Lower Β2-microglobulin Research Articles

High serum cystatin C levels in juvenile myelomonocytic leukemia patients without abnormal kidney function.

In pediatric cancer patients, the estimated glomerular filtration rate based on serum cystatin C (CysC) was reported to be suitable for estimating kidney function because of low serum creatinine (Cr) and high serum β2-microglobulin. Recently, however, serum CysC levels have been reported to be elevated in some cancer patients other than those with juvenile myelomonocytic leukemia (JMML), regardless of normal kidney function. We describe two pediatric cases of JMML with an elevated serum CysC level. Urinalysis tests showed no abnormalities and no evidence of nephritis or nephropathy, and there were no findings indicating abnormal kidney function, such as Cr clearance in one case or the estimated glomerular filtration rate based on serum Cr in both cases, except for the serum CysC levels. There were no other causes of a high serum CysC level, including hyperthyroidism and steroid administration. The patients were treated with a conventional dosage of drugs, and their serum CysC levels decreased to the normal range when they were in complete remission after treatment. An elevated serum CysC level may reflect tumor burden independent of kidney function in JMML patients. Therefore, creatinine or inulin clearance should be determined to more accurately estimate kidney function for administering an optimal dose of anticancer drugs. In addition, a high serum CysC level may be a potential biomarker of cancer progression.

Monocyte or white blood cell counts and β2 microglobulin predict the durable efficacy of daratumumab with lenalidomide.

Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab. We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status. We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database. We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database. In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower β2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen. We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/μl; 1 point for <200/μl) or WBC counts (0 points for ⩾3500/μl; 1 point for <3500/μl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p < 0.001). To confirm this concept, our results will need to be validated in other cohorts.

Study on the Relationship Between the Expression of B Cell Mature Antigen and the Classification, Stage, and Prognostic Factors of Multiple Myeloma.

The expression level of BCMA in bone marrow of 54 MM patients was detected in this study to explore the relationship between the BCMA expression and the classification, stage, and prognostic factors of MM. The BCMA expression level of the stable group and remission group was lower than that of the newly diagnosed group and relapse group (P=0.001). There was no significant difference in BCMA expression of MM patients in different types and stages (P>0.05), but it was found that for the newly diagnosed MM patients, the BCMA expression level of IgG patients was higher than that of IgA or light-chain patients (rank average 11.20 vs 5.44, P=0.014). There was no significant correlation between the BCMA expression and the age and serum creatinine of MM patients (P>0.05). And there was no significant difference in BCMA expression between patients with different levels of age and serum creatinine (P>0.05). But it was found that the BCMA expression level of the newly diagnosed MM patients was moderately positively correlated with their age (P=0.025, r=0.595). There was no significant correlation between the BCMA expression and serum β2-microglobulin, serum lactate dehydrogenase, free kap/lam ratio, and urine β2-microglobulin (P>0.05). But we found that the BCMA expression of patients with high serum β2-microglobulin was higher than that of patients with low serum β2-microglobulin (rank average 28.89 vs 17.54, P=0.017). And the BCMA expression of patients with abnormal serum free kap/lam ratio was higher than that of patients with normal ratio (rank average 28.49 vs 13.55, P=0.004). The BCMA expression was strongly positively correlated with 24-h urine protein, was moderately positively correlated with serum M protein and the percentage of plasma cells in bone marrow, was moderately negatively correlated with albumin and hemoglobin count, and was weakly positively correlated with serum corrected calcium (P<0.05). And it was found that the BCMA expression of positive serum immunofixation electrophoresis patients was higher than that of negative patients (rank average 29.94 vs 16.75, P=0.017). And we try to clarify the relationship between the bone marrow BCMA expression and the peripheral blood sBCMA expression. However, we have not found a clear correlation between them so far (P>0.05).

Abstract 1372: Model based approach to evaluate Isatuximab (Isa) monthly dosing regimen in relapsed/refractory multiple myeloma (RRMM)

