Efstathios Koulieris

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

Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom's macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH)

The recently proposed, ISSWM staging system for symptomatic patients with WM was based on patients treated with alkylating agents and nucleoside analogs and has not been externally validated nor has been validated for cause-specific survival (CSS). We independently validated ISSWM both for overall survival (OS) and for CSS and assessed whether addition of elevated serum LDH may add to the strength of ISSWM in 335 patients treated upfront mainly with alkylating agents (43%), and rituximab-based therapies (47%). ISSWM could discriminate three groups with significantly different OS and CSS (p<0.01 for both). High serum LDH was predictive of shorter OS and CSS (p<0.01). The combination of high risk according to ISSWM and elevated serum LDH identified a subset of patients for whom innovative treatment approaches are needed.

The combination of lenalidomide and dexamethasone reduces bone resorption in responding patients with relapsed/refractory multiple myeloma but has no effect on bone formation: Final results on 205 patients of the Greek myeloma study group

The combination of lenalidomide plus dexamethasone (RD) is very effective for patients with relapsed/refractory myeloma. However, the effect of RD on bone metabolism has not been previously evaluated in these patients. To address this issue, we initially performed a retrospective study in 106 consecutive patients with relapsed or refractory myeloma who received RD. We measured the following bone indices on Cycle 1/Day 1 and then on Cycles 3 and 6/Day 28: dickkopf‐1 (Dkk‐1), sRANKL, osteoprotegerin (OPG), bone resorption markers (C‐telopeptide of collagen type‐I, CTX and TRACP‐5b) and bone formation markers (bone‐specific alkaline phosphatase‐bALP and osteocalcin). RD produced a reduction of CTX only in responders, with no effect on bone formation. To validate these results, we then evaluated prospectively 99 patients who received either RD (n = 50) or VRD (bortezomib + RD, n = 49). RD reduced CTX, mainly in responders but showed no effect on bone formation, confirming the result of the retrospective study. However, the addition of bortezomib to RD (VRD arm) reduced Dkk‐1, sRANKL/OPG, and CTX, while it increased bALP and OC after six cycles of therapy. These changes were irrespective of treatment response, which was similar between treatment arms. No skeletal‐related events were observed in the VRD arm while two, nonresponding patients treated with RD developed a vertebral fracture. We conclude that RD reduces bone resorption only in responding patients with relapsed/refractory myeloma but has no effect on bone formation. Combination with bortezomib, which enhances bone formation, seems to be preferred for the management of myeloma patients with osteolytic disease. Am. J. Hematol. 89:34–40, 2014.

No significant improvement in the outcome of patients with Waldenström's macroglobulinemia treated over the last 25 years†‡

The treatment of Waldenströms macroglobulinemia (WM) has changed over the last decades, mainly because of the introduction of nucleoside analogues and of rituximab while novel agents such as bortezomib have been recently introduced. We performed an analysis to investigate whether the outcome of patients with WM has improved over the last years, compared to that of patients who started treatment before new drugs became widely available, especially as part of the frontline treatment. We analyzed 345 symptomatic patients with WM: 130 who initiated treatment before and 215 who started treatment after January 1, 2000. Patients who started treatment in the latter group were older and had more often elevated beta2‐microglobulin but the other characteristics were similar between the two groups. Most patients who started treatment before January 1, 2000 were treated upfront with alkylating agent‐based regimens and most patients who started treatment after January 1, 2000 received rituximab‐based regimens as initial treatment. Objective response (63 and 59%, respectively) and median overall survival, OS, (106.5 months for Group A and is estimated at 94 months for Group B, P = 0.327) were similar. There was also no difference regarding OS or cause specific survival (CSS) in each risk group according to IPSSWM. Our observation may be explained by the indolent course of WM in several patients and by the lack of profound cytoreduction in patients with high‐risk disease. Possible differences in the 15‐ or 20‐year survival rate between the two groups may be detected with further follow‐up of these patients. Am. J. Hematol. 2011.

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.

