Diagnostic Criteria For Multiple Myeloma Research Articles

Whole-Body Imaging of Multiple Myeloma: Diagnostic Criteria.

Multiple myeloma (MM) is a clonal plasma cell proliferative disorder characterized by primary infiltration of bone marrow and excessive production of abnormal immunoglobulin. This disease is the second most common hematologic malignancy (after lymphoma), and its spectrum of characteristic features are widely known by the acronym CRAB (hypercalcemia, renal impairment, anemia, and bone lesions). Traditionally, the diagnosis and treatment of MM have been triggered by clear end-organ damage. However, owing to recently introduced treatment options that can extend patient survival and the increasing recognition of biomarkers that can be used to identify patients at high risk of progression to active disease, the diagnostic criteria have been revised. Bone disease is one of the most prominent features of MM, and imaging has an important role in diagnosis and follow-up, with each whole-body imaging modality having different indications in distinct disease situations. Skeletal survey has been the standard imaging procedure used during the past decade, but it should no longer be used unless it is the only option. Whole-body low-dose CT is a reasonable and cost-effective initial imaging approach. Whole-body MRI is the most sensitive technique for detecting bone involvement and assessing painful complications. PET/CT is the best tool for evaluating treatment response. The importance of radiologists has increased in this scenario. Therefore, to properly assist hematologists and improve the care of patients with MM, it is essential that radiologists know the updated diagnostic criteria for MM, indications for and limitations of each imaging option, and recommendations for follow-up. Online supplemental material is available for this article. ©RSNA, 2019.

Correlation between expressions of stromal cell-derived factor 1α and osteoprotegerin and bone disease in multiple myeloma

Objective To understand the correlation of expression levels of serum stromal cell-derived factor 1α (SDF-1α), osteoprotegerin (OPG) and β2 microglobulin (β2-MG) in patients with multiple myeloma (MM) with or without myeloma bone disease (MBD). Methods Eighty patients with MM who were admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2014 to June 2017 were selected; all of the patients met the international diagnostic criteria for MM. According to the symptoms such as bone pain, the patients were divided into group with MBD (45 cases) and group without MBD (35 cases). Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of SDF-1α and OPG, and radioimmunoassay was used to detect the expression of MM major prognostic indicator β2-MG. The MBD score was evaluated in 45 patients selected by random number table after sacroiliac joint X-ray and three-dimensional bone reconstruction. The χ 2 test was used to compare the categorical variables; the two independent sample t-test was used to compare the continuous variables that conformed to the normal distribution between two groups, and the Pearson method was used for the correlation analysis. Results The expression level of serum SDF-1α in the group with MBD was significantly higher than that in the group without MBD [0.31±0.17) pg/ml vs. (0.18±0.06) pg/ml], and the difference was statistically significant (t=-4.21, P < 0.001). The expression level of serum OPG in the group with MBD was significantly lower than that in the group without MBD [(0.73±0.50) pg/ml vs. (1.08±0.31) pg/ml], and the difference was statistically significant (t= 3.62, P < 0.001). Pearson analysis showed that β2-MG level in the group was positively correlated with SDF-1α level (r= 0.84, P < 0.001), and negatively correlated with OPG level (r=-0.48, P < 0.001). The β2-MG level in the group without MBD did not show a correlation with the SDF-1α and OPG levels. Conclusions In the serum of patients with MBD, the expression levels of β2-MG and SDF-1α are increased, and the expression level of OPG is decreased. SDF-1α and OPG may be new clinical biochemical indicators for diagnosis, treatment and prognosis assessment in MBD. Key words: Multiple myeloma; Myeloma bone disease; Stromal cell-derived factor; Osteoprotegerin; β2 microglobulin

Revised diagnostic criteria for plasma cell leukemia: results of a Mayo Clinic study with comparison of outcomes to multiple myeloma