Abstract Introduction: Isa is a CD38 monoclonal antibody with multiple modes of action for killing tumor cells. Isa, in combination with pomalidomide and dexamethasone (Pd), is approved for the treatment of adult pts with RRMM who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor. This study characterized the relationship between serum M-protein kinetics and progression free survival (PFS) in RRMM pts from the Phase 3 ICARIA-MM study, and simulated expected PFS outcomes when switching to a hypothetical monthly Isa dosing regimen after 6 months. Methods: A joint model of serum M-protein dynamics and PFS was developed using data from 256 pts. Pts received Isa intravenously, 10 mg/kg once weekly (QW) for 4 weeks (wks), then every other wk (Q2W) for 28-day cycles plus standard Pd (Isa-Pd) or Pd alone (control). A tumor growth inhibition model described serum M-protein kinetics under treatment effects of Isa-Pd or Pd alone; Isa exposure was predicted using individual PK parameters from the population PK analysis (Fau, PAGE Congress, 2019) and Pd exposure was predicted from K-PD model using dosing history. Trial simulations were performed using individual PK/PD parameters of ICARIA-MM pts. Results: The joint model identified instantaneous changes (slope) in serum M-protein as the best on-treatment predictor for PFS and identified baseline pt characteristics impacting serum M-protein kinetics (serum albumin and serum β2 microglobulin on the baseline serum M-protein levels and the non-IgG type on the serum M-protein growth rate, the serum M-protein slope) and PFS (presence of plasmacytomas). Non-IgG MM pts have similar behavior on serum M-protein kinetics for the first 60 wks even with higher exposure and similar PFS vs IgG MM pts supporting non-dose adjustment based on IgG status. Clinical trial simulation of the Isa-Pd regimen showed that switching pts on treatment at 6 months to a monthly Isa regimen would shorten the median time to progression (TTP) by 4.1 wks and median PFS by 2.3 wks (14.03 to 13.45 months). Based on TTP criteria, pts with no risk of earlier progression while switching to a monthly Isa regimen (57.7%) tend to have lower baseline tumor burden (lower serum M-protein and lower percent of bone marrow plasma cell) and better prognostic factors (higher glomerular filtration rate, higher albumin, lower β2 microglobulin). At 6 months, 85% of these pts had predicted stable ≥VGPR status. Conclusions: Trial simulations support the approved Isa 10 mg/kg QW/Q2W regimen and show that switching to a monthly Isa regimen after 6 months may reduce clinical benefit in the overall population. However, some pts with good prognosis (low tumor burden, low ISS stage, good renal function) and obtaining stable ≥VGPR status by 6 months may switch to a monthly regimen after 6 months without compromising disease progression risk; this hypothesis will be tested in a prospective clinical trial. Citation Format: Hoai-Thu Thai, Nadia Gaudel-Dedieu, Marc Cerou, Bernard Sebastien, Helgi van de Velde, Dorothee Semiond, Christine Veyrat-Follet. Model based approach to evaluate Isatuximab (Isa) monthly dosing regimen in relapsed/refractory multiple myeloma (RRMM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1372.

Model Based Approach to Evaluate Isatuximab Monthly Dosing Regimen in Relapsed/Refractory Multiple Myeloma Patients

Background: Isatuximab (Isa) is a CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement (Moreno, Clin Cancer Res, 2019). The addition of Isa to pomalidomide (P) and dexamethasone (d) was associated with a significant and clinically meaningful benefit in progression-free survival (PFS) in heavily pre-treated patients with relapsed/refractory multiple myeloma (RRMM) (ICARIA-MM, NCT02514668) (Attal, Lancet, 2019). Isa, in combination with Pd, is approved in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult patients with RRMM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. Aim: The objectives were to characterize the relationship between serum M-protein kinetics and PFS in RRMM using data from the Phase 3 ICARIA-MM study and to simulate expected longitudinal serum M-protein and PFS when switching to a hypothetical monthly dosing regimen after 6 months. Methods: A joint model of serum M-protein dynamics and PFS was developed using data from 256 evaluable ICARIA-MM patients. Patients received Isa intravenously at 10 mg/kg once weekly (QW) for 4 weeks, then every other week (Q2W) for 28-day cycles in combination with standard Pd (Isa-Pd) or Pd alone in the control arm. A tumor growth inhibition model was used to describe the serum M-protein kinetics under treatment effects of Isa-Pd or Pd alone, in which Isa exposure was predicted using individual PK parameters obtained from the population PK analysis (Fau, Population Approach Group in Europe, 2019) and Pd exposure was predicted from K-PD model using dosing history. Trial simulations were then performed using individual PK/PD parameters of ICARIA-MM patients to evaluate whether efficacy is maintained after switching to a monthly dosing regimen. Results: The joint model identified the instantaneous changes (slope) in serum M-protein as the best on-treatment predictor for PFS and also identified baseline patient characteristics impacting serum M-protein kinetics (serum albumin and serum β2 microglobulin on the baseline serum M-protein levels and the non-IgG type on the serum M-protein growth rate, the serum M-protein slope), and PFS (presence of plasmacytomas). Non-IgG MM patients have similar behavior on serum M-protein kinetics for the first 60 weeks even with higher exposure and similar progression free survival compared to IgG MM patients supporting the non-dose adjustment based on IgG status. Clinical trial simulation of the ICARIA-MM Isa-Pd regimen demonstrated that switching all patients on treatment at 6 months to a monthly Isa regimen would shorten the median time to progression (TTP) (i.e. increase in serum M-protein greater than 25% and an absolute increase greater than 5 g/L compared to nadir) by 4.1 weeks and would shorten median PFS by 2.3 weeks (from 14.03 to 13.45 months). Based on TTP criteria, patients with no risk of earlier progression (57.7%) due to 6 months switch tend to have lower baseline tumor burden (lower serum M-protein and lower percent of bone marrow plasma cell) and better prognostic factors (higher glomerular filtration rate, higher albumin, lower β2 microglobulin). At 6 months, 85% of these patients had predicted stable "at least" VGPR status. Conclusions: Trial simulations supported the choice of the approved isatuximab 10 mg/kg QW/Q2W regimen and showed that switching to a monthly Isa regimen after 6 months may reduce clinical benefit in overall population. However, a subpopulation of patients with good prognosis and obtaining stable at least VGPR status by 6 months may switch to a monthly regimen after 6 months without compromising disease progression risk; this hypothesis will be tested in a prospective clinical trial. Model-based drug development has been successfully applied to support treatment decisions in RRMM patients. Disclosures Thai: Sanofi: Current Employment. Gaudel-Dedieu:Sanofi: Current Employment. Cerou:Sanofi: Current Employment. Sebastien:Sanofi: Current Employment. van de Velde:Sanofi: Current Employment, Current equity holder in publicly-traded company. Semiond:Sanofi: Current Employment. Veyrat-Follet:Sanofi: Current Employment.

