Multiple Myeloma: Plasma Cell Cancer — Symptoms, Diagnosis, and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Multiple myeloma (MM) is a malignant clonal plasma cell disorder characterized by bone marrow infiltration and monoclonal immunoglobulin (M-protein) production. It represents approximately 10% of hematological malignancies and 1-2% of all cancers, with approximately 35,000 new US cases annually. Median age at diagnosis is 70 years. Precursor states include MGUS (monoclonal gammopathy of undetermined significance) and smoldering myeloma. MM causes anemia, bone pain and lytic lesions, renal failure, hypercalcemia, and recurrent infections from immunosuppression.

The etiology of MM is incompletely understood. MGUS progresses to MM at a rate of approximately 1% per year. Black Americans have a 2-3 times higher incidence of MM than White Americans, and typically present at a younger age. Obesity, radiation exposure, and agricultural chemical exposure are associated with slightly elevated risk. Hereditary factors include germline variants in MYC, CCND1, and HGF pathways. Genomic landscape of MM involves initiating events (IgH translocations, hyperdiploidy) and acquired secondary events (RAS mutations, TP53 deletion, MYC rearrangement, del17p, gain 1q21) that drive progression.

CRAB manifestations define symptomatic MM requiring treatment: hyperCalcemia (nausea, confusion, polyuria), Renal insufficiency (elevated creatinine, cast nephropathy from free light chains), Anemia (fatigue, pallor, dyspnea from marrow suppression), and Bone lesions (severe, persistent bone pain particularly in the spine and ribs, pathological fractures, vertebral compression fractures with back pain). Recurrent bacterial infections from hypogammaglobulinemia (pneumonia, sinusitis). Hyperviscosity syndrome (visual changes, headache, bleeding) from very high M-protein levels. Peripheral neuropathy from AL amyloidosis complication.

Diagnosis requires bone marrow biopsy (greater than or equal to 10% clonal plasma cells) plus any CRAB criterion or IMWG biomarker of malignancy, or biopsy-proven plasmacytoma. Serum and urine protein electrophoresis with immunofixation identify M-protein type. Serum free light chain (FLC) assay detects non-secretory or oligosecretory disease. FISH panel identifies high-risk cytogenetics: del(17p), t(4;14), t(14;16), t(14;20), gain 1q21. PET-CT or whole-body MRI for skeletal staging. Revised ISS (R-ISS) integrates ISS stage, LDH, and FISH cytogenetics for prognosis. MRD negativity by flow cytometry or NGS (sequencing sensitivity less than 10^-5 or 10^-6) is the new treatment response standard.

Transplant-eligible newly diagnosed MM: Dara-VRd (daratumumab plus bortezomib plus lenalidomide plus dexamethasone) for 4-6 cycles, stem cell mobilization, high-dose melphalan plus auto-SCT, consolidation, then lenalidomide maintenance. Transplant-ineligible: Dara-Rd (MAIA regimen) or VRd-lite. Relapsed/refractory MM: Dara-Pd (daratumumab plus pomalidomide plus dexamethasone), carfilzomib-based regimens, isatuximab combinations. Fourth-line or later: ide-cel or cilta-cel CAR-T; belantamab mafodotin (BCMA-ADC); selinexor; bispecific antibodies (teclistamab, talquetamab). Bone disease: zoledronic acid or denosumab; vertebroplasty or kyphoplasty for vertebral fracture.

MM remains incurable with conventional therapy but has become a chronic condition with modern treatments. Median OS with modern quadruplet therapy exceeds 6-8+ years for standard-risk disease. R-ISS I 5-year OS approximately 80%; R-ISS III approximately 40%. High-risk cytogenetics (del17p, t(4;14), t(14;16), gain 1q21, complex karyotype) confer median OS of 2-3 years despite aggressive therapy. Achievement of MRD negativity (greater than or equal to 10^-5 sensitivity) is strongly associated with longer PFS and OS across all cytogenetic risk groups. CAR-T cell therapy shows unprecedented response rates in heavily pre-treated patients.

MGUS patients require periodic monitoring (annually for low-risk, every 3-6 months for high-risk) to detect early myeloma progression. Annual serum protein electrophoresis (SPEP) plus serum FLC ratio is the standard monitoring approach for MGUS. The PREVENT trial and other studies are investigating whether treatment of high-risk smoldering myeloma (greater than or equal to 20% plasma cells plus M-protein greater than 2 g/dL plus elevated FLC ratio) can prevent or delay progression to symptomatic MM. Obesity management may reduce risk of progression. No general population screening is currently recommended.