The current definition of plasma cell leukemia (PCL)— ≥ 20% circulating plasma cells (CPCs) on peripheral smear and plasma cell count ≥ 2 × 109/L—may be too stringent. We reviewed outcomes of 176 multiple myeloma (MM) patients diagnosed between 1971 and 2016, and who had CPCs detectable at diagnosis, to determine whether a lower threshold could be used to diagnose PCL. Median overall survival (mOS) was 1.1 years (95% CI 0.8–1.4) and was similar between patients with < 5% (n = 54, mOS = 1.4 years [0.7–2.0]), 5–19% (n = 63, mOS = 1.1 years [0.7–1.4]), and ≥ 20% CPCs (n = 59, mOS = 1.1 years [0.7–1.5], p = 0.349). As survival was similar between those with 5–19% and ≥ 20% CPCs, we stratified patients by < 5% (mOS = 1.4 years [0.7–2.0]) and ≥ 5% CPCs (mOS = 1.1 years [0.8–1.4], p = 0.154). Outcomes of those with ≥ 5% CPCs were much poorer when compared with a cohort of MM patients diagnosed between 1971 and 2016, who did not have CPCs at diagnosis (n = 9724, mOS = 4.4 yrs [4.3–4.5], p < 0.001); survival was also lower in patients diagnosed after 2001 with ≥ 5% CPCs (n = 62, mOS = 1.4 years [0.8–2.5]) compared with patients with standard risk (n = 1326, mOS = 7.5 years [7.0–8.7]) and high-risk MM (n = 381, mOS = 4.3 years [3.5–4.9], p < 0.001). We therefore propose that the definition of PCL be revised to patients with ≥ 5% CPCs on peripheral blood smear, who otherwise meet diagnostic criteria for MM.

Comparing five diagnostic criteria for multiple myeloma: a retrospective study of 227 cases.

Several diagnostic criteria for multiple myeloma are used in clinical practice, and it can be difficult to reach a diagnosis when a patient's clinical presentation is consistent with one criterion but not with another. However, no study to date has compared the superiority of the different diagnostic criteria. The aim of this research is to compare the efficacy of five diagnostic criteria for multiple myeloma and to find the reasons for misdiagnosis of atypical multiple myeloma cases. A total of 227 multiple myeloma cases were retrospectively studied. The clinical data (including plasma cell morphology, flow cytometry, immunofixation electrophoresis, imaging information and clinical manifestations) were scrutinized and the reasons underlying the misdiagnoses analyzed. The Traditional Domestic criteria had the highest misdiagnosis rate due to the high fixed bone marrow plasma cell percentage and serum M-protein thresholds. The WHO criteria and the International Myeloma Working Group 2009 criteria exhibited relatively low misdiagnosis rates due to their lower bone marrow plasma cell percentage thresholds, flexible criteria and detailed end-organ damage descriptions. The 2003 International Myeloma Working Group criteria and the 2011 Chinese Myeloma Working Group criteria exhibited perfect performance, as each focused on monoclonal plasma cell proliferation and not on fixed bone marrow plasma cell percentage and serum M-protein thresholds. The 2003 International Myeloma Working Group criteria and the 2011 Chinese Myeloma Working Group criteria have advantages in diagnosing early or atypical multiple myeloma cases. To avoid misdiagnosing some atypical cases of multiple myeloma, attention should be paid to evidence of monoclonal plasma cell proliferation, and flow cytometry may be a useful tool for discovering monoclonal plasma cell proliferation. Advanced imaging techniques should be used to confirm any suspected or atypical findings on metastatic bone survey.

Shall we treat smoldering multiple myeloma in the near future?

In recent years, several new drugs have been approved for the treatment of multiple myeloma. Many of these newer drugs are highly efficacious and less toxic than older chemotherapy drugs. In 2014, the diagnostic criteria for multiple myeloma were revised. The intent with the new criteria was to identify patients who require therapy at an earlier stage than at manifestation of organ complications. A subset of patients who were previously defined as having high-risk smoldering multiple myeloma was redefined as having multiple myeloma. In this context, it is logical to raise questions regarding the optimal clinical management of patients who are diagnosed with smoldering multiple myeloma in the current era. When is the optimal time to start therapy? Do the clinical trajectories for patients suggest there are distinct sub-entities hidden in the current category of smoldering multiple myeloma? How can we move the field forward from here? This paper reviews and dissects data and models on the topics of clinical features, underlying biology, and early treatment trials in smoldering multiple myeloma. The text highlights assumptions, facts, and gaps in the literature. As indicated in the title of the paper, the recurrent theme of the text is this: shall we treat smoldering multiple myeloma in the near future?

Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group

For decades, conventional skeletal survey (CSS) has been the standard imaging technique for multiple myeloma (MM). However, recently whole-body computed tomography (WBCT) has been implemented into the diagnostic criteria of MM. This analysis compares sensitivity and prognostic significance of WBCT and CSS in patients with smoldering MM (SMM) and MM. Fifty-four of 212 patients (25.5%) had a negative CSS and a positive WBCT for osteolytic lesions (P<0.0001). Of 66 patients with SMM based on CSS, 12 (22.2%) had osteolytic lesions on WBCT. In comparison, WBCT failed to detect some bone destructions in the appendicular skeleton possibly due to limitations of the field of view. Presence of lytic bone lesions in WBCT was of borderline prognostic significance (P=0.051) for SMM patients, with a median time to progression of 38 versus 82 months for those without bone destructions. In conclusion, WBCT identifies significantly more sites of bone destruction than CSS. More than 20% of patients with SMM according to CSS have in fact active MM detectable with WBCT. On the basis of this and other studies, WBCT (either computed tomography (CT) alone or as part of a positron emission tomography-CT protocol) should be considered the current standard for the detection of osteolytic lesions in MM.

Anterior horn lesion of spinal cord as the initial manifestation of multiple myeloma: A case report

&lt;p&gt;Multiple myeloma (MM) is a malignant proliferation of abnormal plasma cell tumour that often violates multiple body systems. Its clinical manifestations vary greatly, thus leading to a high rate of misdiagnosis. Herein, we report a clinical case of non-compressive spinal cord lesion, which manifested early signs of multiple myeloma. Retrospective analyses of MM pathogenesis, clinical manifestation, and diagnosis were based on the clinical features and diagnostic criteria of MM that have been published in the literature. This study was initiated to improve current awareness of MM and to reduce the rate of misdiagnosis. &lt;/p&gt;

Bone Marrow DKK-1 Levels in Smoldering Multiple Myeloma Patients: A New Independent Risk Factor for Progression

The presence of bone disease is the hallmark to differentiate patients with active multiple myeloma (MM) from those with smoldering MM (SMM). The diagnostic criteria for active MM have been recently updated; including patients previously defined high-risk SMM among those with active MM in the presence of biomarkers of malignity. Actually SMM patients can be stratified for the risk of progression to active MM based on several factors but new parameters to identify patients with a high risk of progression need to be defined. Particularly there are not any molecular factors able to differentiate the new high-risk SMM patients. Recently, we analyzed bone marrow (BM) levels of several cytokines and chemokines involved in the MM-induced alterations of the bone remodeling finding that BM levels of Activin A, C-C motif chemokine ligand 20 (CCL20), Dickkopf 1 (DKK-1) and osteoprotegerin (OPG) were significantly different among patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), SMM and MM (Dalla Palma B et al. Leukemia 2016). Thus, in this study we focused on those soluble factors in order to evaluate their possible role as new markers of risk progression in SMM patients.We analyzed a total cohort of 87 patients with SMM as defined by the International Myeloma Working Group updated diagnostic criteria for MM and related disorders (serum monoclonal protein (IgG or IgA) ≥ 3 g/dL, or urinary monoclonal protein ≥500 mg/24 h and/or clonal BM plasma cells 10%-60%, and absence of myeloma defining events or amyloidosis) admitted to our Myeloma Unit between 2007 and 2015 and who underwent to BM aspirate. The median age of the patients was 65 years (range 38-92); 50 were males and 37 were females; light chain was kappa in 68% of patients and lambda in 32%, whereas heavy chain was IgG in 76%, IgA in 23% and IgD in 1%. Standard risk factors evaluated were size of serum M protein (≥ 3 g/dL in 14% of patients), percentage of BM plasma cells and immunoparesis (present in 66% of patients). Free Light Chain (FLC) ratio was not available in all patients. DKK-1, Activin A, CCL20, and OPG BM plasma levels were measured by ELISA assay. Quantitative variables were compared by non-parametric Kruskal-Wallis and Mann-Whitney tests as appropriate and categorical variables were analyzed by Chi-square and Fisher’s exact test. P value of <0.05 was considered significant. The influence of BM cytokine and chemokine levels on the progression to active MM in SMM patients was examined by Kaplan-Meier and Cox regression analysis.With a median follow-up time of 42 months, 21 patients progressed to active MM; median time to progression was 16 months. BM Activin A, CCL20 and OPG median levels were not significantly different between progressed and not SMM patients (median levels: Activin A 401.97 pg/mL vs 402.93 pg/ml, p=0.70; CCL20 68.68 pg/mL vs 62.08 pg/mL, p=0.80; OPG 101.94 pg/mL vs 118.74 pg/mL, p=0.86). Conversely SMM patients progressed to active MM showed significantly higher DKK-1 BM levels as compared to patients who had not progressed (median levels: 1777.50 pg/mL vs 782.77 pg/mL, p=0.007). The progression-free survival was significantly worse in patients with BM DKK-1 above the median (DKK-1 median level: 971 pg/mL; p=0.021 by log rank test). In multivariate analysis, adjusted for standard risk factors such as the size of serum M protein, the percentage of BM plasma cells, the presence of the immunoparesis, we found that BM DKK-1 levels remained an independent prognostic factor for progression to active MM (p=0.001).In conclusion, our study indicates that BM median levels of DKK-1 are able to identify the SMM patients with higher risk of progression to active MM, and may represent a new independent risk factor for progression in SMM patients. DisclosuresGiuliani:Celgene: Research Funding; Janssen: Research Funding.

