IMV 2015: New diagnostic criteria for multiple myeloma

Multiple myeloma is unique amongst cancers in that the diagnosis is made by the clinician, not the pathologist. The pathologist merely states that the patient has a clonal plasma cell disorder; it is then up to the clinician to evaluate the clinical features to confirm the MM diagnosis and assess the risk of progression. In a plenary session at this year’s IMW, Professor Vincent Rajkumar from the Mayo Clinic reviewed the new diagnostic criteria for MM that were published by the International Myeloma Working Group (IMWG) in 2014 and discussed its implications for improved clinical outcomes and the potential for a MM cure.

 

The previous definition of MM relied entirely on the presence of so-called CRAB features: hypercalcaemia, renal failure, anaemia, and lytic bone disease in patients with a clonal plasma cell disorder. Patients with no CRAB features were defined as having either monoclonal gammopathy of unknown significance (MGUS) or smouldering MM (SMM) depending on their levels of bone marrow plasma cells and M protein, whereas a diagnosis of MM required CRAB features to be present.  However, as a sizeable proportion of SMM patients are at risk of progressing to MM; the IMWG deemed it would not be appropriate to wait for CRAB features to appear before initiating treatment of these patients and revised criteria were therefore published in 2014.¹

 

The significantly larger proportion of SMM at risk of progressing to MM within two years of presentation compared with MGUS patients,² was one of key three rationales for making this change – in the new criteria, the IMWG recognises that SMM is not actually a disease in itself but more likely represents a mixture of MGUS and MM patients that cannot be differentiated due to lack of biomarkers. Another key rationale for the change is improvements in therapy. Clinicians no longer need to be paralysed by fear of harming the patient by initiating treatment too early – on the contrary, the Spanish trial showed that early initiation of lenalidomide plus dexamethasone in SMM patients significantly prolonged the time to progression to MM and survival compared with observation only.³ Thirdly, we now have biomarkers that can predict progressive disease and that should be used to optimise interventions. Patients with bone marrow plasma cell levels of 60% or over at the time to presentation have been shown to have a median time to progression of seven months and thus cannot be left without treatment for many years even if the may not show any other symptoms.⁴ Similarly, a free light chain (FLC) ratio of 100 or more⁵ and more than one focal lesion on magnetic resonance imaging (MRI) have been shown to predict progression from SMM to MM within two years at a probability rate of 75-80%.⁶

 

These revised criteria will ensure that the highest-risk SMM patients – those with a yearly risk of progression of 40% or more – are reclassified as MM and eligible for treatment. However, this will still leave a significant proportion in the SMM group with a risk of progression of 25%/year, equivalent to a median time to progression of two years. High-risk SMM is defined as SMM with M protein levels ≥3mg/ml and ≥10% bone marrow plasma cells, with less than 5% normal plasma cells on immunophenotyping.⁷ Additional diagnostic criteria for high risk SMM include an abnormal FLC ratio of 8-100, deletions in 17p, t(4;14) or Amp1q, or increased circulating plasma cells,⁷ although further clinical trials are required to correlate these with disease progression and potential cure. Professor Rajkumar finished by reminding the audience that whilst the new diagnostic criteria for MM represent a major paradigm shift, they must not override the need to apply clinical judgement when making a clinical-pathological diagnosis.

References

1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538-48.
2. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007;356:2582-90.
3. Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 2013;369:438-47.
4. Rajkumar SV, Larson D, Kyle RA. Diagnosis of smoldering multiple myeloma. N Engl J Med 2011;365:474-5.
5. Larsen JT, Kumar SK, Dispenzieri A, et al. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia 2013;27:941-6.
6. Rajkumar SV, Kyle RA. Haematological cancer: Treatment of smoldering multiple myeloma. Nat Rev Clin Oncol 2013;10:554-5.
7. Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood 2015;125:3069-75.