expanding therapeutic armamentarium of multiple myeloma (MM), it remains an incurable disease. Therefore, there is a need to assess the impact of deeper hematological responses to better gauge treatments in clinical trials and routine practice. The presence of minimal residual disease (MRD), is becoming crucial and a new standard in monitoring remission status. Clinical evidence shows that MRD status after treatment is an independent prognostic factor for MM. This review summarizes current data on MRD status and its role in predicting progression-free survival (PFS) and overall survival (OS) outcomes. Methods: We performed a literature search on four databases (PubMed, Embase, Cochrane, and Web of Science) following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. We screened 1307 studies using the Mesh terms “Multiple Myeloma and Minimal Residual disease.” After excluding review, duplicate, and non-relevant articles, 7 studies were included. Results: The association between MRD status and outcomes, including survival in TIE-NDMM patients was assessed in 7 studies, including 1083 patients. MRD status was determined using different techniques, such as flow cytometry and clonoSEQ. Different regimens were used in all studies. PFS was reported in all studies. Compared with MRD positive status, achieving MRD negativity improved PFS to 58 months versus 28.65 months as per cumulative analysis. The cumulative OS reported in 2 studies (n=196) was 95.85% in MRD-negative patients compared to 55.65% in MRD positive patients. Conclusions: Further clinical data focusing on post-treatment assessment of MRD will be useful in clinical decision-making and could be practice changing. MRD status may serve as surrogate end-points for PFS and OS in ongoing and future clinical trials. Achieving durable MRD negativity with PFS improvement might also increase the time between treatment relapses for MM and might help switch to a lesser aggressive regimen, chemotherapy-free period, avoiding drug toxicity. [Table: see text]

CD24 Is a Prognostic Marker for Multiple Myeloma Progression and Survival.

Surface antigens are commonly used in flow cytometry assays for the diagnosis of multiple myeloma (MM). Some of these are directly involved in MM pathogenesis or interactions with the microenvironment, but most are used for either diagnostic or prognostic purposes. In a previous study, we showed that in-vitro, CD24-positive plasma cells exhibit a less tumorigenic phenotype. Here, we assessed the prognostic importance of CD24 expression in patients newly diagnosed with MM as it correlates to their clinical course. Immunophenotyping by flow cytometry of 124 patients uniformly treated by a bortezomib-based protocol was performed. The expression of CD24, CD117, CD19, CD45, and CD56 in bone marrow PCs was tested for correlations to clinical parameters. None of the CD markers correlated with the response rates to first-line therapy. However, patients with elevated CD24+ expression on their PCs at diagnosis had a significantly longer PFS (p = 0.002) and OS (p = 0.044). In contrast, the expression of CD117, CD56, or CD45 was found to have no prognostic value; CD19 expression was inversely correlated with PFS alone (p < 0.001) and not with OS. Thus, elevated CD24 expression on PCs appears to be strongly correlated with survival and can be used as a single-surface antigenic prognostic factor in MM.

Serum Abnormal Metabolites for Evaluating Therapeutic Response and Prognosis of Patients With Multiple Myeloma.