Incidence, clinical features, laboratory findings and outcome of patients with multiple myeloma presenting with extramedullary relapse

Abstract Extramedullary plasmacytomas constitute a rare and not well studied subset of multiple myeloma (MM) relapses. We report the incidence, clinical–laboratory features and outcome of patients with MM and extramedullary relapse (ExMeR). A total of 303 patients with symptomatic MM were recorded in a 13-year period in two institutions. Twenty-eight cases of ExMeR (9%) were recorded. There was an increased frequency of elevated lactate dehydrogenase (LDH) (p = 0.026), bone plasmacytomas (p = 0.001) and fractures (p = 0.002) at diagnosis, in patients with ExMeR compared to the others. ExMeR was associated with an ominous outcome, high LDH, constitutional symptoms and a statistically significant decrease of monoclonal paraprotein compared to levels at diagnosis (p = 0.009). Prior treatment with bortezomib was associated with a decreased hazard of ExMeR (p = 0.041). Overall survival (OS) was decreased in patients with ExMeR compared to the others (38 vs. 59 months, p = 0.006). Patients with MM with ExMeR have a lower OS and their clinical and laboratory features differ from those without.

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.

New Insights into Monoclonal B-Cell Lymphocytosis

Monoclonal B-cell lymphocytosis (MBL) is a premalignant condition characterized by the presence of less than 5000/μL circulating clonal B cells in otherwise healthy individuals. Three subcategories have been identified according to the immunophenotypic features: CLL-like, CD5(+) atypical, and CD5(−) MBL. CLL-like MBL is by far the most frequent and best studied category and further divided in low-count [LC] and high-count [HC] MBL, based on a cutoff value of 500/μL clonal B cells. LC-MBL typically remains stable and probably does not represent a truly premalignant condition, but rather an age-related immune senescence. On the other hand, HC-MBL is closely related to CLL-Rai0, bearing similar immunogenetic profile, and is associated with an annual risk of progression to CLL requiring therapy at a rate of 1.1%. Currently there are no reproducible factors for evaluating the risk of progression to CLL. CD5(−) MBL is characterized by an immunophenotype consistent with marginal zone origin and displays many similarities with marginal zone lymphomas (MZL), mainly the splenic MZL. The cutoff value of 5000/μL clonal B cells cannot probably be applied in CD5(−) MBL, requiring a new definition to describe those cases.

Detection of L265P MYD-88 mutation in a series of clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ).

Clonal B‐cell lymphocytosis of marginal zone origin (CBL‐MZ) is a recently described entity characterized by the presence of clonal B cells in the blood and/or bone marrow (BM) with morphologic and immunophenotypic features consistent with marginal zone derivation in otherwise healthy individuals. CBL‐MZ is commonly associated with paraproteinemia, usually immunoglobulin M (IgM), raising diagnostic difficulties from Waldenstrom macroglobulinemia (WM). The aim of the present study was to determine the presence of MYD‐88 L265P mutation in a well‐characterized series of CBL‐MZ to identify cases that may in fact represent WM. Fifty‐three CBL‐MZ cases were retrospectively evaluated. MYD‐88 L265P mutation was determined by allele‐specific polymerase chain reaction in blood and/or BM mononuclear cells. Almost half of the CBL‐MZ cases (49%) were associated with paraproteinemia mainly of the IgM type (65%). MYD‐88 L265P mutation was identified in 10 cases (19%). These cases may truly represent WM, whereas 43 cases (81%) are still classified as CBL‐MZ. Mutated cases were all associated with paraproteinemia compared with 37% of the nonmutated ones (P < .0001). In addition, mutated cases displayed more frequently CD38 and CD25 positivity (P = .002 and P = .005, respectively). Moreover, cases without paraproteinemia presented more frequently with lymphocytosis, irrespective of the presence of the MYD‐88 mutation (P = .02). The present study demonstrates that MYD‐88 L265P mutation may represent the only sensitive marker for the differentiation of CBL‐MZ from probable WM. However, further studies are warranted to better define the biological significance of MYD‐88 L265P mutation and to clarify whether the presence of the mutation establishes WM diagnosis or that it can also be present in borderline cases associated with paraproteinemia.