Dimitrios Maltezas

Re-evaluation of prognostic markers including staging, serum free light chains or their ratio and serum lactate dehydrogenase in multiple myeloma patients receiving novel agents

International Staging System (ISS), serum free light chain ratio (sFLCR) and lactate dehydrogenase (LDH) are well known, easily assessed independent prognostic indicators of outcome in multiple myeloma (MM). The purpose of the study was to re‐examine the prognostic contribution of these variables in a multicenter setting with special attention to MM patients treated with autologous stem cell transplantation (ASCT) or novel agents (NA). Three hundred and five symptomatic newly diagnosed MM patients were retrospectively studied. Twenty‐seven per cent, 32% and 41% were in ISS stages 1, 2, and 3, respectively. Fifty‐six per cent of them presented kappa light chain monoclonality; median sFLCR was 27.04 (0.37–1.9 × 105) and 47.97 (0.26–2.3 × 107) for kappa patients and lambda patients, respectively; patients with sFLCR above median constituted the high sFLCR group. Thirty‐one per cent of patients had increased LDH. As first line treatment, 55.7% received conventional treatment and 44.3% NA. After induction, 24% underwent ASCT, whereas 76% received NA at any line, either bortezomib (82.5%), thalidomide (48%) or lenalidomide (27%). When the 305 patients were analyzed together, staging, high sFLCR and abnormal LDH were predictive of survival. The same was true for patients that never received NA, whereas neither high sFLCR nor abnormal LDH constituted adverse factors in patients that received NA frontline. In the last group of patients, no difference was observed between ISS stages 2 and 3. The median 5‐year survival of patients that never received NA versus those who did frontline was 29% vs 47%, 7% vs 52% and 24% vs 40% in patients with abnormal LDH, high sFLCR and ISS stage 3, respectively (p = 0.03, p < 0.00001 and p = 0.035). In conclusion, patients gaining the most from NA are those with an aggressive disease as reflected by advanced stage, abnormal LDH and high sFLCR. In addition, the adverse impact of these three variables is obscured by NA. Copyright

Staging Systems and Prognostic Factors as a Guide to Therapeutic Decisions in Multiple Myeloma

Multiple myeloma (MM) patients have a highly variable disease course and survival varies from a few months to more than 10 years. Numerous prognostic factors have been identified, including age, performance status (PS), serum albumin, beta2-microglobulin (beta2M), lactate dehydrogenase (LDH), renal function, genetic factors, and serum free light chains (sFLCs) or their ratio (sFLCR). Several models have been built to separate patients into various risk groups with different outcomes. Staging systems need to be simple, accurate, and readily available in order to effectively guide treatment decisions now that effective treatments exist that prolong survival. The International Staging System (ISS) is currently in use; it is highly prognostic but presents some limitations. We suggest that the ISS prognostic potential could be improved with the addition of sFLCR and eventually LDH.

Novel M-Component Based Biomarkers in Waldenström's Macroglobulinemia

Waldenstroms macroglobulinemia (WM) is an indolent B-cell lymphoma of the lymphoplasmacytic type accompanied by a serum IgM component. However, conventional IgM quantification lacks sensitivity, does not precisely reflect tumor burden of WM, and, although being the main marker for monitoring response to treatment, may not be accurate. New serum M-component based biomarkers were developed for routine practice in recent years, such as the Freelite® test and more recently the Hevylite test®. Studies have shown that Freelite was a prognostic marker for time to treatment in WM that helps monitoring disease response or progression. Hevylite measures IgMkappa and IgMlambda, separately, and might provide true quantitative measurement of the IgM M-spike. Although current data are preliminary, Hevylite® might replace the current technique to measure IgM M-spike in the years to come. We summarize herein studies conducted to delineate the role of these tests in WM.

