Multiple myeloma (MM) is a plasma cell malignancy characterized by clonal proliferation of abnormal plasma cells, production of monoclonal immunoglobulins, and organ dysfunction, often defined by the CRAB criteria (hypercalcemia, renal impairment, anemia, and bone disease). Laboratory testing is central to diagnosis, risk assessment, and monitoring during therapy and remission.

Hematology and Biochemistry

- CBC with differential → detection of anemia, leukopenia, or thrombocytopenia.

- Biochemistry panel → creatinine, urea, calcium, albumin, LDH.

- β2-microglobulin and albumin → incorporated into the Revised International Staging System (R-ISS).

- CRP may reflect disease activity (IL-6 driven).

- Serum protein electrophoresis (SPEP): quantifies the M-spike.

- Urine protein electrophoresis (UPEP, 24 h): detects Bence Jones proteinuria.

- Immunofixation (serum and urine): confirms the type of heavy and light chain.

- Serum free light chain (sFLC) assay: critical for light-chain, non-secretory, and oligo-secretory myeloma.

Bone Marrow Examination

- Morphology: percentage of plasma cells.

- Multiparameter flow cytometry: demonstrates clonality and immunophenotype.

- Cytogenetics/FISH: identifies high-risk abnormalities (del[17p], t[4;14], t[14;16]) that influence prognosis.

Laboratory Evaluation During Follow-Up

Routine Monitoring

- M-protein quantification (SPEP/UPEP): mainstay of monitoring.

- Immunofixation: required to confirm complete response.

- sFLC assay: sensitive tool for relapse, especially in light-chain disease.

- CBC, renal function, calcium, LDH, β2-microglobulin: routine for treatment toxicity and disease burden.

Advanced Monitoring

- Minimal Residual Disease (MRD): assessed via next-generation flow cytometry or next-generation sequencing. MRD negativity correlates with superior survival and is increasingly used as a response endpoint.

- Mass spectrometry and liquid biopsy are promising future tools for detecting residual disease with high sensitivity.

Preferred Tests in Clinical Practice

- At diagnosis: a comprehensive panel including SPEP, UPEP, serum/urine immunofixation, sFLC, bone marrow studies (with cytogenetics/FISH), and advanced imaging is essential.

- During follow-up: routine monitoring can be streamlined to SPEP and sFLC, supplemented by basic hematology and chemistry. UPEP is reserved for patients with baseline significant proteinuria.

- In specialized centers: MRD testing should be incorporated, especially in clinical trials, to refine response evaluation.

Conclusion Laboratory evaluation remains the cornerstone of myeloma diagnosis and long-term management. While a full diagnostic panel is indispensable at baseline, streamlined monitoring with SPEP and sFLC is sufficient in most patients during follow-up. Advanced tools such as MRD assessment and mass spectrometry are reshaping the landscape, providing unprecedented sensitivity in disease monitoring. The optimal combination of tests ensures accurate diagnosis, appropriate risk stratification, and effective treatment monitoring in multiple myeloma.