Monoclonal gammopathy of undetermined significance: a new proposal of workup.

OBJECTIVE: Diagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS) require quantification of bone marrow plasma cells (BMPCs) and skeletal survey to discriminate between MGUS and multiple myeloma (MM). By contrast, recent published guidelines suggest that these procedures could be avoided in the presence of serum monoclonal spike (M-spike) of small amount (≤1.5 g/dL). Aim of this study is to better quantify the risk of missing a diagnosis of MM, not performing bone marrow aspirate and skeletal survey in patients with M-spike ≤ 1.5 g/dL asymptomatic for bone pain. METHODS: We reviewed data of 2282 patients consecutively observed from January 1974 to December 2010 in our single hematology department. We considered eligible for this study 1271 patients with grade <2 NCI bone pain, confirmed to have an MGUS or an MM after extensive standardized diagnostic workup including bone marrow biopsy, skeletal bone survey and laboratory tests. RESULTS: The risk of finding a BMPC infiltration ≥10% in patients with an M-spike ≤ 1.5 g/dL was very low (7.3%), although significantly different according to IgH isotype (4.7% for IgG vs. 20.5% for IgA). The risk of finding bone lesions with M-spike ≤ 1.5 g/dL was negligible (2.5%), regardless of IgH isotype. CONCLUSION: In asymptomatic patients with M-spike of small amount (≤1.5 g/dL): (i) BMPC evaluation may be reasonably avoided in patients with IgG M-spike, while should always be part of diagnostic workup in the presence of IgA M-spike and (ii) skeletal survey, less predictive for MM, should not be routinely indicated irrespective of IgH isotype.

Smoldering multiple myeloma: the role of different scoring systems in identifying high-risk patients in real-life practice.

We explore the predictive role of 2014-updated International Myeloma Working Group (IMWG) diagnostic criteria and of some of currently available risk models for progression to symptomatic myeloma when applied in our unselected population of 75 smoldering multiple myeloma (SMM) patients observed between 2000 and 2015. Risk scores including routinely used clinical parameters such as bone marrow plasmacell infiltration rate, immunoparesis, serum monoclonal component (sMC) value, and altered free light chain ratio (FLCr), were clinically useful to identify SMM patients at higher risk of progression. Time to myeloma progression in our ultra-high risk SMM according to IMWG diagnostic update criteria was very short (12.4 months). Our analysis identified as independent reliable predictors of progression altered FLCr as well as increasing plasma cell infiltration which are part of most commonly applied risk models. Waiting for new scoring systems, bone marrow evaluation and complete laboratory screening are still milestones for SMM management.

Sequential evaluation of CALR mutant burden in patients with myeloproliferative neoplasms.

We investigated the variation of CALR-mutant burden during follow-up in 105 CALR-mutant MPN and compared it to the variation of JAK2-mutant burden in 226 JAK2-mutant MPN.The median allele burden at last evaluation was significantly higher than at first evaluation in essential thrombocythemia (ET) (49.5% vs 45%, P < .001) but not in primary myelofibrosis (PMF) (52% vs 51%, P 0.398). Median values of slope were positive both in ET (0.071) and in PMF (0.032). In CALR-mutant ET there was a difference between natural and therapy-related slope (P 0.006).In the JAK2-mutated cohort, the median allele burden at last evaluation was not different respect to that at first evaluation, neither in ET (22.9% vs 23.2%, P = 0.216) nor in PMF (50.5% vs 45.0%, P = 0.809), despite a positive slope. Multivariate analysis to evaluate the effect of mutation (CALR vs JAK2) on the slope of mutant burden in not treated pts with a positive slope adjusting for diagnosis (ET vs PMF) showed a trend toward a higher increase of mutant burden in CALR vs JAK2 (ß = 0.19, P = 0.061) with no difference between diagnosis (P = 0.419). The findings of this study suggest that clonal expansion in CALR-mutant MPN is faster than that observed in JAK2-mutant MPN.

Clinical course and outcome of essential thrombocythemia and prefibrotic myelofibrosis according to the revised WHO 2016 diagnostic criteria.

The recently revised World Health Organization (WHO) classification of myeloid neoplasms recognizes prefibrotic myelofibrosis (prePMF) as a distinct entity, characterized by well-defined histopathologic features together with minor clinical criteria (leukocytes, anemia, increased LDH, splenomegaly). The aim of the study was to examine the clinical relevance of distinguishing prePMF from essential thrombocythemia (ET). We identified in our database all patients affected with ET, prePMF and primary myelofibrosis (PMF) diagnosed according to 2008 WHO criteria with a bone marrow fibrosis grade 0-1 at diagnosis and one DNA sample to define the mutational status. The bone marrow morphology of all 404 identified patients was reviewed by an expert pathologist and patients were reclassified according to the 2016 WHO criteria. After reclassification, our cohort included 269 ET, 109 prePMF, and 26 myeloproliferative neoplasm unclassificable. In comparison with ET, patients with prePMF had higher leukocyte count, lower hemoglobin level, higher platelet count, higher LDH values, and higher number of circulating CD34-positive cells; they showed more frequently splenomegaly (all P values < ·001). CALR mutations were more frequent in prePMF than in ET (35·8% vs 17·8%, P < ·001). PrePMF patients had shorter overall survival (P < ·001) and a trend to a higher incidence of leukemic evolution (P ·067) compared to ET patients, while they did not differ in terms of thrombotic and bleeding complications. In conclusion, ET and prePMF diagnosed according to 2016 WHO criteria are two entities with a different clinical phenotype at diagnosis and a different clinical outcome.