Risk Of Progression To Multiple Myeloma Research Articles

Tracking Clonal Evolution of Multiple Myeloma Using Targeted Next-Generation DNA Sequencing.

Clonal evolution drives treatment failure in multiple myeloma (MM). Here, we used a custom 372-gene panel to track genetic changes occurring during MM progression at different stages of the disease. A tumor-only targeted next-generation DNA sequencing was performed on 69 samples sequentially collected from 30 MM patients. The MAPK/ERK pathway was mostly affected with KRAS mutated in 47% of patients. Acquisition and loss of mutations were observed in 63% and 37% of patients, respectively. Four different patterns of mutation evolution were found: branching-, mutation acquisition-, mutation loss- and a stable mutational pathway. Better response to anti-myeloma therapy was more frequently observed in patients who followed the mutation loss—compared to the mutation acquisition pathway. More than two-thirds of patients had druggable genes mutated (including cases of heavily pre-treated disease). Only 7% of patients had a stable copy number variants profile. Consequently, a redistribution in stages according to R-ISS between the first and paired samples (R-ISS″) was seen. The higher the R-ISS″, the higher the risk of MM progression and death. We provided new insights into the genetics of MM evolution, especially in heavily pre-treated patients. Additionally, we confirmed that redefining R-ISS at MM relapse is of high clinical value.

Association of Progression Patterns in Monoclonal Gammopathy of Undetermined Significance (MGUS) with Outcome in Multiple Myeloma: A Cohort Study of over 35 Years

Introduction: Guidelines suggest following monoclonal gammopathy of undetermined significance (MGUS) according to risk of multiple myeloma progression. Follow-up of low-risk MGUS is debated as progression risk is low. Worse myeloma-related outcome was observed in patients followed for low-risk MGUS, potentially due to less optimal follow-up (Bianchi et al. Blood 2010, Sigurdardottir et al. Jama Oncology 2015). However, it is not clear if progressing low-risk MGUS by its nature displays more aggressive biological behavior. To gain better understanding of progression patterns in MGUS, we investigated, independent of follow-up, whether progression from low-risk MGUS is associated with worse outcome in multiple myeloma. The main outcome was overall survival from the time of myeloma diagnosis.Methods: The Northern Sweden Health and Disease Study (NSHDS) is a longitudinal prospective cohort with more than 100,000 participants. Typically, NSHDS participants donate repeated blood samples at intervals of several years. Samples are frozen within one hour and stored at -80° C at Umea University Hospital. Linkage to the Swedish Cancer Registry facilitated identification of myeloma patients with two pre-diagnostic samples in NSHDS (N = 61). Of these, we screened repeated pre-diagnostic samples using protein- and immunofixation electrophoresis and free light chain assays. We identified 42 individuals who had detectable monoclonal gammopathy in both pre-diagnostic samples without MGUS follow-up before myeloma diagnosis, allowing to investigate natural progression patterns in relation to outcome. Overall survival was determined using Kaplan-Meier plots. Hazard ratios and 95% confidence intervals were calculated using multivariable Cox regression including known prognostic factors. Fisher's exact test was used to compare categorical variables.Results: The first pre-diagnostic sample was collected in November 1986 and the last follow-up since myeloma diagnosis was in February 2021, resulting in a 35-year study duration. Median age at myeloma diagnosis was 62 (range 48-84) with a median follow-up of 7 years (range 0.2-18). At first pre-diagnostic blood draw, 12 had low-risk and 30 had MGUS of other risk (Mayo Clinic criteria). Characteristics at myeloma diagnosis except sex were similarly distributed between the two groups. Comorbidities, myeloma treatment and access to novel drugs were balanced between groups. Bone disease (osteolytic lesions and/or vertebral compression fractures attributable to myeloma) at myeloma diagnosis was more common in patients who had low-risk MGUS at first pre-diagnostic blood draw (P = 0.04). This association was pronounced excluding light chain myeloma (P = 0.01). Access to other radiographic imaging than conventional skeletal survey such as CT or MRI was similar for both groups.In low-risk vs. other MGUS, median overall survival since myeloma diagnosis was 2.3 (95% CI, 1.8-2.9) years and 7.5 (95% CI, 4.8-10.2) years (Figure A). Results were similar investigating overall survival since frontline therapy start (excluding 5 patients not requiring therapy) (Figure B). Sex and bone disease were not associated with survival.At repeated pre-diagnostic blood draw (in median 3.7 years prior myeloma diagnosis), 67% vs. 19% had low- or low-intermediate risk MGUS in patients with low-risk vs. other MGUS at first pre-diagnostic blood draw (P = 0.01), suggesting more rapid progression close to myeloma diagnosis in patients with low-risk MGUS at first blood draw. Investigating this further, we plotted M spikes in low-risk vs. other MGUS of IgG isotype (Figures C-D). M spike trajectories were largely similar between groups, although the annual median M spike increase from repeated pre-diagnostic blood draw to myeloma diagnosis was 6.0 g/L in low-risk vs. 2.3 g/L in other MGUS (P = 0.14).Conclusions: Progression from low-risk MGUS is, independent of MGUS follow-up, associated with a higher proportion of bone disease and worse survival. Based on the known phenotypic heterogeneity in multiple myeloma, we speculate that low-risk MGUS in case of malignant progression belongs to a group of more aggressive tumors. Our results need to be interpreted carefully because of the small sample size. Replication and further investigation are needed. If replicated, these findings could help to improve current MGUS follow-up strategies, which are solely based on progression risk. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Multiple Myeloma Management in COVID-19 Era

