What are the criteria for diagnosing relapse in multiple myeloma?

Multiple Myeloma Relapse Criteria

The diagnosis of multiple myeloma relapse requires specific criteria defined by the International Myeloma Working Group, which includes progressive disease, clinical relapse, relapse from complete response, and relapse from minimal residual disease negative state. 1

Progressive Disease Criteria

Progressive disease requires one or more of the following:

• Increase of ≥25% from lowest confirmed response value in one or more of:
  • Serum M-protein with absolute increase ≥0.5 g/dL 1
  • Serum M-protein increase ≥1 g/dL if lowest M component was ≥5 g/dL 1
  • Urine M-protein with absolute increase ≥200 mg/24h 1
  • In patients without measurable serum and urine M-protein: difference between involved and uninvolved free light chain (FLC) levels with absolute increase >10 mg/dL 1
  • In patients without measurable serum/urine M-protein and FLC levels: bone marrow plasma cell percentage with absolute increase ≥10% 1
• Appearance of new lesion(s), ≥50% increase from nadir in sum of products of diameters of >1 lesion, or ≥50% increase in longest diameter of previous lesion >1 cm in short axis 1
• ≥50% increase in circulating plasma cells (minimum 200 cells per μL) if this is the only measure of disease 1

Clinical Relapse

Clinical relapse requires one or more of the following:

• Direct indicators of increasing disease and/or end-organ dysfunction (CRAB features) related to the underlying clonal plasma cell disorder 1
• Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression) 1
• Definite increase in existing plasmacytomas or bone lesions, defined as 50% (and ≥1 cm) increase measured by sum of products of diameters 1
• Hypercalcemia (>11 mg/dL) 1
• Decrease in hemoglobin ≥2 g/dL not related to therapy or other non-myeloma conditions 1
• Rise in serum creatinine by ≥2 mg/dL from start of therapy attributable to myeloma 1
• Hyperviscosity related to serum paraprotein 1

Relapse from Complete Response

For patients who previously achieved complete response (used only if endpoint is disease-free survival):

• Reappearance of serum or urine M-protein by immunofixation or electrophoresis 1
• Development of ≥5% plasma cells in bone marrow 1
• Appearance of any other sign of progression (new plasmacytoma, lytic bone lesion, or hypercalcemia) 1

Relapse from MRD Negative State

For patients who previously achieved minimal residual disease (MRD) negative status:

• Loss of MRD negative state (evidence of clonal plasma cells on next-generation flow cytometry or sequencing, or positive imaging study) 1
• Reappearance of serum or urine M-protein by immunofixation or electrophoresis 1
• Development of ≥5% clonal plasma cells in bone marrow 1
• Appearance of any other sign of progression 1

Important Considerations for Diagnosis

• All relapse categories require two consecutive assessments before classification as relapse or disease progression 1
• Radiographic studies are not required to satisfy response requirements except for FDG PET if imaging MRD-negative status is reported 1
• For calculation of time to progression and progression-free survival, clinical relapse is not used but may be reported optionally or for clinical practice 1

Clinical Implications of Relapse Type

• Patients with biochemical progression have longer median time to next treatment compared to those with clinical progression (17.0 vs 9.6 months) 2
• Patients with biochemical progression have longer median overall survival from first relapse compared to clinical progression (59.4 vs 26.2 months) 2
• Risk factors for developing clinical progression include male sex, plasma cell labeling index ≥2%, and extramedullary disease at diagnosis 2
• Patients who achieved very good partial response or better to first-line therapy have decreased risk of clinical progression 2

Treatment Considerations After Relapse

• Treatment should be initiated immediately for all clinically relapsed patients with symptoms due to myeloma 1
• For biochemical relapse, treatment should be initiated 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
• Close observation may be appropriate for patients with slowly progressive and asymptomatic biochemical relapse 1
• Triplet therapy (two novel agents plus steroids) is generally recommended over doublet therapy at first relapse 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 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

Multiple myeloma relapse criteria are well-defined and standardized, allowing for consistent assessment of disease progression and appropriate timing of therapeutic interventions to optimize patient outcomes.