What is the next step if lab results show an elevated M (Monoclonal) protein spike?

From the Guidelines

If lab results show an elevated M (monoclonal) protein spike, the next step should be a comprehensive hematology-oncology evaluation to determine if a plasma cell disorder is present. This typically includes additional testing such as a complete blood count, comprehensive metabolic panel, serum free light chain assay, 24-hour urine protein electrophoresis, bone marrow biopsy, and skeletal survey or advanced imaging like CT or MRI 1. The hematologist will use these results to distinguish between conditions such as monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, Waldenström macroglobulinemia, or amyloidosis. Some key points to consider in the evaluation process include:

• Detection and evaluation of the monoclonal (M-) component by serum and/or urine protein electrophoresis
• Evaluation of bone marrow (BM) plasma cell infiltration: BM aspiration and/or biopsies
• Evaluation of lytic bone lesions: a radiological skeletal bone survey, including spine, pelvis, skull, humeri and femurs
• Complete blood cell count, with differential serum creatinine and calcium level 2. The urgency of follow-up depends on the M protein level, associated symptoms, and other abnormal findings. Patients should be prepared to discuss any symptoms like bone pain, fatigue, recurrent infections, or unexplained weight loss at their specialist appointment, as these could indicate more serious disease. Early evaluation is important because while some conditions like MGUS may only require monitoring, others like multiple myeloma might need prompt treatment to prevent complications such as kidney damage or bone fractures. It's also important to note that the diagnosis of symptomatic MM requires ≥10% clonal plasma cells on BM examination or a biopsy proven plasmacytoma; and evidence of end-organ damage, the so-called CRAB criteria (hypercalcaemia, renal insufficiency, anaemia or bone lesions) that is felt to be related to the underlying plasma cell disorder 2. The International Myeloma Working Group (IMWG) Uniform Response Criteria provide a framework for assessing response to treatment, including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), and progressive disease 1. Overall, a comprehensive evaluation and timely diagnosis are crucial in managing plasma cell disorders and improving patient outcomes.

From the FDA Drug Label

Interference with Serum Protein Electrophoresis and Immunofixation Tests Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein) False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria In patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, to facilitate determination of a complete response.

The next step if lab results show an elevated M protein spike is to consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, especially if daratumumab interference is suspected 3. This can help facilitate the determination of a complete response. Key considerations include:

• The potential for false positive SPE and IFE assay results due to daratumumab interference
• The importance of distinguishing between daratumumab and endogenous M protein to accurately assess treatment response
• The use of daratumumab-specific IFE assays to mitigate interference and ensure accurate test results 3.

From the Research

Next Steps for Elevated M Protein Spike

If lab results show an elevated M (Monoclonal) protein spike, the next steps involve further evaluation and monitoring to determine the underlying cause and risk of progression to a malignant condition.

• The size of the serum M protein, the type of serum M protein, the number of plasma cells in the bone marrow, and the serum free light chain ratio are risk factors for progression 4, 5.
• Patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) require lifelong follow-up 4.
• Assessment of the risk of progression is based on various factors, including serum paraprotein concentration, isotype of M protein, and infiltration of bone marrow plasmocytes 5.
• Three risk stratification models (MAYO, PETHEMA, and CMG) can be used to predict the risk of progression of MGUS into malignant forms of monoclonal gammopathy 5.
• Early recognition of monoclonal gammopathies and a careful workup are essential in determining the next steps in patient care 6.
• The integration of novel biological markers, molecular imaging, and clinical monitoring could facilitate the development of early treatment strategies for high-risk patients 7.
• Recent advances have improved understanding of the complex genetic and immunologic factors that permit progression from the aberrant plasma cell clone to MGUS and overt MM, however there are no robust prognostic biomarkers 8.