Evaluation of Coronavirus Disease 2019 Severity Using Urine Biomarkers.

Early detection of coronavirus disease 2019 in patients likely to develop severe manifestations enables appropriate interventions, including rapid ICU admission. This study was conducted to determine whether noninvasive urine biomarkers can predict the clinical severity of coronavirus disease 2019. Not applicable. This is single-center study, national center hospital designated for infectious disease. Fifty-eight patients who tested positive for severe acute respiratory syndrome coronavirus 2 in respiratory specimens through real-time reverse transcription-polymerase chain reaction were retrospectively studied. Urinary β2-microglobulin, liver-type fatty acid-binding protein were serially measured. Serum interferon-γ and monocyte chemotactic protein-1 were also evaluated. The 58 patients were assigned into three groups. Patients requiring intensive care were assigned to the severe group (n = 12). Patients treated with oxygen were assigned to the moderate group (n = 13). Other patients were assigned to the mild group (n = 33). Urine tests revealed that low β2-microglobulin and liver-type fatty acid-binding protein levels were associated with mild disease, whereas high levels were associated with severe disease. In severe cases, liver-type fatty acid-binding protein tended to be persistently high. The resulting cutoff values were β2-microglobulin; severe versus moderate + mild: 2,457 μg/dL (specificity 76.9% and sensitivity 90.0%, area under the receiver operating characteristic curve 85.9%), liver-type fatty acid-binding protein; severe versus moderate + mild: 22.0 μg/gCre (specificity 84.6% and sensitivity 90%, area under the receiver operating characteristic curve 91.8%). Urinary β2-microglobulin and serum interferon-γ/monocyte chemotactic protein-1 showed a similar trend. Evaluating urinary biomarkers such as β2-microglobulin and liver-type fatty acid-binding protein may allow determination of coronavirus disease 2019 patients with active cytokines and recognition of patients likely to become critically ill and requiring careful observation and early intervention.

Combination of baseline total metabolic tumor volume measured on FDG-PET/CT and β2-microglobulin have a robust predictive value in patients with primary breast lymphoma.

The aim was to build a prognostic model to stratify patients at diagnosis into different risk categories. We investigated the prognostic value of functional PET parameters and clinical features in 64 primary breast lymphoma (PBL) patients. With a median follow-up of 60 months, 5-year progression-free survival (PFS) and overall survival (OS) was 62.5% and 73.4%. In multivariate analysis, baseline total metabolic tumor volume (TMTV0) and β2-microglobulin remained more reliable predictors of survival than other prognostic factors. The optimal TMTV0 cut-off value was 90 cm3 . Among 29 patients with high TMTV0, 5-year PFS and OS were 44.8% and 62.1%, respectively, while 5-year PFS and OS of 35 patients with low TMTV0 were 74.3% and 85.7%, respectively. TMTV0 combined with β2-microglobulin identified three groups with very different prognosis, including low-risk group with low TMTV0 and β2-microglobulin≤normal (n = 30), intermediate-risk group with high TMTV0 or β2-microglobulin>normal (n = 20), and high-risk group with high TMTV0 and β2-microglobulin>normal (n = 14). In the three groups, 5-year PFS rates were 80%, 55% and 28.6% (P = .003), and 5-year OS rates were 90%, 65%, and 50% (P = .023) respectively. We established a new prognostic model through TMTV0 and β2-microglobulin, and can divide PBL at diagnosis into different risk categories.

