Dimitrios Maltezas

ABSTRACT Backgroud. Serum s-synd-1 levels at diagnosis constitute an independent prognostic factor in MM. In addition, the magnitude of its diminution from diagnosis to plateau phase after conventional induction treatment was shown to predict for patients’ overall survival. Each time MM relapse after induction and is retreated, remission duration is shorter than the first time. However, new treatment modalities, bortezomib or lenalidomide - containing, have emerged for the management of relapsed/refractory MM patients, and they may improve patients’ outcome after relapse, thus prolonging life expectancy. If s-synd-1 levels’ decrease results in plateau phase or survival prolongation after treatment with new drugs (bortezomib, lenalidomide), is unknown. Aims. to evaluate the magnitude of serum s-synd-1 levels’ reduction from relapse to plateau phase in a series of relapsed/refractory MM patients treated with bortezomib or lenalidomide. Patients and methods. Serum s-synd-1 was determined in 32 relapsed/refractory MM patients treated with Velcade and dexamethasone (VD) and 16 treated with Revlimid and dexamethasone (RD) before treatment induction and in plateau phase. In addition, s-synd-1 levels were also determined in 30’s healthy individuals’ sera (HI). s-synd-1 measurements were performed in duplicate by ELISA with a commercially available kit (Diaclone research, France). Results. MM type was IgG in 59% vs. 69% and IgA in 22% vs. 19% in the VD and RD group respectively. Light chain myeloma was present in 13% in both groups, 1 VD patient had IgD MM. More than 50% were in advanced ISS stage. The median time of relapses before treatment was 3 in both VD and RD groups. 90% of patients (including 44% nCR or better) responded in the VD group vs. 81% an the RD one (including 38% nCR or better). The median follow-up time from VD or RD treatment to relapse was 8.8 and 13.8 months respectively. At the time of relapse, before treatment, median s-synd levels in all VD and RD patients, were 90.5 ng/mL (10-1100) [median 105 for VD vs. 62ng/mL for RD] and became 22.5 ng/mL (7-650) [median 20 for VD vs. 26ng/mL for RD], while they were 27 ng/mL in HI (12-40). In the whole group, the achievement of >50% reduction of serum s-synd-1 from relapse to plateau was accompanied with increased plateau duration (median 4.9 months without vs. 16,6 months with s-synd-1 fall >50% at plateau, P=0.01). Increased plateau duration was also observed in all patients when a nCR or better was achieved (P=0.006). However, when the VD and RD group were analyzed separately, the quality of response obtained was more important for plateau duration in the VD group (P=0.001 vs. 0.65 in RD), while the decrease of s-synd-1 by >50% was more important in the RD group (P=0.01 vs. 0.12 for VD). With regard to overall survival after VD or RD treatment, only s-synd-1 decrease was important in the RD group (P=0.04, Figure 1). Conclusions. if confirmed in a larger series, our results suggest that the biologic modulation of lenalidomide implicates s-synd-1 and that there is a subgroup of patients that mostly benefit from this modality.

ABSTRACT We studied aberrant changes (A-IgC) in the production of monoclonal intact immunoglobulin (M-Ig) or serum free light chains (sFLC) during symptomatic MM patients’ relapse and we evaluated their frequency and the associated disease characteristics. Patients and Methods: 234 symptomatic MM patients, with available follow-up M-Ig and sFLC measurements, were retrospectively studied. Light chain escape (LCE) was defined as sFLC increase with stable or falling M-Ig, M-Ig escape (MCE) as decreasing sFLC with increasing M-Ig, de-differentiation (DD) as clinical relapse with normal or decreased MIg and sFLC and Clonal Domination (CD) as normalization of formerly increased IgG, IgA or FLC in relapsing patients presenting increase of another monoclonal component. Results: A-IgC was observed in 18% of patients, LCE in 8%, MCE in 3%, DD in 2% and CD in 5%; The median time from diagnosis to A-IgC was 48.5, 35.5, 31 and 46 months for LCE, MCE, DD and CD respectively. Median survival from A-IgC to last follow-up or death was 2.6, 3.3 and 6.3 months respectively for LCE, MCE and DD versus 31.1 months for CD patients (p=0.0002). Patients received a median of 3 treatment lines, including novel agents and/or ASCT, prior to A-IgC. In conclusion, LCE, MCE and DD are late events in the course of MM, observed in heavily pre-treated patients, associated with a very aggressive disease with shortened survival thereafter, probably due to the emergence of new resistant clones or to the dominance of pre-existing minor ones.

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.

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.