Findings of Whole Body Computed Tomography Compared to Conventional Skeletal Survey in Patients with Monoclonal Plasma Cell Disorders - a Study of the International Myeloma Working Group

Findings of Whole Body Computed Tomography Compared to Conventional Skeletal Survey in Patients with Monoclonal Plasma Cell Disorders - a Study of the International Myeloma Working Group

Serum-free light-chain analysis in diagnosis and management of multiple myeloma and related conditions

The introduction of the serum-free light-chain (S-FLC) assay has been a breakthrough in the diagnosis and management of plasma cell dyscrasias, particularly monoclonal light-chain diseases. The first method, proposed in 2001, quantifies serum-free light-chains using polyclonal antibodies. More recently, assays based on monoclonal antibodies have entered into clinical practice. S-FLC measurement plays a central role in the screening for multiple myeloma and related conditions, in association with electrophoretic techniques. Analysis of S-FLC is essential in assessing the risk of progression of precursor diseases to overt plasma cell dyscrasias. It is also useful for risk stratification in solitary plasmacytoma and AL amyloidosis. The S-FLC measurement is part of the new diagnostic criteria for multiple myeloma, and provides a marker to follow changes in clonal substructure over time. Finally, the evaluation of S-FLC is fundamental for assessing the response to treatment in monoclonal light chain diseases.

Updated Diagnostic Criteria and Staging System for Multiple Myeloma.

There has been remarkable progress made in the diagnosis and treatment of multiple myeloma (MM). The median survival of the disease has doubled as a result of several new active drugs. These advances have necessitated a revision of the disease definition and staging of MM. Until recently, MM was defined by the presence of end-organ damage, specifically hypercalcemia, renal failure, anemia, and bone lesions (CRAB features) that can be attributed to the clonal process. In 2014, the International Myeloma Working Group (IMWG) updated the diagnostic criteria for MM to add three specific biomarkers that can be used to diagnose the disease in patients who did not have CRAB features: clonal bone marrow plasma cells greater than or equal to 60%, serum free light chain (FLC) ratio greater than or equal to 100 provided involved FLC level is 100 mg/L or higher, or more than one focal lesion on MRI. In addition, the definition was revised to allow CT and PET-CT to diagnose MM bone disease. These changes enable early diagnosis and allow the initiation of effective therapy to prevent the development of end-organ damage for patients who are at the highest risk. A new staging system has been developed that incorporates high-risk cytogenetic abnormalities in addition to standard laboratory markers of prognosis.

Fatal Cryocrystalglobulinemia With Intravascular and Renal Tubular Crystalline Deposits

Cryocrystalglobulinemia is a rare variant of cryoglobulinemia in which monoclonal immunoglobulins self-assemble into crystalline arrays. We report a case of a 53-year-old man who presented with systemic thrombotic microangiopathy causing multiorgan failure, including decreased kidney, lung, and gastrointestinal function; skin necrosis; and mental status changes. Skin and kidney biopsy specimens showed intravascular thrombi, along with intravascular, intratubular, and periglomerular crystalline deposits. Typical morphologic features of cryoglobulinemia, such as a leukocytoclastic vasculitis and pseudothrombi, were absent. Spindled crystals precipitated in the cryoglobulin assay, and immunofixation showed them to be composed of monoclonal immunoglobulin G κ light chains. Ultrastructural analysis demonstrated deposits to have an array-like substructure. The patient was successfully treated with a combination of plasmapheresis, steroids, and bortezomib, but experienced a relapse and died 12 months after his initial diagnosis. Cryocrystalglobulinemia causes significant morbidity and mortality and should be classified as a monoclonal gammopathy of renal significance when it occurs in patients not meeting diagnostic criteria for multiple myeloma.

