The Application of NextGen Sequencing in the Diagnosis of Myeloid Neoplasms in Myeloma Patients With Cytopenia

BackgroundMultiple myeloma (MM) is an incurable clonal neoplasm that usually requires long-term treatment, which may result in secondary cytopenia(s) and myeloid neoplasms. We investigated the landscape of mutations detected by NextGen sequencing (NGS) in myeloma patients with cytopenia.Methods and MaterialsMM patients (n = 196) with cytopenia(s) and NGS results were identified and divided into 4 groups: 1) patients with myeloma only and no myeloid neoplasms; 2) patients with myeloid neoplasms but no myeloma; 3) patients with concurrent myeloma and myeloid neoplasms; and 4) patients with no myeloma or myelodysplasia.ResultsThe most frequently mutated genes were TP53, DNMT3A, TET2, ASXL1, and KRAS. TP53 mutations were predominantly found among patients with myeloid neoplasms with or without concomitant MM. SF3B1 and TET, the genes most commonly mutated in myelodysplastic syndromes, were less frequently identified among MM patients. ASXL1 mutations were more commonly associated with myeloid neoplasms, whereas KRAS and DNMT3A mutations were more closely associated with MM than myeloid neoplasms. RUNX1 mutations showed closer association with myeloid neoplasms. Fifty-eight patients harbored clonal myeloid gene mutations but no overt morphologic or cytogenetic abnormalities, of which 7 patients had myelodysplastic syndromes that was missed by the original pathologists. Thrombocytopenia appeared to be a more reliable marker than anemia or neutropenia to trigger work-up for myeloid neoplasms.ConclusionNGS could greatly help with diagnosing myeloid neoplasms in MM patients with cytopenia(s). The depicted gene landscape may facilitate our daily interpretation of NextGen sequencing (NGS).     

Analysis of chromosome 12p deletion in plasma cell dyscrasias

The prognostic relevance of 12p deletion is controversial in multiple myeloma (MM) and the status of 12p deletion is unknown in other plasma cell disorders. We investigated 12p deletion in 88 patients with MM, 19 patients with monoclonal gammopathy of undetermined significance (MGUS), and 17 patients with plasma cell leukemia (PCL). Cytoplasmic immunoglobulin light chain immunofluorescence with simultaneous FISH analysis (cIg-FISH) detected hemizygous 12p deletion in 8% of MM and 24% of PCL, respectively, but in none of the MGUS cases (p = 0.0366). 12p deletions were found in 5 of 7 (71%) MM patients at diagnosis with stage III disease (Durie-Salmon), 2 of 7 (28%) with stage I or II. Of 11 cases with 12p deletions, 6 (55%) had coexistence of p53 deletions, including 3 of 7 (42%) MM, and 3 of 4 (75%) PCL cases. There were no significant differences in progression free or overall survivals in MM patients with or without 12p deletions. Our results do not support the use of 12p deletion as a prognostic marker in MM, rather, it tends to occur in advanced disease, may represent a secondary change associated with the disease progression.     

Monoclonal Gammopathies After Renal Transplantation: A Single-center Study

IntroductionPlasma cell disorders (PCDs) are clonal plasma cell disorders that include conditions such as monoclonal gammopathy of undetermined significance (MGUS), monoclonal gammopathy of renal significance (MGRS), multiple myeloma (MM), smoldering MM (SMM), solitary plasmacytoma, and light-chain (AL) amyloidosis. The risk factors associated with and the clinical course of PCDs after renal transplantation is not well established although immunosuppressive protocols may impact the incidence and natural history of PCDs posttransplant.Patients and MethodsThis single-center retrospective study evaluated patients with a history of renal transplant who developed a PCD between January 1, 2014-December 31, 2018.ResultA total of 41 patients met the inclusion criteria including 29 with MGUS and 12 with symptomatic PCD (4 with MM, 2 with SMM, 4 with MGRS, 1 with AL amyloidosis, and 1 with solitary plasmacytoma). The median follow-up of survivors was 41.6 months. Three patients (1 with MGUS and 2 with MGRS) progressed to MM during the follow-up period. There was a male preponderance in both groups. There was no correlation between the donor and immunosuppressive regimen and the development of a PCD. Patients with symptomatic PCD had higher serum creatinine and M-protein levels at diagnosis and higher free light chain ratio and plasma cell burden. There was also a higher percentage of allograft failure noted in the symptomatic PCD subset 50% (n = 6), whereas only 23% (n = 7) of patients had allograft failure in the MGUS group.ConclusionThis study shows the importance of considering monoclonal gammopathy in the differential of renal dysfunction after kidney transplant and the need to follow these patients closely to monitor for progression to symptomatic PCD.     

