Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis

Importance: Numerous studies have evaluated the prognostic value of minimal residual disease (MRD) in patients with multiple myeloma (MM). Most studies were small and varied in terms of patient population, treatment, and MRD assessment methods. Objective: To evaluate the utility of MRD detection in patients with newly diagnosed MM. Data Sources: A Medline search was conducted for articles published in English between January 1990 and January 2016. Study Selection: Eligible studies reported MRD status and progression-free survival (PFS) or overall survival (OS) in 20 or more patients following treatment. Among 405 articles identified, 21 met the initial eligibility criteria and were included in the analysis. Data Extraction and Synthesis: Information on patient characteristics, treatment, MRD assessment, and outcomes were extracted using a standard form. Main Outcomes and Measures: The impact of MRD status on PFS and OS was assessed by pooling data from relevant trials. Data were adjusted to allow for different proportions of patients with MRD in different studies, and analyzed using the Peto method. Forest plots were created based on Cox model analysis. Other prespecified research questions were addressed qualitatively. Results: Fourteen studies (n = 1273) provided data on the impact of MRD on PFS, and 12 studies (n = 1100) on OS. Results were reported specifically in patients who had achieved conventional complete response (CR) in 5 studies for PFS (n = 574) and 6 studies for OS (n = 616). An MRD-negative status was associated with significantly better PFS overall (hazard ratio [HR], 0.41; 95% CI, 0.36-0.48; P < .001) and in studies specifically looking at CR patients (HR, 0.44; 95% CI, 0.34-0.56; P < .001). Overall survival was also favorable in MRD-negative patients overall (HR, 0.57; 95% CI, 0.46-0.71; P < .001) and in CR patients (HR, 0.47; 95% CI, 0.33-0.67; P < .001). Tests of heterogeneity found no significant differences among the studies for PFS and OS. Conclusions and Relevance: Minimal residual disease-negative status after treatment for newly diagnosed MM is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of MM

A DNA target-enrichment approach to detect mutations, copy number changes and immunoglobulin translocations in multiple myeloma.

Genomic lesions are not investigated during routine diagnostic workup for multiple myeloma (MM). Cytogenetic studies are performed to assess prognosis but with limited impact on therapeutic decisions. Recently, several recurrently mutated genes have been described, but their clinical value remains to be defined. Therefore, clinical-grade strategies to investigate the genomic landscape of myeloma samples are needed to integrate new and old prognostic markers. We developed a target-enrichment strategy followed by next-generation sequencing (NGS) to streamline simultaneous analysis of gene mutations, copy number changes and immunoglobulin heavy chain (IGH) translocations in MM in a high-throughput manner, and validated it in a panel of cell lines. We identified 548 likely oncogenic mutations in 182 genes. By integrating published data sets of NGS in MM, we retrieved a list of genes with significant relevance to myeloma and found that the mutational spectrum of primary samples and MM cell lines is partially overlapping. Gains and losses of chromosomes, chromosomal segments and gene loci were identified with accuracy comparable to conventional arrays, allowing identification of lesions with known prognostic significance. Furthermore, we identified IGH translocations with high positive and negative predictive value. Our approach could allow the identification of novel biomarkers with clinical relevance in myeloma

AT7519, a Novel Small Molecule Multi-Cyclin Dependent Kinase Inhibitor, Induces Apoptosis in Multiple Myeloma VIA GSK3 beta

Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [(3)H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3beta (GSK-3beta) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3beta knockdown restored MM survival, suggesting the involvement of GSK-3beta in AT7519-induced apoptosis. GSK-3beta activation was independent of RNA pol II dephosphorylation confirmed by alpha-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3beta phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3beta in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM

Comparison of Technetium-99m-MIBI imaging with MRI for detection of spine involvement in patients with multiple myeloma

