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Summary:The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.

Supplementary Table from Perspectives on the Risk-Stratified Treatment of Multiple Myeloma

Supplementary Tables: Supplementary table 1: Demographics of the 463 patients included in the Myeloma XI analysis Supplementary table 2: List of epigenetic modifier genes used to interrogate the list of mutations in the Myeloma XI dataset Supplementary table 3: Demographics of the 156 patients included in the UAMS dataset Supplementary table 4: List of epigenetic modifier genes sequenced in UAMS dataset Supplementary table 5: SIFT analysis of Histone 1 family gene mutations Supplementary table 6: Multivariate cox-regression model for overall survival in Myeloma XI patients Supplementary table 7: Percentage of patients with mutations in genes encoding epigenetic modifiers sequenced in both the MYXI and UAMS datasets (as shown in Supplementary table 4) - Supplementary Figures: Supplementary Figure 1: Epigenetic genes mutated in {greater than or equal to}5/463 patients (>1%) in Myeloma XI dataset - location of mutation with respect to protein functional domains Supplementary Figure 2: Translocation subgroup distribution by presence or absence of epigenetic modifier mutation in the Myeloma XI dataset Supplementary Figure 3: Survival curves for Histone 1 mutations in Myeloma XI dataset Supplementary Figure 4: A comparison of the variant allele frequency between the MyXI and UAMS mutations Supplementary Figure 5: The distribution of mutations in epigenetic modifiers in previously treated patients by GEP70 risk score Supplementary Figure 6: A comparison of the UAMS molecular subgroup distribution by presence of epigenetic modifier mutations in previously treated patients

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Purpose: Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison.Experimental Design: Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease.Results: In diagnostic myeloma patient samples, we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX. The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers.Conclusions: Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. Clin Cancer Res; 22(23); 5783–94. ©2016 AACR.

Purpose:Copy-number changes and translocations have been studied extensively in many datasets with long-term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets.Experimental Design:We performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the total therapy trials.Results:As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF, making up 44% of patients. Double-Hit and BRAF and DIS3 mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF-mutated patients showed co-occurring alterations in KRAS, NRAS, or activating BRAF mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance.Conclusions:Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutation-driven treatment approaches.

International audience; Familial forms of monoclonal gammopathy, defined as multiple myeloma (MM) or Monoclonal Gammopathy of Undetermined Significance (MGUS), are relatively infrequent and most series reported in the literature describe a limited number of families. MM rarely occurs in a familial context. MGUS is observed much more commonly, which can in some cases evolve toward full-blown MM. Although recurrent cytogenetic abnormalities have been described in tumor cells of sporadic cases of MM, the pathogenesis of familial MM remains largely unexplained. In order to identify genetic factors predisposing to familial monoclonal gammopathy, the Intergroupe Francophone du Myélome identified 318 families with at least two confirmed cases of monoclonal gammopathy. There were 169 families with parent/child pairs and 164 families with cases in at least two siblings, compatible with an autosomal transmission. These familial cases were compared with sporadic cases who were matched for age at diagnosis, sex and immunoglobulin isotype, with 10 sporadic cases for each familial case. The gender distribution, age and immunoglobulin subtypes of familial cases were unremarkable in comparison to sporadic cases. With a median follow-up of 7.4 years after diagnosis, the percentage of MGUS cases having evolved to MM was 3%. The median overall survival of the 148 familial MM cases was longer than that of matched sporadic cases, with projected values of 7.6 and 16.1 years in patients older and younger than 65 years, respectively. These data suggest that familial cases of monoclonal gammopathy are similar to sporadic cases in terms of clinical presentation and carry a better prognosis.