Introduction Coronavirus disease 2019 (COVID-19) has become a world pandemic since early 2020. The complexity of handling multiple myeloma (MM) has increased substantially during this pandemic. The objective of this review is to know the current recommendation to manage MM in the COVID-19 era. Materials and Methods Electronic databases, including PubMed central and PubMed, were used to conduct a literature search. It was conducted on May 18, 2020, using the keywords “multiple myeloma” AND “COVID-19” AND “Prevalence OR Impact OR treatment OR prophylactic.” The included articles were review articles, recommendations, case reports or series, or population-based studies (cross-sectional, cohort, case-control, or interventional), and full-text if available. Results A total of 124 articles were identified through the search strategy. The two reviewers screened titles and abstracts of all articles. Most articles were excluded because of ineligible to the criteria. Ultimately, 18 articles were included in the final evaluation. MM patients might have higher risk to become severe COVID-19 if they got infected due to their immunocompromised condition. Due to the pandemic, precise treatment priorities should be made by considering its benefit and the risk of MM progression. For the young, especially healthy patients, the most effective therapy should be offered and tailored to the patient’s goal. Several MM societies have published the recommendation regarding the special stage of MM. Conclusion Myeloma societies in the world have released recommendations related to the management of myeloma patients. However, there is scarce of evidence to do the recommendation.