Impact of Induction Therapy on the Outcome of Immunoglobulin Light Chain Amyloidosis after Autologous Hematopoietic Stem Cell Transplantation

With the availability of immunomodulatory imide drugs (IMiDs) and proteasome inhibitors (PI), most patients with immunoglobulin light chain amyloidosis (AL) receive induction therapy before autologous hematopoietic stem cell transplantation (auto-HCT). In this study we evaluated the type of induction therapy and its impact on the outcome of auto-HCT in AL. We identified 128 patients with AL who underwent high-dose chemotherapy and auto-HCT at our institution between 1997 and 2013. Patients were divided into 3 groups: no induction, conventional chemotherapy (CC)-based induction (melphalan, steroids), and IMiD/PI-based induction (thalidomide, lenalidomide, or bortezomib). The hematologic response (HR) and organ response were defined according to the established criteria. Median age at auto-HCT was 58 years (range, 35 to 75). Twenty patients (15.5%) received no induction, 25 (19.5%) received CC, and 83 (65%) received IMiDs/PIs. One, 2, or 3 or more organs were involved in 90 (70%), 20 (16%), and 18 (14%) patients, respectively. After auto-HCT 12 of 20 (60%), 15 of 24 (62%), and 72 of 83 (87%) assessable patients achieved HR at 100 days in no induction, CC, and IMiD/PI groups, respectively (P = .001). Organ response at 1 year after auto-HCT was seen in 7 of 18 (39%), 14 of 24 (58%), and 37 of 79 (47%) assessable patients in no induction, CC, and IMiD/PI groups, respectively (P = .3). Achieving a hematologic complete response was associated with a significantly higher probability of achieving an organ response (P = .02). After a median follow-up of 26 months, rates of 2-year progression-free survival were 67%, 56%, and 73% in no induction, CC, and IMiD/PI groups, respectively (P = .07; hazard ratio, .5; 95% confidence interval [CI], .3 to 1.1). Rates of 2-year overall survival were 73%, 76%, and 87% in no induction, CC, and IMiD/PI groups, respectively (P = .05; hazard ratio, .4; 95% CI, .2 to .9).On multivariate analysis a low β2-microglobulin (P = .01; hazard ratio, .3; 95% CI, .1 to .7) and induction therapy with IMiD/PI (P = .01; hazard ratio, .3; 95% CI, .1 to .7) were associated with a better overall survival. Induction therapy with either CC or IMiDs/PIs is safe and feasible in selected patients with AL. IMiD/PI-based induction is associated with a longer overall survival compared with patients who received no induction or CC before auto-HCT.

Low Suvmax Measured on Baseline FDG-PET/CT and Elevated β2 Microglobulin Are Negative Predictors of Outcome in High Tumor Burden Follicular Lymphoma Treated By Immunochemotherapy: A Pooled Analysis of Three Prospective Studies