AimsTo evaluate abnormal metabolites related to treatment response and prognosis of multiple myeloma (MM) patients through ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS).MethodsForty-six symptomatic MM patients were included in this study who had a prior high level of positive monoclonal proteins before receiving targeted therapy with bortezomib-based regimens. UPLC-MS along with traditional immunofixation was performed on MM diagnostic samples and effective serum samples, and UPLC-MS was used to target valuable metabolic markers related to M protein.MM patients were segregated into pre-therapy (pre-T) and post-therapy (post-T) groups according to the response after chemotherapy. A monoclonal protein could be detected at baseline in 33 newly diagnosed MM (NDMM), 13 refractory and relapsed MM (RRMM) patients and 20 healthy controls (HC) by immunofixation.ResultsBetween pre-T and post-T patients, the data showed that 32, 28 and 3 different metabolites were significantly correlated with M protein in IgG, IgA and light chain-type MM, respectively. These identified metabolites were significantly enriched in arginine and proline metabolism as well as glycerophospholipid metabolism pathways. Among them, PC (19:0/22:2) was displayed to increase significantly and consistently with M protein in each subtype of MM after treatment, which obviously indicated that it was related to the treatment response of MM. Further survival analysis of metabolic markers found that aspartic acid, LysoPE (16:0), SM (d18:1/17:0), PC (18:0/24:1), PC (16:0/16:0), TG (18:1/18:1/22:5) and LysoPE (18:2) reaching a certain cutoff value may be associated with shorter progression free survival (PFS). Finally, Cox multivariate regression analysis identified three factors were independent prognostic factors of MM. Moreover, there were significantly different in PC (19:0/22:2) and in aspartic acid between MM patients and healthy people.ConclusionThis work identified significant metabolic disorders in 46 pairs off pre- and post-therapy MM patients, specifically in arginine, proline and glycerophospholipid pathways. The abnormal metabolites have the potential to serve as new biomarkers for evaluating treatment response and prognosis, as well as early monitoring of disease activity. Therefore, these systematic studies on abnormal metabolites as biomarkers for diagnosis and treatment will provide the evidence for future precise treatment of MM.

ALCAM regulates multiple myeloma chemoresistant side population

Drug-resistance is a major problem preventing a cure in patients with multiple myeloma (MM). Previously, we demonstrated that activated-leukocyte-cell-adhesion-molecule (ALCAM) is a prognostic factor in MM and inhibits EGF/EGFR-initiated MM clonogenicity. In this study, we further showed that the ALCAM-EGF/EGFR axis regulated the MM side population (SP)-mediated drug-resistance. ALCAM-knockdown MM cells displayed an enhanced ratio of SP cells in the presence of bone marrow stromal cells (BMSCs) or with the supplement of recombinant EGF. SP MM cells were resistant to chemotherapeutics melphalan or bortezomib. Drug treatment stimulated SP-genesis. Mechanistically, EGFR, primed with EGF, activated the hedgehog pathway and promoted the SP ratio; meanwhile, ALCAM inhibited EGFR downstream pro-MM cell signaling. Further, SP MM cells exhibited an increased number of mitochondria compared to the main population. Interference of the mitochondria function strongly inhibited SP-genesis. Animal studies showed that combination therapy with both an anti-MM agent and EGFR inhibitor gefitinib achieved prolonged MM-bearing mice survival. Hence, our work identifies ALCAM as a novel negative regulator of MM drug-resistance, and EGFR inhibitors may be used to improve MM therapeutic efficacy.

Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma.

It has been previously shown that (never in mitosis gene A)‐related kinase 2 (NEK2) is upregulated in multiple myeloma (MM) and contributes to drug resistance. However, the mechanisms behind this upregulation remain poorly understood. In this study, it is found that amplification of NEK2 and hypermethylation of distal CpG islands in its promoter correlate strongly with increased NEK2 expression. Patients with NEK2 amplification have a poor rate of survival and often exhibit TP53 deletion, which is an independent prognostic factor in MM. This combination of TP53 knockout and NEK2 overexpression induces asymmetric mitosis, proliferation, drug resistance, and tumorigenic behaviors in MM in vitro and in vivo. In contrast, delivery of wild type p53 and suppression of NEK2 in TP53−/− MM cell lines inhibit tumor formation and enhance the effect of Bortezomib against MM. It is also discovered that inactivating p53 elevates NEK2 expression genetically by inducing NEK2 amplification, transcriptionally by increased activity of cell cycle‐related genes like E2F8 and epigenetically by upregulating DNA methyltransferases. Dual defects of TP53 and NEK2 may define patients with the poorest outcomes in MM with p53 inactivation, and NEK2 may serve as a novel therapeutic target in aggressive MM with p53 abnormalities.