ISH/BSH 2016: Professor Philippe Moreau from Nantes in France reviewed the rationale for the new diagnostic criteria and highlighted the gaps in current risk models for stratifying the risk of progression to MM… Also included article entitled ‘High-risk smouldering myeloma’

High-risk smouldering myeloma

by Maria Dalby

Professor Philippe Moreau, University Hospital Hôtel-Dieu, Nantes, France

Subsequent to the publication of updated diagnostic criteria for MM in 2014,¹ MM clinicians have had to adopt new approaches for managing smouldering multiple myeloma (SMM). Professor Philippe Moreau from Nantes in France reviewed the rationale for the new diagnostic criteria and highlighted the gaps in current risk models for stratifying the risk of progression to MM.

In his presentation Professor Moreau described the updated diagnostic criteria for MM as one of the most important papers published in recent years. Prior to this publication, MM patients had to show one or more of the CRAB symptoms (elevated calcium levels, renal failure, anaemia, and bone lesions) to receive treatment. The revised diagnostic criteria include three biomarkers of malignancy that are classed as myeloma-defining events (MDE); each of these markers, if present, lets the clinician diagnose MM and commence treatment in the absence of CRAB symptoms. These MDEs are: a clonal bone marrow percentage of ≥60%; an involved/uninvolved serum free light chain ratio of ≥100; and >1 focal lesion on magnetic resonance imaging (MRI) that is 5 mm or greater in size.¹ These cut-off values were chosen on the basis of clinical trials which showed that these patients are at ultra-high risk of progressing to MM within 2 years.^2-5

It has been argued that the updated diagnostic criteria will lead to over-treatment of up to 30% of MM patients. The benefits of treating MM in accordance with the updated diagnostic criteria – delay of symptomatic disease and the potential for curing a proportion of patients – should be weighed against the risks of toxicity and the increased costs. In addition, early treatment could lead not only to progression to chronic disease, but in the worst-case scenario to selection of an aggressive and drug-resistant clone.⁶ However, by the same argument, electing not to treat early MM carries the risk of undertreating at least 70% of patients. Treatment of SMM (according to the prior classification) with lenalidomide and dexamethasone induction therapy followed by lenalidomide maintenance has been shown to significantly improve not only progression-free survival but also overall survival,⁷ although the latter finding should be interpreted with caution as the study was not powered for this outcome.

Whilst the updated diagnostic criteria mean that a proportion of MM patients previously defined as indolent will receive treatment, the question remains how and when to treat SMM. The updated criteria define SMM as patients with a serum monoclonal (M) protein level of ≥3 g/dL and 10-60% clonal bone marrow cells, in the absence of any MDE.¹ A variety of models for predicting the risk of progression to MM have been proposed; the most widely used, the Mayo Clinic model, which is based on M-protein levels, bone marrow plasma cells and the free light chain ratio, and the Spanish PETHEMA model which is based on the percentage of abnormal plasma cells and evidence of immunoparesis, differ dramatically in their classification of low versus high-risk patients.⁸ Biomarkers that have been shown to predict progression from SMM to MM include the presence of del(17p), t(4; 14) and +1q21 mutations in the tumour cells,⁹ positive PET/CT scans,¹⁰ high levels of peripheral blood circulating plasma cells,¹¹ and an increased risk score in the gene expression profile GEP70 of ≥0.26.^{12, 13}

Professor Moreau’s recommendation for managing patients with SMM at high risk of progression to MM is close monitoring and if possible enrolment in a clinical trial; patients deemed to be at ultra-high risk should be treated as though they have MM. A number of clinical trials are currently in progress, including a phase II trial of siltuximab versus no treatment, a phase III trial of lenalidomide versus observation, the phase II CENTAURUS trial which will evaluate three different doses of daratumumab as monotherapy, and a phase II trial of triplet therapy carfilzomib, lenalidomide and dexamethasone which suggests that a subset of SMM patients can become MRD negative very rapidly on this regimen.¹⁴ The results of these trials should confirm whether it is indeed possible to cure patients from MM by treating the disease at a very early stage.

 

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. Rajkumar SV, Larson D, Kyle RA. Diagnosis of smoldering multiple myeloma. N Engl J Med 2011;365:474-5.
3. Kastritis E, Terpos E, Moulopoulos L, et al. Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease. Leukemia 2013;27:947-53.
4. Waxman AJ, Mick R, Garfall AL, et al. Classifying ultra-high risk smoldering myeloma. Leukemia 2015;29:751-3.
5. Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 2010;28:1606-10.
6. Korde N, Mailankody S, Landgren O. The road to treating smoldering multiple myeloma. Clin Lymphoma Myeloma Leuk 2014;14 Suppl:S59-64.
7. 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.
8. Cherry BM, Korde N, Kwok M, et al. Modeling progression risk for smoldering multiple myeloma: results from a prospective clinical study. Leuk Lymphoma 2013;54:2215-8.
9. Neben K, Jauch A, Hielscher T, et al. Progression in smoldering myeloma is independently determined by the chromosomal abnormalities del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load. J Clin Oncol 2013;31:4325-32.
10. Zamagni E, Nanni C, Gay F, et al. 18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease. Leukemia 2016;30:417-22.
11. Bianchi G, Kyle RA, Larson DR, et al. High levels of peripheral blood circulating plasma cells as a specific risk factor for progression of smoldering multiple myeloma. Leukemia 2013;27:680-5.
12. Dhodapkar MV, Sexton R, Waheed S, et al. Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood 2014;123:78-85.
13. Khan R, Dhodapkar M, Rosenthal A, et al. Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120). Haematologica 2015;100:1214-21.
14. Korde N, Roschewski M, Zingone A, et al. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol 2015;1:746-54.