Multiple Myeloma

The answer first

Multiple myeloma is a clonal expansion of malignant plasma cells in the bone marrow that produces a monoclonal immunoglobulin (the paraprotein or M-protein) and causes end-organ damage. The diagnosis rests on the International Myeloma Working Group (IMWG) 2014 criteria: clonal bone marrow plasma cells at or above 10 per cent (or a biopsy-proven plasmacytoma), plus one or more myeloma-defining events ^[1]. Those events are the CRAB features (hyperCalcaemia, Renal impairment, Anaemia, Bone lesions) and the three biomarkers that allow treatment before end-organ damage — marrow plasma cells at or above 60 per cent, an involved-to-uninvolved serum free light chain ratio at or above 100 (with the involved light chain at least 100 mg/L), or more than one focal lesion on MRI.

Three rules that change outcome: ^[1]

1. Send serum free light chains and serum electrophoresis on every older patient with unexplained back pain, anaemia, renal impairment or hypercalcaemia. Cast nephropathy is reversible if caught early; the best predictor of renal recovery is a falling free light chain with prompt treatment. The ESR is characteristically very high (often over 100); a normal ESR does not exclude myeloma because some patients are hypogammaglobulinaemic.
2. Acute back pain with neurological signs in myeloma is malignant epidural spinal cord compression — urgent MRI whole spine and dexamethasone now. Do not wait for plain films or CT. This is an oncological emergency that can leave a patient paraplegic within hours.
3. Hypercalcaemia of myeloma responds to bisphosphonates, not just fluids. Give aggressive intravenous hydration, then zoledronic acid 4 mg intravenously (or denosumab if renal failure precludes a bisphosphonate). Calcitonin works within hours for the symptomatic patient while the bisphosphonate takes 48 to 72 hours. ^[1]

For a transplant-eligible patient (broadly under 70 with good performance status and no major comorbidity) the modern standard is bortezomib-lenalidomide-dexamethasone (VRd) induction, then high-dose melphalan with autologous stem cell transplant, then lenalidomide maintenance ^[4][5][7]. For the transplant-ineligible patient the standard is now a daratumumab-based triplet such as daratumumab-lenalidomide-dexamethasone (DRd), which improves both progression-free and overall survival over lenalidomide-dexamethasone ^[8].

Myeloma is treatable but, in nearly all patients, not yet curable. Median overall survival has improved from about 3 years in the melphalan-prednisone era to over 8 to 10 years with modern combinations, autologous transplant and maintenance — and the trajectory continues to improve with anti-CD38 antibodies, CAR-T cell therapy and bispecific antibodies entering earlier lines. ^[1]

---

References9ShowHide

1. [1]Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol, 2014.PMID 25439696
2. [2]Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group J Clin Oncol, 2015.PMID 26240224
3. [3]Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma J Clin Oncol, 2005.PMID 15809451
4. [4]Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial Lancet, 2017.PMID 28017406
5. [5]Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma N Engl J Med, 2017.PMID 28379796
6. [6]Cavo M, Gay F, Beksac M, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study Lancet Haematol, 2020.PMID 32359506
7. [7]McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma N Engl J Med, 2012.PMID 22571201
8. [8]Facon T, Kumar S, Plesner T, et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma N Engl J Med, 2019.PMID 31141632
9. [9]Kyle RA, Larson DR, Therneau TM, et al. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance N Engl J Med, 2018.PMID 29342381