MGUS and Smoldering Multiple Myeloma: Diagnosis and Epidemiology.

Monoclonal gammopathy of undetermined significance (MHUS) is characterized by the presence of a serum M-protein less than 3g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of myeloma-defining event. Smoldering multiple myeloma (SMM) is an asymptomatic disorder characterized by the presence of ≥3g/dL serum M-protein and/or 10-60% bone marrow plasma cell infiltration with no myeloma-defining event. The risk of progression to multiple myeloma (MM) requiring therapy varies greatly for individual patients, but it is uniform and 1% per year for MGUS, while higher (10% per year) and not uniform for SMM patients. The definition of MM was recently revisited patients previously labeled as SMM with a very high risk of progression (80-90% at 2years) were included in the updated definition of MM requiring therapy. The standard of care is observation for MGUS patients and although this also applies for SMM, a recent randomized trial targeting high-risk SMM showed that early intervention was associated with better progression-free and overall survival. Biomarkers have become an integrated part of diagnostic criteria for MM requiring therapy, as well as clinical risk stratification of patients with SMM. This paper reviews and discusses clinical implications for MGUS and SMM patients.

Diagnostics for multiple myeloma.

Multiple myeloma (MM) has been diagnosed based on the International Myeloma Working Group (IMWG) diagnostic criteria since 2003. In 2014, the IMWG updated these diagnostic criteria to add three specific biomarkers, i.e., 1) Clonal bone marrow plasma cell percentage ≥60%; 2) Involved: uninvolved serum free light chain ratio ≥100; 3) >1 focal lesion on MRI studies, based on CRAB features (hypercalcemia, renal failure, anemia, and bone lesions). An early diagnosis of MM can be made, allowing timely anti-MM treatment, in patients with the ultra-high-risk smoldering form of this disease. This review focuses on the new IMWG diagnostic criteria for MM and evaluation of patients newly diagnosed with MM.

Evolving diagnostic criteria for multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy historically defined by the presence of end-organ damage, specifically, hypercalcemia, renal failure, anemia, and bone lesions (CRAB features) that can be attributed to the neoplastic process. In 2014, the International Myeloma Working Group (IMWG) updated the diagnostic criteria for MM to add specific biomarkers that can be used to make the diagnosis of the disease in patients who did not have CRAB features. In addition, the update allows modern imaging methods including computed tomography (CT) and positron emission tomography-CT to diagnose MM bone disease. These changes enable early diagnosis, and allow the initiation of effective therapy to prevent the development of end-organ damage in patients who are at the highest risk. This article reviews these and several other clarifications and revisions that were made to the diagnostic criteria for MM and related disorders. The updated disease definition for MM also automatically resulted in a revision to the diagnostic criteria for the asymptomatic phase of the disease termed smoldering MM (SMM). Thus the current diagnosis and risk-stratification of SMM is also reviewed in this article. Using specific prognostic factors, it is possible to identify a subset of patients with SMM who have a risk of progression to MM of 25% per year (high-risk SMM). An approach to the management of patients with low- and high-risk SMM is discussed.

Updated diagnostic criteria for multiple myeloma: report from 2015 International Myeloma Working Group conference

With deep understanding of the biological characteristics of multiple myeloma(MM), treatment diversity, and the improvement of laboratory and imaging technology, the International Myeloma Working Group (IMWG) revised the diagnostic criteria for MM in 2014 and held a conference in Vienna in 2015.In this conference, experts made an interpretation and discussion for the revised diagnostic criteria for MM. Redefined active MM as proportion of clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma and any one or more of the following conditions. Sypercalcaemia, renal insufficiency, anemia and osteolytic bone destruction; super high risk smoldering myeloma biomarkers including proportion of clonal bone marrow plasma cells ≥60%, a serum involved to uninvolved free light chain ratio ≥100, and >1 focal lesions on MRI (each focal lesion must be 5 mm or more in size) were included in the MM diagnostic criteria. Key words: Multiple myeloma; Diagnosis

Positron emission tomography-computed tomography in the diagnostic evaluation of smoldering multiple myeloma: identification of patients needing therapy.