Importance of quantitative histology of bone changes in monoclonal gammopathy

Quantitative histology of bone changes, using undecalcified transiliac bone biopsies (UTBB), was performed blindly in 46 individuals with monoclonal gammopathy (MG), including 17 with MG of undetermined significance (MGUS) and 29 with overt multiple myeloma (MM). Three MGUS presented an excess of osteoclastic resorption (OR) in the vicinity of clusters of tumour cells and developed overt B cell malignancies, chronic lymphocytic leukaemia, Waldenström''s disease and MM respectively. On the other hand, MGUS with normal OR remained stable (median follow-up = 28 months), with one exception who developed a systemic amyloidosis. In MM, excessive OR was only observed in areas invaded by myeloma cells. OR was frequently normal in active MM lacking myeloma cells in UTBB. Active MM without lesions on radiography had excessive OR. IgA and pure Bence Jones MM appeared more osteoclastic than IgG cases (P less than 0.05). Of major interest was the finding that one third of MM presented histological bone changes similar to osteoporosis, osteosclerosis or osteoblastic metastasis. Two major findings must be emphasized from the current data: UTBB could be of major interest for the early detection of a B cell malignancy; heterogeneity of myeloma bone condition is unexpected. If some changes appear directly related to the tumour (i.e. excessive OR or osteoblastic dysfunction), some others are probably accidentally associated with it (i.e. osteoporosis), both needing treatment other than chemotherapy.     

Mature B-cell neoplasms in Chernobyl clean-up workers of 1986-1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident

The data on the verified cases of mature B-cell neoplasms (chronic lymphocytic leukemia - CLL, B-prolymphocytic leukemia, non-Hodgkin's lymphoma in leukemization phase and multiple myeloma - MM; 146 cases in total) in the consecutive group of Ukrainian clean-up workers within 10-25 years after Chernobyl accident are summarized. B-cell neoplasms represent the most prevalent group among all diagnosed neoplasms of hematopoietic and lymphoid tissues in clean-up worker patients under study (49.4%). MM percentage in the patients of Chernobyl clean-up worker group turned out to be significantly higher than in the patients of the general populations studied at the same period. While the percentage of B-CLL is similar in clean-up worker patients and patients of general population, the trend towards younger age of patients with mature B-cell neoplasms in clean-up worker group is evident. The current concepts on the possible association between mature B-cell neoplasms (mainly B-CLL) and radiation exposure are briefly outlined. Only the precise diagnosis of hematopoietic malignancies combining with large-scale analytical epidemiological studies with careful dose assessment and long-term follow-up may represent the basis for resolving the question whether mature B-cell neoplasms may be radiogenic.     

