Diagnostic Workup for Suspected Multiple Myeloma
Immediately obtain serum protein electrophoresis (SPEP) with immunofixation, serum free light chain assay, complete blood count, comprehensive metabolic panel including calcium and creatinine, and proceed with bone marrow biopsy if initial testing suggests plasma cell disorder. 1, 2
Understanding Your Laboratory Findings
Your constellation of borderline high total protein, borderline high calcium, and low MCV raises concern for multiple myeloma, though the low MCV is atypical (anemia in myeloma is typically normocytic). 3, 4 The elevated total protein may reflect increased immunoglobulin production from clonal plasma cells, while borderline hypercalcemia is one of the CRAB criteria defining end-organ damage. 1, 2
Essential Initial Laboratory Panel
Complete the following tests immediately:
Serum protein electrophoresis (SPEP) with immunofixation - This detects the M-protein spike in approximately 80% of myeloma cases and is fundamental to diagnosis. 5, 2 The immunofixation identifies the specific heavy and light chain type. 5
Serum free light chain (FLC) assay with kappa/lambda ratio - Critical because 20% of myeloma patients have only urinary secretory proteins, and the combination of SPEP with FLC yields the highest sensitivity for plasma cell disorders. 5, 2 An abnormal FLC ratio (involved/uninvolved ≥100 with involved FLC ≥100 mg/L) is itself a myeloma-defining event. 6
Nephelometric quantification of IgG, IgA, and IgM - Measures total immunoglobulin levels and helps characterize the monoclonal protein. 1, 2
24-hour urine collection for protein electrophoresis and immunofixation - Not a random sample, as this is mandatory for complete evaluation. 1, 2
Complete blood count - Assess for anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal defines the "A" in CRAB criteria). 1, 2 Your low MCV warrants investigation for concurrent iron deficiency or thalassemia trait, as myeloma typically causes normocytic anemia. 3
Comprehensive metabolic panel - Specifically evaluate serum calcium (>11.5 mg/dL defines hypercalcemia in CRAB criteria) and creatinine (>2 mg/dL or clearance <40 mL/min defines renal insufficiency). 1, 2
Beta-2 microglobulin, albumin, and LDH - These are essential for Revised International Staging System risk stratification. 4, 6
Diagnostic Criteria You Must Meet
Multiple myeloma requires BOTH of the following: 1, 6
- ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma)
- Evidence of end-organ damage (CRAB criteria) OR myeloma-defining biomarkers:
- Calcium >11.5 mg/dL
- Renal insufficiency (creatinine >2 mg/dL or clearance <40 mL/min)
- Anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal)
- Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures)
- OR bone marrow plasma cells ≥60%
- OR involved/uninvolved FLC ratio ≥100 (with involved FLC ≥100 mg/L)
- OR >1 focal lesion on MRI
When Initial Labs Suggest Plasma Cell Disorder
If SPEP shows M-protein or FLC ratio is abnormal, proceed immediately with:
Bone marrow aspiration and biopsy - Quantify plasma cell percentage with CD138 staining for accuracy. 1, 2 This is required for diagnosis (need ≥10% clonal plasma cells). 6
Cytogenetics and FISH studies - Test for del(17p), t(4;14), t(14;16), t(14;20), gain 1q, and p53 mutation for risk stratification. 2, 6 Presence of any two high-risk factors defines "double-hit" myeloma, three or more defines "triple-hit" myeloma. 6
Skeletal survey - Plain radiographs of spine, pelvis, skull, humeri, and femora to detect lytic bone lesions (the "B" in CRAB). 2, 6
MRI of thoracic-lumbar spine and pelvis - Especially important if skeletal survey is negative, as >1 focal lesion on MRI is a myeloma-defining event. 7, 2
Critical Distinctions to Avoid Misdiagnosis
You must differentiate between three entities:
MGUS (Monoclonal Gammopathy of Undetermined Significance): M-protein <3 g/dL, bone marrow plasma cells <10%, NO CRAB criteria. No immediate treatment required, but lifelong follow-up needed. 1, 2
Smoldering Multiple Myeloma: M-protein ≥3 g/dL and/or bone marrow plasma cells ≥10%, but NO CRAB criteria or myeloma-defining biomarkers. Observation at 3-6 month intervals is standard (category 1 recommendation), not immediate treatment. 7, 2 Risk of progression is 10% per year for first 5 years. 7
Active Multiple Myeloma: Meets diagnostic criteria above with CRAB or myeloma-defining biomarkers. Requires immediate treatment. 7, 1
Follow-Up Strategy Based on Initial Results
If diagnosed with smoldering myeloma:
Monitor at 3-month intervals for the first year to establish evolving versus non-evolving pattern. 7, 2 Evolving type has median time to progression of ~1.5 years, non-evolving type ~4 years. 7
Each visit: CBC, calcium, creatinine, albumin, hemoglobin, serum and urine M-protein quantification. 7
Annual skeletal survey or as clinically indicated. 7
Full bone marrow and imaging only when progression is suspected. 7
If diagnosed with active myeloma:
- Immediate referral to hematology/oncology for treatment initiation. 7, 1 Standard induction therapy is bortezomib, lenalidomide, and dexamethasone (VRd) for transplant candidates, with consideration of adding daratumumab (Dara-VRd) for high-risk disease. 6
Common Pitfalls to Avoid
Do not assume serum FLC alone is sufficient - SPEP provides M-protein quantification needed for response criteria and monitoring. 5
Do not skip the 24-hour urine collection - Random urine samples are inadequate; 20% of patients have only urinary secretory proteins. 5, 2
Do not overlook the atypical low MCV - Investigate for concurrent iron deficiency or thalassemia, as this is not typical for myeloma-related anemia. 3
Do not treat smoldering myeloma immediately - Observation is the standard approach unless enrolled in clinical trials. 7
Do not delay bone marrow biopsy if initial labs suggest plasma cell disorder - This is essential for definitive diagnosis and cannot be deferred. 1, 2