We studied 188 patients with a suspected smoldering multiple myeloma (MM) who had undergone a positron emission tomography-computed tomography (PET-CT) scan as part of their clinical evaluation. PET-CT was positive (clinical radiologist interpretation of increased bone uptake and/or evidence of lytic bone destruction) in 74 patients and negative in 114 patients. Of these, 25 patients with a positive PET-CT and 97 patients with a negative PET-CT were observed without therapy and formed the study cohort (n=122). The probability of progression to MM within 2 years was 75% in patients with a positive PET-CT observed without therapy compared with 30% in patients with a negative PET-CT; median time to progression was 21 months versus 60 months, respectively, P=0.0008. Of 25 patients with a positive PET-CT, the probability of progression was 87% at 2 years in those with evidence of underlying osteolysis (n=16) and 61% in patients with abnormal PET-CT uptake but no evidence of osteolysis (n=9). Patients with positive PET-CT and evidence of underlying osteolysis have a high risk of progression to MM within 2 years when observed without therapy. These observations support recent changes to imaging requirements in the International Myeloma Working Group updated diagnostic criteria for MM.

New Diagnostic Criteria for Multiple Myeloma

Multiple myeloma (MM) has been traditionally defined by the presence of end-organ damage, specifically, hypercalcemia, renal failure, anemia, and bone lesions (CRAB features) that are felt to be a consequence of the underlying clonal plasma cell proliferation. The International Myeloma Working Group (IMWG) has updated the diagnostic criteria for MM in 2014, adding 3 specific biomarkers that can be used to make the diagnosis in patients who do not have CRAB features. These 3 biomarkers are: presence of ≥60% clonal plasma cells in the marrow, serum free light chain (FLC) ratio ≥100 (provided involved FLC level ≥100), and more than 1 focal lesion (≥5mm in size) on magnetic resonance imaging (MRI) or whole body or spine/pelvis (Table1). Each of these biomarkers has been validated in 2 or more independent studies to have a very high risk (∼80%) of progression to symptomatic disease within 2 years. In addition, the update allows modern imaging methods including computed tomography (CT) and positron emission tomography-CT to diagnose MM bone disease. The new diagnostic criteria provide 3 important clarifications on requirements for bone and renal disease in the diagnosis of MM. First, the presence of osteoporosis, vertebral compression fractures, or bone densitometric changes in the absence of lytic lesions is not considered sufficient evidence of myeloma bone disease. Second, only suspected or proven light chain cast nephropathy is considered as meeting the renal component of the CRAB criteria. Renal disorders associated with M proteins such as light chain deposition disease, membranoproliferative glomerulonephritis, and AL amyloidosis, are considered unique diseases and not MM. Third, an estimated GFR less than 40 ml/ minute is preferred to the serum creatinine concentration for purposes of fulfilling the CRAB criteria. One of the main implications of the new diagnostic criteria is that at least one advanced imaging exam (PET-CT, low-dose whole body CT, or MRI of the whole body or spine) is needed for diagnosis in patients with suspected SMM or solitary plasmacytoma. Another implication is that patients with high risk SMM and solitary plasmacytoma who develop symptoms worrisome for progression during the course of follow up can be initiated on therapy before the onset of serious end-organ damage. Table 1International Myeloma Working Group Diagnostic Criteria for Smoldering Multiple Myeloma and Multiple Myeloma Disorder Disease Definition Smoldering multiple myeloma Both criteria must be met: • Serum monoclonal protein (IgG or IgA) ≥3gm/dL, or urinary monoclonal protein ≥500 mg per 24h and/or clonal bone marrow plasma cells 10-60% • Absence of myeloma defining events or amyloidosis Multiple Myeloma Both criteria must be met: • Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma • Any one or more of the following myeloma defining events (MDE): ○ CRAB features felt attributable to the underlying plasma cell proliferative disorder, specifically: ▪ Hypercalcemia ▪ Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177 μmol/L (>2 mg/dL) ▪ Anemia ▪ Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT ○ Clonal bone marrow plasma cell percentage ≥60% ○ Involved: uninvolved serum free light chain (FLC) ratio ≥100 (involved free light chain level must be ≥100 mg/L) ○ >1 focal lesions on MRI (at least 5mm in size) Reproduced from Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538-e548. Open table in a new tab Reproduced from Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538-e548.