BACKGROUND: Recently, radiopharmaceutical scanning with Tc-99m-MIBI was reported to depict areas with active bone disease in multiple myeloma (MM) with both high sensitivity and specificity. This observation was explained by the uptake of Tc-99m-MIBI by neoplastic cells. The present investigation evaluates whether Tc-99m-MIBI imaging and magnetic resonance imaging (MRI) perform equally well in detecting myelomatous bone marrow lesions. METHODS: In 21 patients with MM, MRIs of the vertebral region TH12 to S1 and whole body scans with Tc-99m-MIBI were done. RESULTS: Tc-99m-MIBI scanning missed bone marrow infiltration in 43 of 87 vertebrae (50.5%) in which MRI showed neoplastic bone marrow involvement. In patients with disease stage I+II, Tc-99m-MIBI scanning was negative in all of 24 vertebrae infiltrated according to MRI. In patients with disease stage III, Tc-99m-MIBI scanning detected 44 of 63 (70%) vertebrae involved by neoplastic disease. CONCLUSION: Tc-99m-MIBI scanning underestimated the extent of myelomatous bone marrow infiltration in the spine, especially in patients with low disease stage

Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2.

A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4; 14) and del17p, and detection by fluorescence in situ hybridization of t(4; 14), t(14; 16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum beta(2)-microglobulin level and International Staging System stages II and III, incorporating high beta(2)-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations. (Blood. 2011; 117(18): 4696-4700

Clinical features associated with COVID-19 outcome in multiple myeloma: first results from the International Myeloma Society data set

The primary cause of morbidity and mortality in patients with multiple myeloma(MM) is an infection. Therefore there is great concern about the susceptibility to the outcome of COVID-19 infected patients with MM. This retrospective study describes the baseline characteristics and outcome data of COVID-19 infection in 650 patients with plasma cell disorders, collected by the International Myeloma Society to understand the initial challenges faced by myeloma patients during COVID-19 pandemic. Analysis were performed for hospitalized MM patients. Among hospitalized patinets, the median age was 69 years, and nearly all patients(96%) had MM. Approximately 36% were recently diagnosed(2019-2020), and 54% of patients were receiving first-line therapy. Thirty-three percent of patients have died, with significant geographic variability, ranging from 27% to 57% of hospitalized patients. Univariate analysis identified age, ISS3, high-risk disease, renal disease, suboptimal myeloma control(active or progressive disease), and one or more comorbidities as risk factors for higher rates of death. Neither history of transplant, including within a year of COVID-19 diagnosis, nor other anti-MM treatments were associated with outcomes. Multivariate analysis found that only age, high-risk MM, renal disease, and suboptimal MM control remained independent predictors of adverse outcome with COVID-19 infection. The management of MM in the era of COVID-19 requires careful consideration of patient and disease-related factors to decrease the risk of acquiring COVID-19 infection, while not compromising disease control through appropriate MM treatment. This study provides initial data to develop recommendations for the management of MM patients with COVID-19 infection

Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression

PURPOSE: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models

Section E6.1–6.4 of the ACMG technical standards and guidelines: chromosome studies of neoplastic blood and bone marrow–acquired chromosomal abnormalities

DISCLAIMER: These American College of Medical Genetics and Genomics standards and guidelines are developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these standards and guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Cytogenetic analyses of hematological neoplasms are performed to detect and characterize clonal chromosomal abnormalities that have important diagnostic, prognostic, and therapeutic implications. At the time of diagnosis, cytogenetic abnormalities assist in the diagnosis of such disorders and can provide important prognostic information. At the time of relapse, cytogenetic analysis can be used to confirm recurrence of the original neoplasm, detect clonal disease evolution, or uncover a new unrelated neoplastic process. This section deals specifically with the standards and guidelines applicable to chromosome studies of neoplastic blood and bone marrow-acquired chromosomal abnormalities. This updated Section E6.1-6.4 has been incorporated into and supersedes the previous Section E6 in Section E: Clinical Cytogenetics of the 2009 Edition (Revised 01/2010), American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories.Genet Med 18 6, 635-642