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Abstract Background HevyLite™ is a new, recently developed method that facilitates separate quantification of the kappa- and lambda-bounded amounts of a given immunoglobulin (Ig). Using this method, we measured intact immunoglobulin (heavy/light chain; HLC) IgG-kappa, IgG-lambda, IgA-kappa, IgA-lambda individually, as well as their deriving ratios (HLCR) in a series of IgG or IgA multiple myeloma (MM) patients, to investigate and assess the contribution of these tests to disease evaluation. Patients and methods HevyLite™ assays were used in sera from 130 healthy individuals (HI) and 103 MM patients, at time of diagnosis. In patients, the level of paraprotein was IgG in 78 (52 IgG-kappa, 26 IgG-lambda) and IgΑ in 25 (13 IgΑ-kappa, 12 IgΑ-lambda). Durie-Salmon and International Staging System stages were evenly distributed. Symptomatic patients (n = 77) received treatment while asymptomatic ones (n = 26) were followed. Patients' median follow-up was at 32.6 months. HLCR was calculated with the involved Ig (either G or A) as numerator. Results In HI, median IgG-kappa was 6.85, IgG-lambda 3.81, IgA-kappa 1.19 and IgA-lambda 0.98 g/L. The corresponding median involving HLC values in MM patients were 25.8, 23.45, 28.9 and 36.4 g/L. HLC-IgG related to anemia, high serum free light chain ratio and extensive bone marrow infiltration, while high HLCR correlated with the same plus increased β2-microglobulin. In addition, increased HLCR and the presence of immunoparesis correlated with time to treatment. Patients with high HLCR had a significantly shorter survival (p = 0.022); HLCR retained its prognostic value in multivariate analysis. Conclusions HLC and HLCR quantify the precise amount of the involved immunoglobulin more accurately than other methods; moreover, they carry prognostic information regarding survival in MM patients.

We investigated incidence, characteristics and outcome of patients with macrofocal multiple myeloma (MFMM) treated mainly with novel therapies. Based on definition (BMPCs <20% and lytic lesions/plasmacytomas, without anemia, renal insufficiency or hypercalcemia) we identified 140 patients with MFMM, among 4650 myeloma patients (3%). Twice the number of patients with typical myeloma were used as controls; 60% were <65 years and 70% had advanced bone disease. Plasmacytomas were more frequent in MFMM compared with standard myeloma (68% vs 15%, P < .05). Adverse prognostic parameters (high lactate dehydrogenase, advanced stage, high risk cytogenetics, immunoparesis) were less common in patients with MFMM compared with controls (P < .05); 90% received novel agents and 47% underwent autologous transplantation upfront; 90% achieved an objective response; 70% had at least very good partial response which was significantly higher compared with controls (P < .05). After a median follow-up of 52 months, 33 patients have died. Early death (<12 months) was infrequent in MFMM. Median progression-free survival and overall survival (OS) were 46 and 129 months respectively, both significantly longer compared with controls (P < .001). Proteasome inhibitor (PI)-based therapy was the only independent predictor for OS in the multivariate analysis (HR: 3.9; P < .001). In conclusion, MFMM is a distinct entity presented in young and elderly subjects, characterized by limited bone marrow infiltration, advanced bone disease and frequent presence of plasmacytomas; MFMM patients have less often adverse prognostic features and achieve excellent responses and prolonged OS especially when treated with PI-based therapies. Novel imaging will help in a more accurate classification of this entity., (© 2020 Wiley Periodicals, Inc.)

Background/aim: Hematological malignancies are frequently complicated by secondary immunodeficiency (SID). Immunoglobulin replacement with intravenous gamma globulins (IVIg) reduces infection incidence, antibiotics' need and hospitalization days in these patients. Facilitated subcutaneous immunoglobulin replacement (fSCIg) has been studied in primary immunodeficiency patients and is equally efficacious with several advantages (self-administration, same bioavailability, long infusion intervals, fewer adverse drug reactions). fSCIg has been less extensively studied in SID. We present our retrospective single-center data of fSCIg administration to hematological patients with SID, focusing on efficacy and safety issues., Patients and Methods: Overall, 33 hematological patients with hypogammaglobulinemia were treated with fSCIg according to ESMO 2015 guidelines, between mid-October 2015 and mid-January 2018 in our Department., Results: The infection rate was very low (18.1%). Shorter infusion intervals further reduced it. ADRs were rare (9%) and mild (grade 1). fSCIg managed to reduce the everyday nursery/hospital burden of our tertiary hospital., Conclusion: fSCIg compares favorably to IVIg replacement in SID patients., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We evaluated bortezomib induced peripheral neuropathy (BIPN) characteristics in an attempt to better clarify the type, grade, duration and reversibility of neuropathy as well as investigate possible peripheral neuropathy (PN) risk factors and detect the best way to manage it. We calculated the grading of neuropathy using the Total Neuropathy Score reduced version (TNSr) in a series of 51 patients with relapsed/refractory multiple myeloma treated with bortezomib. Seventy percent developed clinical PN. BIPN, although manageable, is frequently underestimated in patients treated with bortezomib intravenously. Continuous follow-up and management of PN are needed to avoid quality of life impairment.

