Advances in MGUS diagnosis, risk stratification, and management: introducing myeloma-defining genomic events

In the 1960s, Dr Jan Waldenström argued that patients who had monoclonal proteins without any symptoms or evidence of end-organ damage represented a benign monoclonal gammopathy. In 1978, Dr Robert Kyle introduced the concept of “monoclonal gammopathy of undetermined significance” (MGUS) given that, at diagnosis, it was not possible with available methods (ie, serum protein electrophoresis to define the concentration of M-proteins and microscopy to determine the plasma cell percentage in bone marrow aspirates) to determine which patients would ultimately progress to multiple myeloma. The application of low-input whole-genome sequencing (WGS) technology has circumvented previous problems related to volume of clonal plasma cells and contamination by normal plasma cells and allowed for the interrogation of the WGS landscape of MGUS. As discussed in this chapter, the distribution of genetic events reveals striking differences and the existence of 2 biologically and clinically distinct entities of asymptomatic monoclonal gammopathies. Thus, we already have genomic tools to identify “myeloma-defining genomic events,” and consequently, it is reasonable to consider updating our preferred terminologies. When the clinical field is ready to move forward, we should be able to consolidate current terminologies—from current 7 clinical categories: low-risk MGUS, intermediate-risk MGUS, high-risk MGUS, low-risk smoldering myeloma, intermediate-risk smoldering myeloma, high-risk smoldering myeloma, and multiple myeloma—to future 3 genomic-based categories: monoclonal gammopathy, early detection of multiple myeloma (in which myeloma-defining genomic events already have been acquired), and multiple myeloma (patients who are already progressing and clinically defined cases). Ongoing investigations will continue to advance the field.

Will Mass Spectrometry Replace Current Techniques for Both Routine Monitoring and MRD Detection in Multiple Myeloma?

In recent years, mass spectrometry has been increasingly used for the detection of monoclonal proteins in serum. Mass spectrometry is more analytically sensitive than serum protein electrophoresis and immunofixation, can help distinguish therapeutic monoclonal antibodies from M-proteins, and can detect the presence of post-translational modifications. Mass spectrometry also shows promise as a less-invasive, peripheral-blood-based test for detecting minimal residual disease in multiple myeloma. Studies comparing the clinical utility of mass spectrometry to current blood- and bone-marrow-based techniques have been conducted. Although still primarily limited to research settings, clinical laboratories are starting to adopt this technique for patient care. This review will discuss the current status of mass spectrometry testing for multiple myeloma, the benefits and challenges of this technique, and how it may be incorporated into clinical practice in the future.

The efficiency of hypogammaglobulinemia reflex immunofixation electrophoresis in identifying monoclonal proteins

Introduction/Objective Hypogammaglobulinemia can be a common occurrence in disorders with monoclonal gammopathies. Because hypogammaglobulinemia may mask a monoclonal protein on serum protein electrophoresis (sPEP), its presence in the absence of a discernible M-spike is often the basis of reflexive testing by immunofixation electrophoresis (IFE). At our Institution, reflex IFE has historically been performed in cases where the gamma fraction on sPEP is <0.6 g/dL. The aim of this study was to test the predictive performance of hypogammaglobulinemia in identifying abnormal bands on IFE in newly screened patients. Methods/Case Report All patients that underwent sPEP testing from November 2020 to May 2021 at our Institution were identified. Among them, patients with gamma fraction <0.6 g/dL and no previous sPEP testing were included for analysis. Reflex IFE results were reviewed for identification of abnormal bands. Results (if a Case Study enter NA) Out of a total number of 1,374 patients tested for sPEP in the study period, 72 had serum gamma fraction <0.6 g/dL (5.2%). Among them, 36 patients had no previous sPEP testing, and their reflex IFE were reviewed. In 38.8% of the cases, the IFE showed one or more abnormal (monoclonal) bands. When considering a new threshold for hypogammaglobulinemia IFE reflex of <0.4 g/dL, the diagnostic yield for finding abnormal bands increased to 62.5%. Moreover, a percentage reduction of 64.2% was observed in the number of reflex IFE performed. Conclusion Although these data must be confirmed using a larger sample population, a lower threshold for hypogammaglobulinemia may be proposed at our Institution to reduce labor and costs and to improve efficiency of monoclonal protein detection.

Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma

Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.

Crystalline deposits in the cornea and various areas of the kidney as symptoms of an underlying monoclonal gammopathy: a case report