The Relative Risk of Prognostic Factors of Age Stratified Multiple Myeloma

Background: Age is a pivotal prognostic factor for multiple myeloma (MM). The risk of evolving from MGUS and SMM to symptomatic MM steadily increases with age. And there are nuances in clinical manifestations and cytogenetic characteristics between young and old patients. The aim of this study is to delineate the clinical and laboratory features and determine the relative contribution of ISS, performance status and cytogenetic abnormalities in each age MM patients. Methods: In this study, 778 MM patients were enrolled in the prospective, non-randomized BDH2008/02 clinical trial between January, 2008 and December, 2016. Briefly, the patients accepted bortezomib or thalidomide-based induction therapy. Transplantation eligible patients accepted ASCT, otherwise they accepted the original regimen consolidation therapy. Subsequently, unless intolerance, patients received either thalidomide-based or lenalidomide-based maintenance therapy for two years. Conventional FISH panel included del(13q), del(17p), gain(1q), t(11;14), t(4;14), t(14;16), and t(14;20). The positive cut-off value for chromosome deletion or gain was 20%, and for chromosome translocation was 10%. A multivariate Cox proportional-hazards model was developed to assess the variables with significant effects on PFS and OS. Explained variation of variables was quantified by RD2. Statistical analysis was conducted by Stata/MP 16.0 (Stata Corp., TX, USA) and SPSS 26.0 (IBM Corp., Chicago, Illinois, USA). Results: Among 778 patients with complete data, 59.5% (463/778) were younger than 60 years old, 31.4% (244/778) were 61-70 years old, and only 9.1% (71/778) were over 71 years old. The median PFS of patients≤60, 61-70 and ≥71 years of age was 36.3, 32.6 and 23.1 months, respectively (P<0.001). The median OS in each age group was 86.2, 60.7 and 34.9 months, respectively (P<0.001) (Figure A-D). The median evaluated glomerular filtration rate of the three groups was 89.1, 74.0 and 66.4 ml/min (P<0.001), respectively. The serum β2-microglobulin level gradually increased with age (P<0.001), along with the proportion of patients with ISS 3 stage. Patients ≥71 years old had a higher proportion of ECOG performance status score 3-4, twice than that of patients ≤60 years old. The incidence of high-risk IgH translocation decreased with age, and was 25.4%, 21.3% and 14.3% across age groups. The incidence of gain(1q) increased with age, and was 43.9%, 47.1% and 54.8%, respectively. The incidence of del(17p) and del(13q) seldom changed with age (Figure E). With age, the risk of high-risk cytogenetic abnormalities did not change significantly, accounting for about 50% in each age group. The risk of ISS gradually decreased, accounting for 36%, 27%, and 14% in ≤60, 61-70 and ≥71 year subgroups, respectively. The risk of the ECOG performance status gradually increased with age, accounting for 10%, 17%, and 36% in the three subgroups (Figure F). The overall response rate of induction treatment gradually decreased with age, and were 90.2%, 81.9%, and 69.2%, respectively (P<0.001). Elderly patients with impaired renal function or more than one high-risk cytogenetic abnormalities might benefit more from bortezomib based treatment than younger patients (Figure G). Conclusion: Age is an important prognostic factor in MM. With age, the risk of MM progression or death steadily grows. Cytogenetic abnormalities are equally important in every age group. The risk of poor performance status increases in elderly patients with a reduction risk in ISS. Elderly patients should focus on the status of frailty and molecular events to determine treatment. Figure Disclosures No relevant conflicts of interest to declare.

Outcomes of Autologous Hematopoietic Stem Cell Transplantation Depending on Body-Mass Index in Patients with Multiple Myeloma

Introduction. About ten years ago, the International Agency for Research on Cancer corroborated the association of obesity with the risk of cancers of the gastrointestinal tract, breast, endometrium and kidney. In a report published in 2016, eight cancer types were added in this list, including multiple myeloma (MM). Aim of the study. To study the impact of obesity on the efficacy of autologous hematopoietic stem cell transplantation (auto-HSCT) in MM patients. Materials and methods. 99 MM patients (37 males, 62 females), aged from 27 to 66 years (median 54) underwent auto-HSCT in 2016-2017 were enrolled in the study. The diagnosis was made according to IMWG criteria (2014). Induction therapy included bortezomib-containing regimens in all patients (first-line therapy), immunomodulatory drugs were used in 21 % of the patients (second-line therapy). Before auto-HSCT complete response (CR) was documented in 49% of the patients, very good partial response (VGPR) was achieved in 51% of the patients. After induction chemotherapy, patients received melphalan 200 mg/m2 (95% of the patients) and melphalan140 mg/m2 (5% of the patients with dialysis-dependent renal failure) before undergoing auto-HSCT. A standardized body-mass index (BMI) was calculated before performing the transplantation. The median follow-up period since the auto-HSCT was 22 months. Progression-free survival (PFS) was assessed for a period of 3 years after autologous HSCT. Survival curves were constructed using the Kaplan-Meier method. Statistical analysis was done using Statistica 10. Results. A normal body weight (a BMI <25 kg/m2) was documented in 22% of the patients, an overweight status (a BMI between 25 and 29, 9 kg/m2) was established in 53% of the patients. Obesity (a BMI > 30 kg/m2) was diagnosed in 25% of the MM patients. When analyzing the PFS, it was revealed significant differences depending on the body-mass index of the patients. Thus, in patients with a normal BMI the 3-year PFS rates was significantly higher (Cox's F-test, p<0,05) and was 69% versus 45% and 33% in the group of patients with overweight or obese, respectively (fig.1). Conclusion. Obesity has reached epidemic proportions globally. It is important to identify the factors that raise the risk of MM progression. Our study confirmed the hypothesis of the negative impact of obesity on the results of the treatment of MM patients. All patients achieved a good response - CR or VGPR before auto-HSCT. The analysis of the 3-year PFS rates demonstrated, that the results of autologous HSCT in MM patients suffering from obesity was significantly worse than the same results in patients with normal body weight (3-year PFS 33% vs. 69%, p<0,05). Obesity is a modifiable risk factor; shifting a patient's behaviour after diagnosis could reduce their risk of progression, changes in lifestyle and diet can improve the treatment outcomes in MM patients. Disclosures No relevant conflicts of interest to declare.

