What are the criteria for diagnosing relapse in multiple myeloma?

Multiple Myeloma Relapse Criteria

According to the International Myeloma Working Group, multiple myeloma relapse is defined by specific criteria including progressive disease, clinical relapse, relapse from complete response, and relapse from minimal residual disease negative state. 1

Progressive Disease Criteria

• Progressive disease requires an increase of ≥25% from lowest confirmed response value in one or more of the following:
  • Serum M-protein with absolute increase ≥0.5 g/dL
  • Serum M-protein increase ≥1 g/dL if lowest M component was ≥5 g/dL
  • Urine M-protein with absolute increase ≥200 mg/24h
  • Difference between involved and uninvolved free light chain levels with absolute increase >10 mg/dL 1
• Alternatively, progressive disease can be diagnosed by the appearance of new lesion(s) or ≥50% increase from nadir in sum of products of diameters of more than one lesion 1

Clinical Relapse Criteria

• Clinical relapse requires one or more of the following:
  • Direct indicators of increasing disease and/or end-organ dysfunction (CRAB features)
  • Development of new soft tissue plasmacytomas or bone lesions
  • Definite increase in existing plasmacytomas or bone lesions
  • Hypercalcemia attributable to the plasma cell proliferative disorder
  • Decrease in hemoglobin
  • Rise in serum creatinine 1

Relapse from Complete Response

• Relapse from complete response requires any of the following:
  • Reappearance of serum or urine M-protein by immunofixation or electrophoresis
  • Development of ≥5% plasma cells in bone marrow
  • Appearance of any other sign of progression (e.g., new plasmacytoma, lytic bone lesion, hypercalcemia) 1

Relapse from MRD Negative State

• Relapse from MRD negative state requires any of the following:
  • Loss of MRD negative state
  • Reappearance of serum or urine M-protein
  • Development of ≥5% clonal plasma cells in bone marrow
  • Appearance of any other sign of progression 1

Clinical Implications of Different Types of Relapse

• Biochemical progression (BP) is associated with better outcomes compared to clinical progression (CP) with end-organ damage 2
• Patients with BP have longer median time from second-line treatment to next treatment (17.0 vs 9.6 months) and longer overall survival from first relapse (59.4 vs 26.2 months) compared to those with CP 2
• Treatment should be initiated immediately for all clinically relapsed patients with symptoms due to myeloma, and for those with high-risk cytogenetics, extramedullary disease, early relapse after transplant or initial therapy, and/or evidence of rapid rise in myeloma markers 1

Monitoring Recommendations

• Regular monitoring with serum and urine immunofixation electrophoresis is necessary to detect early relapse 1
• Serum free light chain assays should be used consistently throughout monitoring to ensure accurate comparison of results 1
• Bone marrow examination should be performed when complete response is suspected or to evaluate for progression 1
• Imaging studies should be performed when clinically indicated to assess for new bone lesions 1

Treatment Considerations at Relapse

• Triplet therapy is generally recommended over doublet therapy at first relapse 1
• The choice of regimen should consider patient-, disease-, and treatment-related factors, including:
  • Biochemical markers for progression
  • Severity and dynamic of disease relapse
  • Type and number of prior therapy lines
  • Previous toxicities
  • Underlying health status 3

Common Pitfalls in Diagnosing Relapse

• Relying solely on serum protein electrophoresis can miss up to 50% of cases with monoclonal proteins 4
• Neglecting urine studies can lead to missed diagnoses, as some patients may have negative serum but positive urine findings 4
• Failing to use the same serum free light chain assay throughout monitoring can lead to inconsistent results 1, 4
• Not distinguishing between biochemical progression and clinical relapse can lead to suboptimal treatment timing decisions 2

Remember that early detection of relapse through appropriate monitoring allows for timely intervention, which may improve outcomes, particularly in high-risk patients 1, 2.