Microabstract Immunoparesis is associated with poor survival in myeloma (MM). We demonstrate that the etiological cytogenetic abnormality influences the degree and clinical impact of immunoparesis in newly diagnosed patients in a large clinical trial. As the depth of IgM immunoparesis impacts survival for hyperdiploid patients, this may be used to further risk-stratify this cytogenetic subgroup of patients for future clinical decisions. Introduction/Background Immunoparesis, or low polyclonal immunoglobulin levels, is commonly seen in multiple myeloma (MM) and is associated with poor clinical outcomes. MM can be divided into subgroups with distinct biology and outcomes based on etiological cytogenetic abnormalities. These include hyperdiploidy and translocations of t(11;14), t(4;14), t(14;16), and t(14;20), with the latter three associated with high-risk disease. We hypothesized that the different etiological cytogenetic abnormalities drive bone marrow microenvironmental changes, resulting in different degrees of immunoparesis and subgroup-dependent effects on clinical outcomes. Materials and Methods We performed a retrospective review of 985 newly diagnosed patients enrolled in the Myeloma IX and XI trials. Immunoglobulin levels, survival outcomes, and infection rates were evaluated for each cytogenetic subgroup. Results A significant proportion of patients with high-risk t(4;14), t(14;16), or t(14;20) had suppressed polyclonal immunoglobulins compared to standard-risk patients with hyperdiploidy or t(11;14). The clinical impact of immunoparesis depended on the cytogenetic subgroup, with the degree of IgM suppression effecting progression-free and overall survival only in the hyperdiploid subgroup. There was no significant difference in infection rates amongst the etiological subgroups. Conclusions These findings demonstrate that the etiological cytogenetic subgroup influences the degree and clinical impact of immunoparesis. This suggests that the underlying cytogenetic abnormality affects remodeling of the bone marrow plasma cell niche, resulting in suppressed normal plasma cell function and low immunoglobulin levels.

Analysis of the genetic basis for multiple myeloma (MM) has informed many of our current concepts of the biology that underlies disease initiation and progression. Studying these events in further detail is predicted to deliver important insights into its pathogenesis, prognosis and treatment. Information from whole genome sequencing of structural variation is revealing the role of these events as drivers of MM. In particular, we discuss how the insights we have gained from studying chromothripsis suggest that it can be used to provide information on disease initiation and that, as a consequence, it can be used for the clinical classification of myeloma precursor diseases allowing for early intervention and prognostic determination. For newly diagnosed MM, the integration of information on the presence of chromothripsis has the potential to significantly enhance current risk prediction strategies and to better characterize patients with high-risk disease biology. In this article we summarize the genetic basis for MM and the role played by chromothripsis as a critical pathogenic factor active at early disease phases.

Whole genome sequencing (WGS) of newly diagnosed multiple myeloma patients (NDMM) has shown recurrent structural variant (SV) involvement in distinct regions of the genome (i.e. hotspots) and causing recurrent copy number alterations. Together with canonical immunoglobulin translocations, these SVs are recognized as “recurrent SVs”. More than half SVs were not involved in recurrent events. The significance of these “rare SVs” has not been previously examined. In this study, we utilize 752 WGS and 591 RNA-seq data from NDMM patients to determine the role of rare SVs in myeloma pathogenesis. 94% of patients harbored at least one rare SV event. Rare SVs showed an SV-class specific enrichment within genes and superenhancers associated with outlier gene expression. Furthermore, known myeloma driver genes recurrently impacted by point mutations were dysregulated by rare SVs. Overall, we demonstrate the association of rare SVs with aberrant gene expression supporting a driver role in myeloma pathogenesis.SIGNIFICANCECharacterization of multiple myeloma genome revealed that more than half structural variants are not involved in recurrent events. Here, we demonstrate that these rare SVs hold potential for myeloma pathogenesis through their gene expression impact. Rare SVs contribute to MM heterogeneity and have implications for development of individualized treatment.

Despite improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02185-1.