Overweight/Obesity and Monoclonal Gammopathy of Undetermined Significance

BackgroundObesity and high body mass index (BMI) are associated with increased incidence of multiple myeloma (MM). MM usually evolves from a precursor asymptomatic disease, namely monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a 1% annual rate; however, risk factors predisposing to MGUS are not completely understood. We conducted a systematic review to assess the relationship between obesity and high BMI with MGUS prevalence and progression to MM. To our knowledge, this is the first systematic review evaluating the role of obesity in MGUS.Patients and MethodsWe searched the Medline database and ClinicalTrials.gov for studies investigating BMI and obesity association with MGUS incidence and progression. The algorithm consisted of a predefined combination of the words “obesity,” “obese,” “body mass index,” “overweight,” “diet,” “nutrition,” “food,” “dietary,” “adiponectin,” “monoclonal gammopathy,” and “MGUS”.ResultsOverall, 12 articles were retrieved, including 11 eligible articles and 1 clinical trial. More than 57,068 patients were evaluated in this systematic review. Discrepancies between the identified studies were noted. Multiple studies support the notion that obesity or high BMI are positively linked to MGUS prevalence and transition to MM. In contrast, other studies revealed no such association. Visceral adipose tissue metabolic activity and decreased adiponectin concentrations were identified as biomarkers of MGUS progression to MM.ConclusionObesity and increased BMI seem to be implicated both in MGUS development and progression to MM. Further studies should be designed to confirm this hypothesis.     

Acute Myeloid Leukemia Complicating Multiple Myeloma: A Case Successfully Treated With Etoposide,Thioguanine, and Cytarabine

BackgroundThe association of acute leukemia and multiple myeloma (MM) has been usually described not only as a complication of chemotherapy but also in the absence of chemotherapy or together at the time of diagnosis. Such leukemias are typically acute myeloid leukemia (AML). The myelomonocytic subtype is particularly found.Case ReportWe report a case of a 68-year-old female who developed AML 2 years after the diagnosis of light chain (κ) myeloma. She had been treated with oral melphalan and prednisone for MM. The patient was treated with an anthracycline-lacking therapy consisting of etoposide 120 mg/m², thioguanine 100 mg/m² orally twice daily on 1-5 days, and cytarabine 40 mg/m² subcutaneously on day 1 (ETC) because of poor cardiac performance.ConclusionFollowing ETC therapy our particular patient has been in complete hematologic remission for 29 months. This therapy might be a safe alternative in secondary leukemia especially for elderly patients.     

14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myélome.

Clonal plasma cells in monoclonal gammopathy of undetermined significance (MGUS) have been shown to bear copy number chromosome changes. To extend our knowledge of MGUS to structural chromosomal abnormalities, we have performed fluorescence in situ hybridization experiments with probes directed to the 14q32 and 13q14 chromosomal regions in 100 patients with either MGUS or smoldering multiple myeloma (SMM). 14q32 abnormalities were observed in at least 46% of patients with MGUS/SMM, with these abnormalities being present in the majority of clonal plasma cells. Whereas t(11;14)(q13;q32) occurs in 15% of MGUS/SMM patients, an incidence similar to that of overt multiple myeloma (MM) patients, translocation t(4;14)(p16;q32) is observed in only 2% of these cases [P = 0.002 for difference with t(11;14)], as compared with 12% in MM patients (P = 0.013). Monoallelic deletions of the 13q14 region were found in 21% of patients, with two types of situations. In half of the evaluable patients, and especially in patients with SMM, the deletion is present in the majority of clonal plasma cells, as in MM, whereas in the other half of the evaluable patients (essentially in MGUS patients), it is observed in subclones only. These data enable us to elaborate a plasma cell oncogenesis model from MGUS to MM.     

Effect of Exposure to Agent Orange on the Risk of Monoclonal Gammopathy and Subsequent Transformation to Multiple Myeloma: A Single-Center Experience From the Veterans Affairs Hospital,Detroit

BackgroundMonoclonal gammopathy of undetermined significance (MGUS) is an indolent, premalignant plasma cell disorder with the potential of transforming into symptomatic multiple myeloma (MM). There are multiple risk factors that contribute to transformation. Agent Orange (AO) has been linked with multiple malignant and nonmalignant conditions.Patients and MethodsWe conducted a retrospective chart review of patients with monoclonal gammopathy who were seen at John D. Dingell Veterans Affairs Medical Center (Detroit, Michigan) between 2005 and 2015 with MGUS, smoldering multiple myeloma, and MM. We explored baseline patient characteristics and explored AO exposure. Dates of diagnosis, dates of progression, and expiration dates were recorded to time to progression and overall survival (OS).ResultsWe identified 211 patients with monoclonal gammopathy; 96% were male and 122 were African American. Eleven patients had reported AO exposure. Cumulative risk of progression in the overall population was 1.4% at 1 year. Risk of transformation in the population exposed to AO was significantly higher with a hazard ratio (HR) of 11.19 (95% confidence interval [CI], 2.10-59.47; P = .005). OS was numerically shorter in AO-exposed patients with a median OS of 7 years compared with 11.1 years in those not exposed. However, AO exposure was not associated with OS in multivariable analysis (HR, 0.50; 95% CI, 0.07-3.83; P = .508).ConclusionMonoclonal gammopathy is a premalignant condition with the risk of progressing to MM. Exposure to AO has been implicated in multiple conditions including MM. Our study demonstrates an increased risk of progression in exposed patients.     