CD138 Expression Helps Distinguishing Waldenström's Macroglobulinemia (WM) From Splenic Marginal Zone Lymphoma (SMZL)

The distinction between WM and SMZL may be difficult since both entities share overlapping clinical, immunophenotypic, and histopathologic characteristics. In this context we evaluated whether CD138 expression could be added in the armamentarium of tools used to differentiate these entities. Sixty-nine patients were studied, 47 WM and 22 SMZL. Paraffin-embedded sections of bone marrow biopsies were quantitatively and qualitatively evaluated for CD138 expression. Sixty percent of WM cases expressed CD138 in contrast to 18% of SMZL patients. Intermediate/high intensity of CD138 expression was observed in 47% of WM while it was low in all SMZL patients. Differences between WM and SMZL regarding the intensity and the percentage of CD138 positive cells were both significant (P=.0008 and, .00021 respectively). Moreover, CD138 expression was related to serum IgM levels in WM patients (P=.0006). In conclusion, CD138 expression may constitute an additional aid in the distinction between WM and SMZL.

Chapter 8The Contribution of Prognostic Factors to the Better Management of Multiple Myeloma Patients

Multiple myeloma (MM) is an heterogeneous plasma cell disorder of unknown etiology, with a wide range of clinical manifestations and a highly variable disease course. Survival varies from a few months to more than ten years. The disease is characterized by bone marrow (BM) infiltration by malignant plasma cells usually secreting a serum or urine monoclonal immunoglobulin (Ig) component. Progress has been made in the understanding of its pathogenesis including knowledge of BM microenvironment and of cellular and genetic factors implicated in disease mechanisms that are not uniform in all patients, thus partly explaining disease variability. Furthermore, based on these, new very performing biology-based treatment modalities have been developed and are either already available for patients or under evaluation.

New evidence of gene inactivation by aberrant DNA-Methylation in T-cell leukemia, with treatment implications

T-cell neoplasms are rare diseases characterized by an aggresive behavior with the exception of the cutaneous forms. Their athogenesis is less understood as compared to B-cell disorders and o, their management has not improved equally in the recent era of iology-driven treatment modalities. Epigenetic changes including NA hypo/hyper-methylation as well as promoter hypermethyation with consequent specific genes alterations are commonly ound in T-cell malignancies and possibly implicated in their biolgy. In this issue of Leukemia Research Kim et al. [1] provided new vidence concerning the involvement of DNA-methylation in Tell malignant disorders and the positive impact of reversing such pigenetic changes by demethylation. They performed DNA methyation analysis by pyrosequencing in normal blood and in two T-cell eukemia cell lines, one Jurkatt cell line derived from acute T-cell eukemia and the second HH, derived from cutaneous T-cell lymhoma. They found that nine genes, namely CLEC4E, CR1, DBC1, PO, HAL-DOA, IGF2, IL12B, ITGA1, and LMX1B, were considerably ypermethylated in the cell lines as compared to normal blood, ossibly leading to their expressional silencing. They suggested hat this mechanism eventually contributes to disease malignant ransformation. T-cell leukemia is an uncommon aggressive disease comproising children as well as adults. The use of pediatric intensive ombination chemotherapy regimens in adolescents and young dults has led to a significant improvement in patients’ outcome ith response rates ranging from 60 to 100% but there is a coniderable risk of relapse, especially in the central nervous system. n addition, there is no accepted standard of care for patients with elapsed or refractory disease. Therefore, new treatment strategies hat will further enhance survival, especially in those groups that emain of poor prognosis are needed. Thus, understanding moleclar mechanisms implicating in T-cell leukemia pathogenesis has een a challenging task in an effort to set new therapeutic targets. Cutaneous T-cell lymphomas (CTCL) comprise a separate group f primary skin-involving malignancies, the commonest of which re mycosis fungoides (MF) and Sezary syndrome (SS) that constiutes a form of disease evolution. The first entity is usually indolent, hile SS, characterized by erythroderma, lymphadenopathy, and lood involvement has heavier symptomatology a more aggressive ourse. Hypomethylation possibly contributes to the progression of F to more advanced stages, by mechanisms that remain unclear. oss of methylation may activate genes, such as PLS3 and DNM3,