Low back pain (LBP) clinical practice guidelines recommend referral for patients with persistent LBP however discordance persists between recommended care and implementation in practice. Understanding patient experiences of referral practices and physiotherapy care could be important for optimizing LBP management in primary care settings.This study explored referral experiences of people with nonspecific LBP in Australian primary care and their knowledge and experience of physiotherapy.An interpretive descriptive qualitative framework was used with 17 participants interviewed from community-based physiotherapy practices.Four themes described the participants' experiences of referrals in primary care settings: 1) Referral practices ranged from formal to informal to non-existent; 2) Fragmented inter-and intra-professional LBP care management; 3) Patient perceived differences in the roles of physiotherapists and specialist physiotherapists; and 4) Patient nominated barriers and facilitators to optimal referral practices.Physiotherapists support people with LBP to improve strength and function, whereas the specialist physiotherapist's role was seen as more holistic. Referral pathways that align to clinical guideline recommendations for non-surgical management and treatment remain underdeveloped. Improved referral pathways to clinicians such as physiotherapists with additional credentialed skills and competence in musculoskeletal care could improve people's experiences of care and health outcomes.

Despite recent therapeutic advances the outcome of elderly or frail patients with Recurrent/Refractory (R/R) Primary (PCNSL) and Secondary CNS Lymphoma (SCNSL) is particularly dire. We retrospectively analyzed 22 immunocompetent adults with R/R PCNSL or SCNSL treated with both temozolomide and ibrutinib in five French centers, from June 2015 to January 2020. The median age at treatment initiation was 71 (range, 44 - 89 years). All patients had relapsed (n=6) or refractory (n=16) disease, after a median of two lines of therapy (range, 1-3). The median Charlson Comorbidity Index was 5 (range, 2-8). Patients received a median of 3.2 cycles (1-19 cycles). The best overall response rate was 55% (12/22) including three (13.6%) complete responses. After a median follow-up of 18.2 months (range, 5.1 - 61.7), the median progression-free survival (PFS) and overall survival (OS) were 5.3 months (95% confidence interval [CI]; 3.10 - ∞) and 8.9 months (95% CI; 5.2 - ∞) respectively. Among responders, the median PFS and OS were 11.7 months (95% CI; 7 - ∞) and 21.8 months (95% CI; 10 - ∞) respectively. Our data suggest temozolomide combined with ibrutinib displayed clinical activity with manageable side effects might be an option in these frail R/R CNS lymphomas in unmet need.

The summation of 20 years of biological studies and the comprehensive analysis of more than 1000 multiple myeloma genomes with data linked to clinical outcome has enabled an increased understanding of the pathogenesis of multiple myeloma in the context of normal plasma cell biology. This novel data have facilitated the identification of prognostic markers and targets suitable for therapeutic manipulation. The challenge moving forward is to translate this genetic and biological information into the clinic to improve patient care. This review discusses the key data required to achieve this and provides a framework within which to explore the use of response-adapted, biologically targeted, molecularly targeted, and risk-stratified therapeutic approaches to improve the management of patients with multiple myeloma.

Summary: The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.

Circulating cell-free DNA (cfDNA) has the potential to capture spatial genetic heterogeneity in myeloma (MM) patients. We assessed whether cfDNA levels vary according to risk status defined by the 70 gene expression profile (GEP70). cfDNA levels in 77 patients were significantly higher in the GEP70 high-risk (HR) group compared to the low-risk (LR) group and correlated weakly with clinical markers including lactate dehydrogenase, β2 -microglobulin, and ISS. Patients with high cfDNA levels were associated with a worse PFS (hazard ratio 6.4; 95% CI of ratio 1.9-22) and OS (hazard ratio 4.4; 95% CI of ratio 1.2-15.7). Circulating tumor DNA (ctDNA) was elevated in the HR group and ctDNA correlated strongly with GEP70 risk score (Spearman r = .69, P = .0027). cfDNA concentrations were significantly elevated between days 3-5 after chemotherapy before falling back to baseline levels. ctDNA in two patients showed a similar spike in levels between days 3 and 5 after chemotherapy with a concomitant increase in allele fraction of KRAS mutations. We assessed cfDNA levels in 25 patients with smoldering myeloma with serial samples and showed increased allele fraction of mutated KRAS at progression in cfDNA. Our study shows that cfDNA is a dynamic tool to capture genetic events in myeloma.