The use of immunoglobulin light chain assays in the diagnosis of paraprotein-related kidney disease

Kidney involvement is common in paraprotein-related diseases. A diversity of clinical presentations and histopathological features can occur secondary to tissue injury caused by precipitation or deposition of a clonal immunoglobulin, usually an immunoglobulin light chain. The paraprotein is either produced by multiple myeloma or by a clone of B-cell lineage that does not fulfill diagnostic criteria for multiple myeloma. The recent introduction of serum immunoglobulin free light chain assays, which accurately quantify both light chain isotypes to produce a ratio that indicates the presence or absence of a light chain paraprotein, is a major clinical development. However, as the interpretation of the assay can be challenging, the aim of this review is to clarify the role of serum and urinary light chain assays in the screening and diagnosis of paraprotein-related kidney disease.

Dasatinib Inhibits Multiple Myeloma Growth by Blocking PDGF-Rb and c-Src Activity in Patient-Derived Tumor and Endothelial Cells.

Multiple myeloma (MM) is characterized by a clonal proliferation of immunoglobulin-secreting plasma cells in the bone-marrow (BM) and remains an incurable disease, despite the use of high-dose chemotherapies. Since a marked (BM)-angiogenesis is the hallmark of MM, but not of monoclonal gammopathies of undetermined significance (MGUS), validation of novel agents targeting MM tumor cells and their permissive BM-stroma is crucial to improve patient outcome. Patients fulfilling the International Myeloma Working Group diagnostic criteria for MM (n = 21) and MGUS (n = 14) were studied. Healthy donors or patients with benign anemia (due to vitamin B12 deficiency) were also incuded as controls. In plasma cells and endothelial cells (ECs) isolated from BM-aspirates by anti-CD138 and Ulex Europaeus agglutinin-1 (UEA-1) coated-beads, we dissected the contribution of activity against individual targets such as platelet-derived growth factor (PDGF)-receptor beta (PDGF-Rb) and c-Src tyrosine kinases (TKs), to the anti-tumor/vessel efficacy of dasatinib (BMS-354825), a novel orally bioavailable TK inhibitor. The PDGF-BB/PDGF-Rb kinase-axis was found constitutively activated in plasma cells from patients with MM but not with MGUS or benign anemias, thus supporting its pathophysiological role in MM. PDGF-Rb activated, independently of vascular endothelial growth factor (VEGF)-receptors (VEGF-R1 and VEGF-R2), the mitogen-activated protein kinases (ERK1/2) and the phosphatidylinositol 3-kinase (PI3-K)/AKT-dependent cascade, thereby increasing MM plasma cell growth. Expression of PDGF-Rb, at both mRNA and protein levels, was also increased in MMECs compared to MGECs, correlating with AKT phosphorylation. Exposure to recombinant PDGF-BB or conditioned media from MM plasma cells triggered PDGF-Rb phosphorylation and MMEC migration and spontaneous sprouting in vitro (both being mandatory for angiogenesis). Dasatinib abrogated PDGF-elicited tumor/vessel growth and impaired VEGF-signaling via c-Src TK-inhibition (IC50=25–100nM) in both MM-patient tumor and ECs. The use of small-interfering (si)-RNAs validated c-Src as a key VEGF-downstream effector of MMEC proliferation, migration and capillarogenesis in vitro. Nevertheless, the inhibitory effect elicited by siSrc was partially rescued by recombinant PDGF-BB which sustained the expression of pro-angiogenic factors such as VEGF, interleukin (IL)-8, basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) in MMECs. Dasatinib reversed all these transcriptional effects, thereby abrogating MMEC angiogenesis in the CAM assay as well as the neovascularization and tumor growth of MM-xenografts in vivo. More importantly, low-dose dasatinib showed synergistic cytotoxicity in vitro when tested in combination with conventional MM drugs (i.e. bortezomib and thalidomide), thereby increasing therapeutic efficacy and overcoming drug resistance. These findings indicate that:a.the PDGF-BB/PDGF-Rb kinase-axis elicits direct effects on MM plasma cells and could promote the MM “angiogenic switch”, hence disease progression;b.the inhibition of this pathway could provide the rationale for clinical trials with dasatinib which interferes with shared growth-signaling cascades in MM-patient isolated plasma cells and ECs, involving PDGF-Rb and cytosolic c-Src TKs.