Patterns of hematologic malignancies and solid tumors among 37,838 first‐degree relatives of 13,896 patients with multiple myeloma in Sweden

There are emerging data to suggest a role for genetic factors in the pathogenesis of multiple myeloma (MM). Based on small numbers, certain solid tumors have been reported to occur more frequently among blood relatives of patients with MM. Using population‐based data, we assessed risks for hematologic malignancies, monoclonal gammopathy of undetermined significance (MGUS), and solid tumors among first‐degree relatives of patients with MM. We included 13,896 patients with MM and 54,365 matched controls. Also we identified first‐degree relatives of patients with MM (n = 37,838) and controls (n = 151,068). Using a marginal survival model, we estimated relative risks (RRs) and 95% confidence intervals (CIs) for hematologic and solid tumors among family members of patients with MM and controls as measures of familial aggregation. Compared with relatives of controls, relatives of patients with MM had an increased risk of developing MM (RR = 2.1; 95% CI 1.6–2.9), MGUS (2.1; 1.5–3.1), acute lymphoblastic leukemia (ALL) (2.1; 1.0–4.2), any solid tumor (1.1; 1.0–1.1) and bladder cancer (1.3; 1.0–1.5). No significantly increased risk was found for other hematologic or solid malignancies. Our findings support a role for a shared susceptibility (genetic, environmental or both) that predisposes to MM, MGUS, ALL and bladder cancer. © 2009 UICC     

Serum Levels of Total-RANKL in Multiple Myeloma

BackgroundReceptor activator of nuclear factor-κB ligand (RANKL) plays a key role in osteoclast activation in myeloma bone disease. The increased expression of RANKL in the bone marrow microenvironment was demonstrated in several studies, but there are only rare data on circulating RANKL levels in patients with multiple myeloma (MM).Patients and MethodsIn the current study, we investigated the clinical significance of serum RANKL levels, using an enzyme-linked immunosorbent assay test that detects both free and osteoprotegerin (OPG)-bound RANKL (total-RANKL, tRANKL) in patients with newly diagnosed MM (n = 93) and monoclonal gammopathy of undetermined significance (MGUS; n = 20) compared with healthy controls (n = 20).ResultsCirculating serum tRANKL was significantly elevated in patients with MM compared with controls (P < .001) or MGUS (P < .001). Furthermore, tRANKL levels were higher in smoldering MM versus MGUS (P = .031) and in symptomatic versus smoldering MM (P < .001). Serum tRANKL increased parallel to International Staging System stages I to III (P = .004) and correlated with the presence of lytic bone lesions (P < .001). Total-RANKL was a prognostic factor for overall survival in symptomatic MM (P = .043). A significantly longer progression-free survival was observed in patients with a > 50% decrease in tRANKL levels after 3 months of combined chemotherapy and bisphosphonate treatment.ConclusionOur study demonstrates for the first time that serum tRANKL reflects advanced disease, lytic bone destruction, and poor prognosis in MM.     

