Validation of the Novel Criteria for the Definition of Symptomatic Myeloma: A Single Center Experience in 216 Patients with the Previous Diagnosis of Asymptomatic Disease
Authors: Kastritis Efstathios , Terpos Evangelos , Roussou Maria , Koutoulidis Vassilis , Giannouli Stavroula , Gavriatopoulou Maria , Migkou Magdalini , Eleutherakis-Papaiakovou Evangelos , Fotiou Despoina , Ziogas Dimitrios , Panagiotidis Ioannis , Kalapanida Despoina , Katodritou Eirini , Konstantopoulos Kostas , Moulopoulos Lia A. , Dimopoulos Meletios A. 
Published: October 2019

Abstract
Asymptomatic (smoldering) MM (AMM) is defined by the presence of ≥10% of clonal plasma cells in the bone marrow and/or ≥3 g/dl of serum paraprotein and no CRAB. AMM is associated with a significant risk of development of symptomatic MM requiring therapy (~50% within 5 years from diagnosis). However, there is significant heterogeneity among AMM patients: some patients develop symptoms within a few months from diagnosis, while others have a protracted course or never develop symptomatic disease. In 2014, the IMWG, after considering the results of several studies, modified the defining criteria of symptomatic MM (Rajkumar et al; Lancet Oncol 2014), to include patients who were previously considered as having AMM but with specific features that defined a very high risk for progression to symptomatic disease within 2 years from diagnosis. Thus, patients with more than one focal lesion on whole body MRI (or MRI of spine and pelvis) or serum FLC ratio ≥100 or bone marrow plasma cells ≥60% are considered as symptomatic MM, requiring therapy. The aim of our study was to validate these new criteria in our patients with AMM who had been diagnosed before the publication of the new IMWG criteria.
Our analysis included 216 patients with AMM who were diagnosed from 2003 to 2014 in a single center (Alexandra Hospital, University of Athens, Greece). Median age was 63 years (range 33-88) and 58% were females. M-protein was IgG in 69%, IgA in 24%, biclonal in 4% and 2% had light chain only AMM. Median serum monoclonal protein was 1.4 g/dl and 11.5% had M-spike ≥3 g/dl; 54% had low levels of at least one of the uninvolved immunoglobulins. Median BM infiltration was 20% (range <10 to 90%) and 6% had BMPCs ≥ 60%. Abnormal FLC ratio was found in 65.5% of patients; 6% had FLC ratio ≥ 100 (with involved FLC levels ≥1000 mg/L). Among those with available MRI 14% had abnormal findings (at least one focal lesion or diffuse MRI pattern); 8% had more than one focal lesion. Median follow up of the cohort was 4 years and 61 (21%) patients have developed symptomatic disease requiring therapy (PD): 1-, 2- and 5-year rate of PD was 7%, 14%, and 29% respectively. Per the recent IMWG criteria, 13% of patients with a diagnosis of asymptomatic MM would be redefined as symptomatic patients. The median time to PD for these patients was 17 months; it was 44% in the 1st year, 63% in the 2nd year and 82% at 3 years.
According to the Mayo risk stratification for AMM (Kyle et al NEJM 2007), 11.5% of patients had ≥10% of plasma cells and ≥3 gr/dl of M-spike and were considered as high risk. The median time to symptomatic progression for these patients was 24 months and the 1-, 2- and 5-year progression rate was 27%, 53% and 68%, respectively. However, among patients with high risk AMM per Mayo risk, 15% fulfilled the new IMWG criteria for symptomatic MM, while in the intermediate risk group 12% would also fulfill the new criteria. Thus, the new criteria identified a very high risk group, even among patients at intermediate risk per the Mayo risk score. Among the patients who developed symptomatic disease, 92% developed anemia, 46% developed lytic bone lesions, 1% extramedullary plasmacytomas, 2% hypercalcemia and 13% renal failure (creatinine ≥2 mg/dl). The presence of the various high risk features was associated with the development of specific symptoms at progression: BMPCs ≥60% was associated with the development of anemia (Hb <10 g/dl) and abnormal MRI with the development of bone disease.
In order to evaluate possible changes in the diagnosis of AMM during the past years, we compared the characteristics and outcome of patients who were diagnosed with AMM before (n=93) and after 2010 (n=123): 22% vs 16% were high risk per Mayo stage (p=0.210); 15% vs 13% would be considered as symptomatic with the new IMWG criteria (p=0.615). The 3-year progression rate was 18% and 19% for those diagnosed before vs after 2010, respectively (p=0.522).
In conclusion, 13% of patients with the previous diagnosis of AMM would be considered as having symptomatic disease and would start therapy with the new IMWG criteria for the definition of symptomatic MM. About 63% of such patients require therapy within 2 years from diagnosis; thus, justifying the revised definition of symptomatic myeloma to include patients with FLC ratio ≥100, BMPCs ≥60% or >1 focal lesion in MRI. We confirm that the new criteria are more sensitive in the identification of AMM patients who are at very high risk for progression and need immediate treatment.

Disclosures
Terpos: Novartis: Honoraria; Celgene: Honoraria, Other: travel expenses; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Amgen: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Genesis: Honoraria; Onyx: Honoraria.