Serum Free Light Chain Ratio (FLCr) Is a Powerful Prognostic Factor For Survival In Newly Diagnosed Multiple Myeloma (MM) Eligible For High Dose Melphalan (HDM)

Abstract

Introduction MM is a B cell malignancy characterized by the presence of a monoclonal immunoglobulin (Ig) in the serum and/or urine produced by clonal plasma cells. MM has a variable outcome depending on age, stage and cytogenetic abnormalities. FLCr is a readily available laboratory test and has independent prognostic significance in all the plasma cell disease entities, helping to clarify International Staging System (ISS), namely the heterogeneous stage II. In the era of new therapeutic agents trending to personalized therapy, its prognostic value needs to be proved. Purpose To evaluate the prognostic value of baseline serum FLCr on outcome of patients with newly diagnosed MM eligible for HDM treated with thalidomide or bortezomib based regimens. Methods This is a retrospective study, from January 2005 to December 2012. We analyzed the relationship of baseline FLCr with outcome and its contribution to clarify the prognostic value of ISS. Serum FLC levels were measured in frozen sera drew at diagnosis before treatment, using a latex-enhanced immunoassay (The Binding Site, Birmingham, UK) on a Beckman Coulter nephelometric analyzer. FLCr was calculated as k/λ (reference range: 0,26-1,65). Abnormal FLCr was defined of <0,03 or >32,00 and standard FLCr of 0,03-32. Patients have been staged by ISS and Mayo Clinic stratification. All patients received at least two cycles of a bortezomib based regimen (64,7%), with doxorubicin and dexamethasone (PAD) in 55 patients (53,9%), with cyclophosphamide and dexamethasone (Cy-Bor-D) in 11 patients (10,8%) or thalidomide, doxorubicin and dexamethasone (TAD) in 36 patients (35,3%). Median follow-up from diagnosis was 30 months. Follow-up was through the review of each patient’s complete medical records at our center. Statistical analysis was performed with SPSS 20 ®. Results We reviewed 102 patients treated with thalidomide or bortezomib based-regimens eligible for HDM. Fifty one percent of patients were male and median age was 52 years (22-70y). The Ig type was IgG in 62,7%, IgA in 14,7%, IgD in 3,9%, light chains MM in 17,7% and non-secretory MM in 1,0% of patients. The median Hb level was 9,8 g/dL (5,3-16,7mg/L) and median serum albumin was 31,5 g/L (22,3-48,3g/L). Creatinine clearance <30ml/mn occurred in 18,6% of patients, 34,3% had elevated LDH and median β2-microglobulin was 6,61 mg/L (1,06-45,77mg/L). According to ISS, 39,2%% of patients were on stage I, 25,5%% on stage II and 35,3% on stage III. Clonal k light chain present in 58,8% of patients: 64,7% had abnormal FLCr (<0,03 or >32,00). Cytogenetic FISH analysis was performed in 86,3% of patients: 32,4% presented high-risk features. We observed a significant difference on overall survival (OS) and progression free survival (PFS) according to Mayo Clinic risk-factors: 0, not reached (NR), 1, NR, 2, 49 months and 3, 71 months for OS (P=0,000) and 0, 68 months, 1, 55 months, 2, 16 months and 3, 24 months for PFS (P=0,000). According the FLCr there was a significant advantage on OS for standard FLCr: NR vs 71 months (P=0,035). A trend to a better OS (P=0,061) was observed in stage II patients with standard FLCr but no significant difference at any stage. Conclusions Baseline serum FLCr associated to others risk-factors like serum β2-microglobuline and albumin is a powerful prognostic factor for survival in newly diagnosed MM eligible for HDM treated with thalidomide or bortezomib-based therapies. We fail to fully demonstrate FLCr prognostic value on ISS stage II patients, only a trend for better outcome with standard FLCr. Disclosures: Esteves: Janssen-Cylag and Celgene. Consultancy on the area of multiple myeloma and acute myeloid leukaemia: Consultancy. Raposo:Roche; lymphoproliferative diseases: Consultancy. Guerra:Novartis, Bristol-Myers Squibb and Amgen. Advisory bord meetings. Areas involved: Myeloproliferative neoplasms and acute leukaemia: Consultancy.

Development of an Initial Conceptual Model of Multiple Myeloma to Support Clinical and Health Economics Decision Making

“…Explanatory variables: age, 46–48,60,61,63–71,74,77,80 serum LDH level, 46,51,62,64,65,73,76,79–81,88 light chains level, 44,46–54 β 2 microglobulin level, 51,62,64,70,71,79–81,89,90 albumin level, 53,64–66,71,79,80 M protein level, 59,70,91–93 t(14), 55–59 pain, 69,83,85,…”

“…Dependent variables: OS, 45–47,49–51,54–61,63–65,67,68,71–74,76,78–81,87–90,96–122 β 2 microglobulin, 55,73,106,109,123–126 serum LDH level, 62,88,112,117,120…”

“…Numbers in brackets are the number of attributes in each group. In total, 56 MM attributes were identified as significant, that is, those that have a significant relationship with another attribute; these were grouped into five categories: disease characteristics, 44–54 cytogenetic factors, 55–59 patient characteristics, 45–48,51,53,55,60–81 QoL, 69,75,82,83 and symptoms. 46,69,71,82–87 …”

“…BAFF, B-cell activating factor; BLyS, B-lymphocyte stimulator; BMI, body mass index; CCND1, gene encoding cyclin D1; CD81, gene encoding cluster of differentiation 81; ECOG, Eastern Cooperative Oncology Group; ESR, erythrocyte sedimentation rate; FACT-MM, Functional Assessment of Cancer Therapy-Multiple Myeloma; HRQoL, health-related quality of life; IL, interleukin; IRF4, gene encoding interferon regulatory factor 4; ISS, International Staging System; LDH, lactate dehydrogenase; MDR1, multidrug resistance gene 1; MIP-1a, macrophage inflammatory protein 1a; MKI67, gene encoding marker of proliferation Ki-67; MM, multiple myeloma; QoL, quality of life; RBC, red blood cell; sFAS-L, soluble Fas ligand; sFLCR, serum free light-chain ratio.Numbers in brackets are the number of attributes in each group. In total, 56 MM attributes were identified as significant, that is, those that have a significant relationship with another attribute; these were grouped into five categories: disease characteristics,[44][45][46][47][48][49][50][51][52][53][54] cytogenetic factors,[55][56][57][58][59] patient characteristics,[45][46][47][48]51,53,55, QoL,69,75,82,83 and symptoms 46,69,71,[82][83][84][85][86][87].…”