Multiple Myeloma and Other Malignancies: A Pilot Study From the Houston VA

BackgroundThe prognosis of multiple myeloma (MM) has improved in recent years. Therefore, second malignant neoplasms (SMNs) may become an issue for longer term survivors with MM. An increased incidence of second malignancies was reported in patients who received lenalidomide for relapsed or refractory myeloma.Patients and MethodsData from the Tumor Registry of the Michael E. DeBakey VA Medical Center (1995-2010) were analyzed. Kaplan-Meier survival statistics were calculated.ResultsIn 197 patients with MM, 39 different cancers were observed in 33 patients, the large majority occurring before the diagnosis of MM, with most being early-stage or good-prognosis malignancies. Despite this, the prognosis of patients with a second or third cancer was clearly inferior to patients without other cancers. Notable was a significant number of prostate cancers as preexisting malignancies.ConclusionAt present, most other cancers (for which MM is the secondary malignancy) may not be related to the treatment for myeloma, but due to underlying immunologic, genetic, or environmental factors. Larger studies and careful follow-up, especially in good-risk patients treated with novel agents, are indicated.     

Multiple primary neoplasms in patients with multiple myeloma and primary macroglobulinemia

A review of 65 patients with multiple myeloma (MM) and 10 patients with primary macroglobulinemia (PM) seen at our clinic from 1972 through 1988 revealed further cancers that were found in 11 patients with MM and in 2 patients with PM. In 4 of 13 patients with multiple primary neoplasms, either MM or PM was an antecedent. In 6 patients, MM or PM was coincident with the cancers. In 3 patients, the cancer was antecedent. Only one patient with multiple myeloma developed secondary leukemia following treatment with alkylating agents.     

Serum thymidine kinase and beta-2 microglobulin in monoclonal gammopathies

We evaluated the serum thymidine kinase (TK) and beta-2 microglobulin (beta-2) levels of 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and of 29 patients with multiple myeloma (MM). Both parameters were significantly lower in MGUS than in MM patients and in early (stage I + II) than in advanced (stage III) MM. TK was also lower in MGUS than in stage I MM (p less than 0.025). A seven-fold increase of TK level was documented in one patient who developed a full blown picture of MM 6 years after a diagnosis of MGUS. In 3 patients with stage III MM, a sharp decrease in TK (40-77%) and in beta-2 (29-53%) levels at remission was evident with respect to the levels measured at diagnosis. Patients with high levels of TK or beta-2 had a shorter survival than those with low levels; however, this was statistically significant only for beta-2 levels (p less than 0.02). Serum TK as well as beta-2 levels appear to be of clinical value in monoclonal gammopathies and related to the course of the disease.     

Identification of antigenic targets of paraproteins by expression cloning does not support a causal role of chronic antigenic stimulation in the pathogenesis of multiple myeloma and MGUS

Antigenic targets of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) paraproteins have been suggested to play an important role as growth stimulators in the pathogenesis of these neoplasms. To identify such targets, we screened cDNA libraries from human testis, lung and breast cancer, bovine and porcine muscle and wheat germ for reactivity with paraproteins in the sera from 115 patients with MGUS and MM. Of >6 x 10(8) paraprotein-antigen interactions screened, an IgA paraprotein from a female patient bound to sperm-specific cylicin-2, and 3 IgG paraproteins bound to tripeptidyl-peptidase-II (TPP-2), insulin-like growth-factor binding-protein-2 (IGFBP-2) and porcine kinesin. Specificity was confirmed by reverse Western blots using recombinant antigens. The broad spectrum of auto-, allo- and heteroantigens as targets of human paraproteins in patients without signs of chronic antigenic stimulation renders a causal role of the antigenic stimulus in the pathogenesis of MGUS and MM unlikely.     

Serum thymidine kinase in monoclonal gammopathies. A prospective study. The Cooperative Group for Study and Treatment of Multiple Myeloma.