Elotuzumab reduces risk of multiple myeloma progression

Elotuzumab reduces risk of multiple myeloma progression

Development Of a Serum Biomarker Panel That Predicts Imminent Risk Of Multiple Myeloma (MM) Progression From Premalignancy

Premalignant states are known to precede malignancy in many different cancers, including multiple myeloma (MM). Each year, 1% of Monoclonal Gammopathy of Undetermined Significance (MGUS) patients and 10% of Smoldering Multiple Myeloma (SMM) patients transition to symptomatic MM, which remains an incurable disease. By identifying patients at imminent risk (within 2 years) of progression to MM, treatment could begin early and potentially prevent full blown MM and associated morbidity and mortality. Multiple risk-factor models are currently utilized to identify patients at high-risk of developing MM. Commonly cited risk factors include percentage of bone marrow plasma cells, free light chain ratio, serum levels of M-protein, IgG subtype and levels of circulating plasma cells. These tests have individual and combined merit but there remains no consensus for measuring imminent risk of MM progression. To determine whether serum proteomics could help predict progression or provide information on relevant pathways involved in progression to MM, we evaluated 200 MGUS and SMM (187 non-IgM) patient samples on the Myriad DiscoveryMAP(r) platform (250+ serum proteins), supplemented by demographic and clinical information. Of the 187 non-IgM patients, 100 progressed to MM within 2 years (high-risk), and 87 did not progress to MM within 5 years (low-risk). We performed different subset analyses to screen for proteins that were informative and predictive of disease progression from MGUS/SMM to MM. First, a univariate Wilcoxon rank sum test was performed. The top 10 proteins that were found to be differential between high-risk/low-risk for all MGUS and SMM patients were IgM, Progesterone, MCP-2, Kallikrein-5, FGF4, EPO, MCP-4, MIP-1β, MCP-1, and TF. Interestingly, when analyzing MGUS and SMM patients separately, additional proteins that were important in distinguishing high-risk/low-risk patients included IgM, EN-RAGE, BAFF, and several others previously shown to be relevant in MM, as well as a handful of novel proteins with unidentified roles in MM. Second, to determine whether specific combinations of proteins could be utilized together to define high/low-risk, a classification tree was assembled. The combination of 8 features (IgM, Progesterone, Aldose Reductase, E-Selectin, Fas Ligand, Hemoglobin, Age and Creatine kinase-MB) appropriately classified 86% of the 187 patients into high/low-risk. Future analyses will include examining this high/low risk classifier in contrast to current risk factor models, and application to two additional sets of similar patient samples that serve as an independent validation set. Disclosures:No relevant conflicts of interest to declare.

Arterial and Venous Thrombosis in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma: A Population-Based Study.