In Western countries, Cryptosporidium parvum infection is considered a rare opportunistic parasitic disease, most commonly seen in immunocompromised patients. Although most cases have been described in Acquired ImmunoDeficiency Syndrome (AIDS) patients, an increase of cases in other immunocompromised patients has been noted. We hereby describe the case of two patients from our institution in Northern France with heavily pre-treated multiple myeloma, both of whom underwent allogeneic stem cell transplants, who presented late Cryptosporidium infections while treated on novel agents. These cases illustrate novel examples of infection in multiple myeloma as survival improves and novel treatment approaches are being applied.

Multiple myeloma (MM) is plasma cell dyscrasia with marked variability in its clinical presentation and outcome, both of which are dictated by its underlying genetics. Next-generation sequencing te...

Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by the presence of ≥20% circulating plasma cells. Overall survival remains poor despite advances of anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood and, given the rarity of the disease, are challenging to study. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype, we performed whole-exome sequencing and gene expression analysis in 23 and 41 patients with newly diagnosed pPCL, respectively. The results reveal an enrichment of complex structural changes and high-risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular, pPCL patients with traditional low-risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group. Furthermore, gene expression profiling showed upregulation of adverse risk modifiers in pPCL compared to non-pPCL MM, while adhesion molecules and extracellular matrix proteins became increasingly downregulated. In conclusion, this is one of the largest studies to dissect pPCL on a genomic and molecular level.

Purpose: Copy-number changes and translocations have been studied extensively in many datasets with long-term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets. Experimental Design: We performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the total therapy trials. Results: As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF, making up 44% of patients. Double-Hit and BRAF and DIS3 mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF-mutated patients showed co-occurring alterations in KRAS, NRAS, or activating BRAF mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance. Conclusions: Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutation-driven treatment approaches.

Daratumumab is a human monoclonal antibody targeting CD38, an antigen uniformly expressed by plasma cells in multiple myeloma and light-chain amyloidosis (AL). We report the results of a prospective multicenter phase 2 study of daratumumab monotherapy in AL (NCT02816476). Forty previously treated AL patients with a difference between involved and uninvolved free light chains (dFLC) >50 mg/L were included in 15 centers between September of 2016 and April of 2018. Patients received 6 28-day cycles of IV daratumumab, every week for cycles 1 and 2 and every 2 weeks for cycles 3 through 6. Median age was 69 years (range, 45-83). Twenty-six patients had ≥2 organs involved, with heart in 24 and kidney in 26. Median time from diagnosis to enrollment was 23 months (interquartile range, 4-122), with a median of 3 prior therapies (range, 1-5). At data cutoff (September of 2019), all patients discontinued therapy; 33 received the planned 6 cycles. Overall, 22 patients had hematological response, and 19 patients (47.5%) achieved very good partial response (dFLC

Background The study of cancer genomics continually matures as the number of patient samples sequenced increases. As more data is generated, oncogenic drivers for specific cancer types are discovered along with their associated risks. This in turn leads to potential treatment strategies that pave the way to precision medicine. However, significant financial and analytical barriers make it infeasible to sequence the entire genome of every patient. In contrast, targeted sequencing panels give reliable information on relevant portions of the genome at a fiscally responsible cost. Therefore, we have created the Targeted Panel (TarPan) Viewer, a software tool, to investigate this type of data. Results TarPan Viewer helps investigators understand data from targeted sequencing data by displaying the information through a web browser interface. Through this interface, investigators can easily observe copy number changes, mutations, and structural events in cancer samples. The viewer runs in R Shiny with a robust SQLite backend and its input is generated from bioinformatic algorithms reliably described in the literature. Here we show the results from using TarPan Viewer on publicly available follicular lymphoma, breast cancer, and multiple myeloma data. In addition, we have tested and utilized the viewer internally, and this data has been used in high-impact peer-reviewed publications. Conclusions We have designed a flexible, simple to setup viewer that is easily adaptable to any type of cancer targeted sequencing, and has already proven its use in a research laboratory environment. Further, we believe with deeper sequencing and/or more targeted application it could be of use in the clinic in conjunction with an appropriate targeted sequencing panel as a cost-effective diagnostic test, especially in cancers such as acute leukemia or diffuse large B-cell lymphoma that require rapid interventions.

