Plasma cell dyscrasias — types, presentation, diagnostic criteria, course and treatment

Definition and the spectrum. Plasma cell dyscrasias (monoclonal gammopathies) are clonal proliferations of plasma cells or lymphoplasmacytic cells producing a monoclonal immunoglobulin (M protein or paraprotein). The spectrum runs from MGUS → smouldering myeloma → symptomatic multiple myeloma, with related entities of solitary plasmacytoma, AL amyloidosis, Waldenström macroglobulinaemia, POEMS syndrome, heavy chain disease, plasma cell leukaemia and monoclonal gammopathy of renal significance (MGRS).

MGUS. Serum M protein <3 g/dL, clonal marrow plasma cells <10%, and no myeloma-defining events or end-organ damage. It is present in 3% of people over 50 and 5% over 70, is asymptomatic, and progresses at a fixed rate of about 1% per year, indefinitely. Risk factors for progression are non-IgG isotype, M protein ≥1.5 g/dL and an abnormal free light chain ratio. Management is observation only — no treatment, with 6-monthly then annual monitoring.

Smouldering (asymptomatic) myeloma. M protein ≥3 g/dL or urinary M protein ≥500 mg/24 h, and/or clonal marrow plasma cells 10–60%, but no myeloma-defining events. Risk of progression is much higher — about 10% per year for the first 5 years. Standard care is observation, but high-risk smouldering myeloma (the "20-2-20" criteria: M protein >2 g/dL, marrow plasma cells >20%, free light chain ratio >20) is now often treated with lenalidomide.

Multiple myeloma. Clonal marrow plasma cells ≥10% or a biopsy-proven plasmacytoma, plus either end-organ damage (CRAB) or a myeloma-defining biomarker (SLiM). Presents with bone pain, pathological fracture, anaemia, renal failure, hypercalcaemia and recurrent infection. Median survival is now 7–10 years with modern therapy.

Solitary plasmacytoma and plasma cell leukaemia. Solitary plasmacytoma — a single bone or extramedullary lesion with a normal marrow, no CRAB and a negative skeletal survey/MRI; treated with radical radiotherapy (40– 50 Gy), though most bone plasmacytomas progress to myeloma within 3 years. Plasma cell leukaemia — ≥5% circulating plasma cells (revised from 20%); aggressive, requiring intensive combination therapy.

AL (primary) amyloidosis. Deposition of misfolded monoclonal free light chains (usually lambda) as amyloid fibrils. Presents with nephrotic syndrome, restrictive cardiomyopathy with heart failure and raised NT-proBNP, hepatomegaly, peripheral and autonomic neuropathy, macroglossia and periorbital purpura (the two pathognomonic signs). Diagnosis requires Congo red staining with apple-green birefringence on abdominal fat pad, rectal or organ biopsy, plus mass spectrometry typing and demonstration of a clone. Prognosis is driven by cardiac stage (NT-proBNP and troponin).

Waldenström macroglobulinaemia. A lymphoplasmacytic lymphoma secreting IgM, with MYD88 L265P mutation in over 90%. Presents with hyperviscosity (headache, blurred vision, retinal vein engorgement, confusion, bleeding), lymphadenopathy, hepatosplenomegaly, anaemia, peripheral neuropathy (anti-MAG), cryoglobulinaemia and cold agglutinin disease. Bone lesions and hypercalcaemia are characteristically absent — a key contrast with myeloma. Treated with plasmapheresis for symptomatic hyperviscosity, then rituximab-based therapy or a BTK inhibitor (ibrutinib, zanubrutinib).

POEMS syndrome and MGRS. POEMS — Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein (almost always lambda) and Skin changes, with sclerotic bone lesions, raised VEGF, Castleman disease and papilloedema; treated with radiotherapy to an isolated lesion or systemic therapy with autologous transplant. MGRS — a small clone not meeting myeloma criteria that nevertheless causes renal damage (amyloidosis, light chain deposition disease, cryoglobulinaemic glomerulonephritis); it must be treated despite the low tumour burden, because the criterion is organ damage, not clone size.

Diagnostic workup common to all. Serum protein electrophoresis with immunofixation, serum free light chain assay with kappa:lambda ratio, 24-hour urine electrophoresis for Bence-Jones protein, quantitative immunoglobulins; complete blood count, calcium, creatinine, albumin, LDH and β -microglobulin; bone marrow 2 aspirate and trephine with flow cytometry, FISH for cytogenetics; and whole-body low-dose CT, whole-body MRI or PET-CT — skeletal survey is now obsolete. Add echocardiography and NT-proBNP if amyloidosis is suspected.

Principles of treatment. MGUS and standard-risk smouldering myeloma are observed; symptomatic disease is treated. Modern therapy combines a proteasome inhibitor (bortezomib) + immunomodulatory drug (lenalidomide) + anti-CD38 monoclonal antibody (daratumumab) + dexamethasone, with autologous stem cell transplant in fit patients up to about 70–75 years and lenalidomide maintenance. Supportive care is equally examinable: bisphosphonates or denosumab, radiotherapy for bone pain and cord compression, hydration and avoidance of nephrotoxins, VTE prophylaxis with immunomodulatory drugs, antiviral prophylaxis with bortezomib and daratumumab, vaccination and immunoglobulin replacement. In older patients, dose-adapt using frailty scores (IMWG frailty index, R-MCI) rather than chronological age.

MRD negativity as a regulatory endpoint. In April 2024 the FDA's advisory committee accepted minimal residual disease negativity (10-5 by next-generation sequencing or flow cytometry) as a surrogate endpoint for accelerated approval in myeloma — the first haematological malignancy for which this applies. Risk stratification has correspondingly moved to the R2-ISS, which combines ISS stage with LDH, del(17p), t(4;14) and 1q gain.

Immunotherapy has transformed relapsed disease. BCMA-directed CAR T-cell therapy (idecabtagene vicleucel, ciltacabtagene autoleucel) and bispecific T-cell engagers (teclistamab targeting BCMA, talquetamab targeting GPRC5D, elranatamab) now produce deep responses in heavily pre-treated myeloma, and bispecifics are "off-the-shelf" and therefore more feasible in older and frailer patients than CAR-T; the principal toxicities are cytokine release syndrome, neurotoxicity (ICANS) and profound infection risk requiring immunoglobulin replacement. Cross-reference: Multiple myeloma is expanded separately in Question 33; this answer covers the whole spectrum of monoclonal gammopathies.