Abstract 1872Poster Board I-897 BackgroundPatients with multiple myeloma (MM) have an increased risk of venous thrombosis. Additionally, MM has been associated with arterial thrombosis. Interestingly, excess risk of venous thromboembolism has been observed among patients with monoclonal gammopathy of undetermined significance (MGUS). MethodsUsing population-based data from Sweden, we assessed the risks of venous and arterial thrombosis in 18,627 MM and 5,326 MGUS patients, compared to 70,991 and 20,161 matched controls, respectively. Hazard ratios for thrombosis, at 1, 5, and 10 years follow-up were calculated using Cox proportional hazard models. Results>At 1, 5 and 10 years after MM diagnosis, there was an increased risk of venous thrombosis: hazard ratios (95% confidence intervals) were 7.5 (6.4–8.9), 4.6 (4.1–5.1), and 4.1 (3.8–4.5), respectively. The corresponding results for arterial thrombosis were 1.9 (1.8–2.1), 1.5 (1.4–1.6), and 1.5 (1.4–1.5). At 1, 5 and 10 years after MGUS diagnosis, hazard ratios were 3.6 (2.6–4.9), 2.2 (1.8–2.6), and 2.1 (1.8–2.5) for venous thrombosis. The corresponding risks for arterial thrombosis were 1.7 (1.5–1.9), 1.3 (1.2–1.4), and 1.3 (1.3–1.4). IgG/IgA (but not IgM) MGUS patients had increased risks for venous and arterial thrombosis with hazard ratios 4.5 (2.8–7.2) and 1.6 (1.3–1.9) 1 year and 2.2 (1.7–2.8) and 1.2 (1.1–1.4) 5 years after diagnosis. Risks for thrombosis did not vary by M-protein concentration (above/below 10.0 g/L) at diagnosis. MGUS patients with (versus without) thrombosis had no excess risk of MM progression. ConclusionIn this large study including more than 5,000 MGUS patients and 18,000 MM patients, and their matched controls, we found that both MGUS and MM patients had an increased risk of venous as well as arterial thrombosis. Among MGUS patients, an excess risk of thrombosis was observed in patients with IgG/IgA MGUS, but not IgM. Future studies are needed to clarify underlying mechanisms of our findings. Such efforts will be of relevance for physicians managing MGUS and MM patients and have potential implications for the development of better thrombosis prophylaxis strategies. [Display omitted] Disclosures:Mellqvist:Johnson and Johnson: Research Funding; Celgene: Speakers Bureau; Jansen-Cilag: Speakers Bureau.

Angiogenesis in B cell lymphoproliferative diseases. Biological and clinical studies.

Angiogenesis is a necessary step in solid tumor progression (growth, invasion and metastasis) with which it correlates and is indicative of an unfavourable prognosis. We observed bone marrow angiogenesis in patients with active multiple myeloma (MM), though not in patients with non-active MM nor with monoclonal gammopathies of undetermined significance (MGUS). Microvessel density increased in parallel with the labeling index (LI%)--an indicator of plasma cell proliferating activity that correlates with prognosis--and defined a risk of MM progression in much the same way as LI% itself. Consequently, bone marrow angiogenesis could be an indication for unfavourable prognosis in MGUS and MM. Angiogenesis has also been demonstrated in lymph nodes involved by B cell non Hodgkin's lymphoma (B-NHL) belonging to the Working Formulation intermediate-grade (diffuse subtypes), and high-grade categories, but not in the low-grade and intermediate-grade (follicular subtype) categories. It correlated with the B-NHL cell proliferating activity, since large increments in this activity have already been demonstrated in intermediate- and high-grade vs low-grade tumors. Active MM, intermediate-grade, diffuse subtypes, and high-grade B-NHLs correspond to the vascular phases of B cell lymphoproliferative diseases, and could thus be assimilated to locally invasive and metastatic solid tumors. Similarly to solid tumors during these stages of progression, tumor B cells are also capable of inducing angiogenesis, both directly and indirectly by activating the inflammation infiltrate--a possibility that was first demonstrated by means of B-NHL implants onto the chick embryo chorioallantoic membrane. Anti-angiogenic therapy can be envisaged as a possible future development.