Disruption of the normal splicing patterns of RNA is a major factor in the pathogenesis of a number of diseases. Increasingly research has shown the strong influence that splicing patterns can have on cancer progression. Multiple Myeloma is a molecularly heterogeneous disease classified by the presence of key translocations, gene expression profiles and mutations but the splicing patterns in MM remains largely unexplored. We take a multifaceted approach to define the extent and impact of alternative splicing in MM. We look at the spliceosome component, SF3B1, with hotspot mutations (K700E and K666T/Q) shown to result in an increase in alternative splicing in other cancers. We discovered a number of differentially spliced genes in comparison of the SF3B1 mutant and wild type samples that included, MZB1, DYNLL1, TMEM14C and splicing related genes DHX9, CLASRP, and SNRPE. We identified a broader role for abnormal splicing showing clear differences in the extent of novel splice variants in the different translocation groups. We show that a high number of novel splice loci is associated with adverse survival and an ultra-high risk group. The enumeration of patterns of alternative splicing has the potential to refine MM classification and to aid in the risk stratification of patients.

The role of infection and chronic inflammation in plasma cell disorders (PCD) has been well-described. Despite not being a diagnostic criterion, infection is a common complication of most PCD and represents a significant cause of morbidity and mortality in this population. As immune-based therapeutic agents are being increasingly used in multiple myeloma, it is important to recognize their impact on the epidemiology of infections and to identify preventive measures to improve outcomes. This review outlines the multiple factors attributed to the high infectious risk in PCD (e.g. the underlying disease status, patient age and comorbidities, and myeloma-directed treatment), with the aim of highlighting future prophylactic and preventive strategies that could be implemented in the clinic. Beyond this, infection and pathogens as an entity are believed to also influence disease biology from initiation to response to treatment and progression through a complex interplay involving pathogen exposure, chronic inflammation, and immune response. This review will outline both the direct and indirect role played by oncogenic pathogens in PCD, highlight the requirement for large-scale studies to decipher the precise implication of the microbiome and direct pathogens in the natural history of myeloma and its precursor disease states, and understand how, in turn, pathogens shape plasma cell biology.

The summation of 20 years of biological studies and the comprehensive analysis of more than 1000 multiple myeloma genomes with data linked to clinical outcome has enabled an increased understanding of the pathogenesis of multiple myeloma in the context of normal plasma cell biology. This novel data have facilitated the identification of prognostic markers and targets suitable for therapeutic manipulation. The challenge moving forward is to translate this genetic and biological information into the clinic to improve patient care. This review discusses the key data required to achieve this and provides a framework within which to explore the use of response-adapted, biologically targeted, molecularly targeted, and risk-stratified therapeutic approaches to improve the management of patients with multiple myeloma.

Sequencing studies have shed some light on the pathogenesis of progression from smouldering multiple myeloma (SMM) and symptomatic multiple myeloma (MM). Given the scarcity of smouldering samples, little data are available to determine which translational programmes are dysregulated and whether the mechanisms of progression are uniform across the main molecular subgroups. In this work, we investigated 223 SMM and 1348 MM samples from the University of Arkansas for Medical Sciences (UAMS) for which we had gene expression profiling (GEP). Patients were analysed by TC-7 subgroup for gene expression changes between SMM and MM. Among the commonly dysregulated genes in each subgroup, PHF19 and EZH2 highlight the importance of the PRC2.1 complex. We show that subgroup specific differences exist even at the SMM stage of disease with different biological features driving progression within each TC molecular subgroup. These data suggest that MMSET SMM has already transformed, but that the other precursor diseases are distinct clinical entities from their symptomatic counterpart.