BLyS is involved in CLL biology and its low soluble serum levels related to a shorter time to first treatment (TFT). TACI is a BLyS receptor and can be shed from cells' surface and circulate in soluble form (sTACI). We investigated the impact of serum BLyS and sTACI levels at diagnosis in CLL patients and their relationship with disease parameters and patients' outcome. Serum BLyS was determined in 73 patients, while sTACI in 60. Frozen sera drawn at diagnosis were tested by ELISA. sTACI concentrations correlated with BLyS (P = -0.000021), b2-microglobulin (P = 0.005), anemia (P = -0.03), thrombocytopenia (P = 0.04), Binet stage (P = 0.02), and free light chains ratio (P = 0.0003). Soluble BLyS levels below median and sTACI values above median were related to shorter TFT (P = 0.0003 and 0.007). During a ten-year followup, sTACI levels, but not BLyS, correlated with survival (P = 0.048). In conclusion, we confirmed the prognostic significance of soluble BLyS levels with regard to TFT in CLL patients, and, more importantly, we showed for the first time that sTACI is a powerful prognostic marker, related to parameters of disease activity and staging and, more importantly, to TFT and OS.

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.

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 × 10(5) ) and 47.97 (0.26-2.3 × 10(7) ) 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 © 2012 John Wiley & Sons, Ltd.)

Background. Serum free light chains (sFLC), the most commonly detected paraprotein in CLL, were recently proposed as useful tools for the prognostication of CLL patients. Objective. To investigate the prognostic implication of sFLC and the summated FLC-kappa plus FLC-lambda in a CLL patients' series. Patients and Methods. We studied 143 CLL patients of which 18 were symptomatic and needed treatment, while 37 became symptomatic during follow-up. Seventy-two percent, 18%, and 10% were in Binet stage A, B and C, respectively. Median patients' followup was 32 months (range 4-228). Results. Increased involved (restricted) sFLC (iFLC) was found in 42% of patients, while the summated FLC-kappa plus FLC-lambda was above 60 mg/dL in 14%. Increased sFLC values as well as those of summated FLC above 60 were related to shorter time to treatment (P = 0.0005 and P = 0.000003, resp.) and overall survival (P = 0.05 and P = 0.003, resp.). They also correlated with β 2-microglobulin (P = 0.009 and P = 0.03, resp.), serum albumin (P = 0.009 for summated sFLC), hemoglobin (P < 0.001), abnormal LDH (P = 0.037 and P = 0.001, resp.), Binet stage (P < 0.05) and with the presence of beta symptoms (P = 0.004 for summated sFLC). Conclusion. We confirmed the prognostic significance of sFLC in CLL regarding both time to treatment and survival and showed their relationship with other parameters.

Waldenstrom's 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.

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.

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.

Purpose: To study the toxicity of high dose chemotherapy (HDCT) in multiple myeloma (MM) patients and its impact on event free survival (EFS) and overall survival (OS), and also the impact of thalidomide maintenance therapy on EFS and OS after HDCT., Patients and Methods: From April 1999 to November 2006 37 patients (29 males, 8 females) out of a total of 38 scheduled were treated with HDCT and autologous peripheral stem cell transplantation (APSCT), as consolidation treatment after first- or second-line chemotherapy. Their median age was 55 years (range 38-71). HDCT regimen used was melphalan 200 mg/m(2). Following HDCT thalidomide 100 mg/day was administered as maintenance therapy to 28 patients in a random fashion., Results: All patients tolerated well HDCT and APSCT. There was no treatment-related mortality. The median time interval for neutrophil recovery (>500/mm(3)) was 10 days (range 8-20), while the median time interval for platelets to recover to >20.000/mm(3) was 14 days (range 9-32). Twenty (54%) patients achieved complete response (CR), 15 (40%) partial response (PR), and 2 (6%) stable disease (SD). Before receiving thalidomide as maintenance treatment 12 (42%) patients were in CR, while all the others, except one who had progressive disease (PD), were in PR. CR correlated with better EFS and probably OS. Thalidomide maintenance treatment correlated with better EFS., Conclusion: In our series of patients HDCT appears to be a totally feasible, safe and without treatment-related mortality procedure, even in patients older than 60 years of age. It has a major impact in terms of CR achievement, which seems to strongly correlate with a prolonged EFS and OS. The use of thalidomide as a maintenance therapy induces a greater EFS which could possibly yield an improved OS.