Between January 1986 and March 1990, the serum levels of thymidine kinase (TK) were evaluated at diagnosis in 97 patients with monoclonal gammopathy of undetermined significance (MGUS) and 149 patients with multiple myeloma (MM) enrolled in a prospective protocol for treatment of MM. At presentation, patients with MGUS had lower TK levels than those with Stage I MM (P less than 0.05) and the overall population of those with MM (P less than 0.0005). TK levels were increased in advanced stages in comparison with earlier ones (P less than 0.01). The TK level was related to survival. With a median follow-up of 29 months, patients with TK levels greater than 7.0 U/microliters had shorter survival times than those with lower levels (medians, 23 and 42 months; P less than 0.0001). In a multivariate analysis, TK explained most of the variability of survival (P less than 0.0001), the remaining being accounted for by serum creatinine and beta-2 microglobulin. No changes in TK levels occurred during follow-up of patients with stable MGUS, whereas TK levels increased in two patients at time of progression to overt MM. In patients with MM, TK levels decreased (P less than 0.01) in those who responded to treatment but increased in those having relapses (P less than 0.03) and those with progressive disease (P less than 0.03). These results indicate that TK has clinical and prognostic relevance in monoclonal gammopathies, and additional investigations are warranted to determine whether it is a useful tool for the clinical evaluation, staging, and follow-up of patients with MM.     

High Dimensional Immune Profiling of Smoldering Multiple Myeloma Distinguishes Distinct Tumor Microenvironments

BackgroundMultiple myeloma (MM) is a malignancy of plasma cells that arises from premalignant Monoclonal Gammopathy of Undetermined Significance (MGUS) and often progresses through an asymptomatic Smoldering (SMM) phase. Understanding the interactions between abnormal clonal plasma cells and the tumor microenvironment (TME) in the early disease states (MGUS, SMM) may inform risk assessment and therapy.Patients and MethodsWe performed high dimensional immunologic analysis of bone marrow specimens from 73 subjects with SMM by mass cytometry and T cell receptor sequencing of CD138-depleted bone marrow (BM) mononuclear cells, and proteomics and seromic profiling of BM plasma. Analysis of individual assay data identified self-organizing subgroups of SMM patients. We then applied novel bioinformatic methods to integrate data from pairs, trios, and quartets of assays.ResultsMass cytometry, TCRSeq and proteomics identified three taxa (sing. taxon) of subjects that shared common characteristics across all three assays. Differential levels of BM plasma pleiotropin (PTN) and BM T cells and their productive clonality emerged as strong distinguishing factors among these taxa.ConclusionThese results suggest that the continuum from MGUS to MM does not consist of a single pathway in the TME, and that complex interactions between myeloma cells and the TME may ultimately determine progression and inform clinical management.     

Risk and Severity of COVID-19 Infection in Monoclonal Gammopathy of Undetermined Significance: A 3-Year Propensity Matched Cohort Study

IntroductionMonoclonal gammopathy of undetermined significance (MGUS) is a premalignant disorder causing monoclonal plasma cell proliferation in bone marrow. This population is at risk of developing multiple myeloma (MM) and severe viral infections; risk factors of severe COVID-19 infection. Using TriNetX, a global platform providing data of 120 million patients, we aimed to quantify the risk and severity of COVID-19 in MGUS patients.Patients and MethodsA retrospective cohort analysis was performed using the TriNetX Global Collaborative Network. From January 20, 2020, to January 20, 2023, we identified a cohort of 58,859 MGUS patients and compared to non-MGUS patients, determined by relevant diagnosis/LOINC test codes. After 1:1 propensity score-matching, we identified COVID-19 cases to quantify risk and identify patients who had been hospitalized, ventilated/intubated, and deceased to quantify severity. Measures of association and Kaplan-Meier analysis were conducted.ResultsAfter propensity-score matching, there were 58,668 patients in both cohorts. MGUS patients were found to be at a reduced risk of contracting COVID-19 (RR 0.88, 95% CI 0.85-0.91). MGUS patients with COVID-19 showed higher mortality risk and decreased survival time compared to the general population (HR 1.14, 95% CI 1.01-1.27). MGUS patients with COVID-19 who were hospitalized exhibited significantly decreased survival time (log-rank test, P = 0.04).ConclusionAs COVID-19 remains a looming health concern, especially amongst vulnerable populations, our analysis emphasizes the need for adequate vaccination and treatment regimens as well as an understanding of the severity of infection in MGUS patients and justification for precautionary measures.