Background Plasma cell dyscrasias (PCD) are characterized by an abnormal production of intact monoclonal immunoglobulins or parts such as heavy or light chains. In most cases, the monoclonal protein (also termed paraprotein) is produced by a clonal plasma cell population. The production of monoclonal proteins can result in deposits of various types and localization depending on the type, amount, and electrochemical properties of the paraprotein. One histopathologic presentation, albeit rare, are crystalline deposits. They can form in various organs and hence cause a wide spectrum of symptoms. Case presentation A 49-year-old man presented to the emergency department with eyestrain and foreign body sensation after overhead drilling. Examination of the eyes revealed crystalline deposits in the cornea of both eyes. After additional diagnostic testing, deposits were attributed to free light chains. Monoclonal gammopathy of undetermined significance (MGUS) was diagnosed according to serum electrophoresis and immunofixation. Four years later, new onset of proteinuria was detected. A percutaneous biopsy of the kidney showed severe light chain podocytopathy with secondary focal segmental glomerulosclerosis (FSGS) and light chain proximal tubulopathy (LCPT). In these lesions, crystalline deposits identical to the corneal deposits were found in ultrastructural and immunofluorescent analysis. The patient was diagnosed with monoclonal gammopathy of renal significance (MGRS), and a plasma cell directed therapy was initiated. Conclusions PCD can present with a wide array of symptoms and are notoriously difficult to diagnose. Extrarenal manifestations such as crystalline deposits in the cornea are one possible manifestation. The case presented herein emphasizes the notion that extrarenal paraprotein deposits warrant a thorough search for the underlying clonal disease.

MASS-FIX for the detection of monoclonal proteins and light chain N-glycosylation in routine clinical practice: a cross-sectional study of 6315 patients

Immunoenrichment-based matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), termed MASS-FIX, offers several advantages over immunofixation for the detection and isotyping of serum monoclonal protein, including superior sensitivity and specificity, the ability to differentiate therapeutic monoclonal antibodies, and the rapid identification of light chain (LC) N-glycosylation. We identified 6315 patients with MASS-FIX performed at our institution since 2018. Of these, 4118 patients (65%) with a wide array of plasma cell disorders (PCD), including rare monoclonal gammopathies of clinical significance, had a positive MASS-FIX. Two-hundred twenty-one (5%) of the MASS-FIX positive patients had evidence of LC N-glycosylation, which was more commonly identified in IgM heavy chain isotype, kappa LC isotype, and in diagnoses of immunoglobulin light chain (AL) amyloidosis and cold agglutinin disease (CAD) compared to other PCD. This cross-sectional study describes the largest cohort of patients to undergo MASS-FIX in routine clinical practice. Our findings demonstrate the widespread utility of this assay, and confirm that LC N-glycosylation should prompt suspicion for AL amyloidosis and CAD in the appropriate clinical context.

Disease monitoring with quantitative serum IgA levels provides a more reliable response assessment in multiple myeloma patients

Unlike IgG monoclonal proteins (MCPs), IgA MCP quantification is unreliable due to beta-migration of IgA MCPs on serum protein electrophoresis (SPEP). The utility of nephelometric quantitative IgA (qIgA) to monitor IgA multiple myeloma (MM) is unclear. We retrospectively studied disease response kinetics using qIgA versus MCPs by SPEP, and developed and validated novel qIgA disease assessment criteria in 491 IgA MM patients. The SPEP MCP nadir occurred a median of 41 (IQR 0–102) days before the qIgA. The median time to achieve a partial response (PR) was shorter using standard IMWG versus qIgA response criteria (32 vs 58 days, p < 0.001). Stratification by qIgA criteria, unlike IMWG criteria, led to clear separation of the progression-free survival curves of patients achieving a PR or very good PR. There was a consistent trend toward earlier detection of disease progression using qIgA versus IMWG progression criteria. In conclusion, monitoring IgA MM using MCP-based IMWG criteria may be falsely reassuring, given that MCP levels on SPEP decrease faster than qIgA levels. The qIgA response criteria more accurately stratify patients based on the progression risk and may detect disease progression earlier, which may lead to more consistent measurement of trial endpoints and improved patient outcomes.

Case report regarding the evolution of electrocardiographic and echocardiographic features in cardiac amyloidosis

Background Cardiac amyloidosis is an important cause for heart failure with preserved ejection fraction. It is often under diagnosed due to the fact that clinicians do not always recognize the specific diagnostic findings associated with this disease, also leading to the wrong diagnosis. When left untreated further irreversible organ dysfunction occurs, with high morbidity and mortality rates. Case summary A 71-year-old patient presented with progressive exertional dyspnoea and angina pectoris at the outpatient clinic. Medical history noted a percutaneous coronary intervention of the right coronary artery due to stable angina pectoris. The electrocardiogram showed low voltage in the limb leads and pseudo-infarct pattern in the precordial leads. Echocardiographic findings included left and right ventricular hypertrophy, decreased left ventricular systolic function, restrictive diastolic function, and ‘relative’ apical sparing of the left ventricle. This led to the suspicion of cardiac amyloidosis, which was confirmed with a positive bone scintigraphy using 99mTechnecium-DPD and the absence of monoclonal proteins. Treatment with Tafamidis was initiated. Discussion Electrocardiographic findings suggestive of cardiac amyloidosis are low voltage in the limb leads and/or a pseudo-infarct pattern in the precordial leads. Important echocardiographic findings are left and right ventricular hypertrophy, restrictive diastolic function, ‘relative’ apical sparing of the left ventricle and impaired left atrial strain. The next step in confirming the diagnosis is 99mTechnecium PYP/DPD/HMDP bone scintigraphy and testing for monoclonal proteins. The diagnosis ATTR amyloidosis is confirmed by the combination of positive bone scintigraphy (Perugini Grade 2 or 3) and the absence of monoclonal proteins, without the necessity of performing an endomyocardial biopsy.