Early identification of high risk patients is warranted in high tumor burden or advanced follicular lymphoma. In this regard post induction FDG-PET/CT and parameters obtained from quantitative baseline FDG-PET such as total metabolic tumor volume (TMTV) have been proposed as prognostic tools (J Clin Oncol, 2016, in press). It has been shown recently that the presence of large TMTV>510cm3 can help to early detect patients who relapse within two years of therapy but TMTV is not yet used routinely. The aim of this study was to assess the prognostic impact of SUVmax measured on baseline FDG-PET/CT as an index of tumor proliferation and its added value to other prognostic parameters in this population.Methods: A pooled analysis of patient data and centrally reviewed baseline PET/CT scan for 181 patients with high tumor burden follicular lymphoma receiving R-chemotherapy within three prospective trials was performed (PET-FOLL and PRIMA from the LYSA, FOLL05 from the FIL), (Lancet Haematol, 2014). 82% of patients received R-CHOP, 14% R-CVP, 4% R-FM and 16 patients received R maintenance. Baseline SUVmax was computed on quality controlled PET/CT scan and the optimal cut-off for survival prediction was determined by Receiver Operating Curves and X-tile analysis. Multivariate analysis stratified by study were performed between SUVmax and the different components of FLIPI2 and between SUVmax and baseline TMTV.Results: Median age was 55 years; 92% of patients had stage III/IV disease; 37% had FLIPI 3-5; 31% had FLIPI2 3-5. With a median follow up of 64 months, 5y-PFS was 55% and 5y-OS 92%. Only two patients had disease transformation. Median SUVmax was 10 (Q1-Q3:7-14). There was no correlation between the SUVmax and histological grade. The optimal SUVmax cut-off was 9.4. Surprisingly the 47% of patients with a SUVmax ≤9.4 had markedly inferior PFS. 5y PFS was 47.4% vs. 62.4% (HR= 1.62, p=0.032). On multivariate analysis between SUVmax, age, Longest diameter of Largest involved lymph node LodLin> 6cm, positive Bone marrow biopsy and β2 microglobulin, only SUVmax (HR=1.81, p=0.04) and β2 microglobulin (HR=2.48, p=0.006) were independent predictors of PFS (Table1). When SUVmax and β2 microglobulin were combined they identified three risk groups: low SUVmax and high β2 microglobulin with 5y-PFS 32% (HR=3.95, p=0.0005), low SUVmax or high β2 microglobulin with 5y-PFS 54% (HR=2.29, p=0.018) and high SUVmax and low β2 microglobulin with 5y-PFS 73 % (Fig1). In multivariate analysis TMTV>510cm3 remains the only significant predictor against SUVmax≤9.4. There was no difference in the SUVmax values in high or low TMTV groups and similar % of high and low TMTV in low and high SUVmax groups. Furthermore, the 17% of patients with SUVmax≤9.4 and TMTV>510cm3 had a 22% 5y PFS vs 67.4% for the 40% of patients with SUVmax>9.4 and TMTV≤510cm3 (HR=3.96, p<0.001).Conclusions: SUVmax and β2 microglobulin are readily available parameters at staging. A low SUVmax observed on a baseline PET or an elevated β2 microglobulin is predictive of progression in patients with high tumor burden follicular lymphoma having received R-chemotherapy. The risk of progressive disease increases when patients have both these risk factors, and such patients deserve special consideration in treatment planning and follow-up. [Display omitted] [Display omitted] DisclosuresDupuis:janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Luminari:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel, Accomodations, Expenses; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria.

Can We Improve Quality of Life of Patients on Dialysis?

The idea of health-related quality of life (HRQOL) is not new. In 1946, the constitution of the World Health Organization defined health as “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity” ([1][1]). Today, the HRQOL concept addresses

Superior Complete Response Rate (CR) and Progression-Free Survival (PFS) with Bortezomib-Thalidomide-Dexamethasone (VTD) Versus Thalidomide-Dexamethasone (TD) As Consolidation Therapy After Autologous Stem-Cell Transplantation (ASCT) in Multiple Myeloma (MM)

Abstract 1871 Introduction: In a randomized phase 3 study, the use of VTD as induction therapy prior to and consolidation therapy following double ASCT increased the rate of complete or near complete response (CR/nCR) and extended PFS in comparison with TD given as induction and post-ASCT consolidation therapy in 474 newly diagnosed MM patients (Cavo et al , Lancet 2010). However, the specific impact of VTD consolidation on improved clinical outcomes was not defined. Methods: To address this issue, we performed a per-protocol analysis of 321 patients who received the entire treatment program, including the two pre-planned cycles of consolidation therapy with either VTD (160 of 236 patients, 68%) or TD (161 of 238 patients, 68%). By study design, two 35-d cycles of VTD (V 1.3 mg/m 2 on days 1, 8, 15, and 22; T 100 mg/d on days 1–35; D 40 mg on the days of and after each V administration) or TD (at the same doses as in VTD) were given as consolidation therapy to patients randomly assigned to each of the two respective induction regimens. Patient and disease characteristics at baseline were comparable in the two groups of patients. Results: The rates of CR and CR/nCR were significantly higher after consolidation therapy with VTD compared with TD (CR: 61% vs 47%; p=0.012; CR/nCR: 73% vs 61%; p=0.020). The impact of VTD consolidation on post-ASCT enhanced rates of CR and CR/nCR was confirmed by the McNemar test (CR: p=0.0009; CR/nCR: p=0.004) which conversely failed to demonstrate a significant increase in the frequencies of CR (p=0.052) and CR/nCR (p=0.110) with TD consolidation therapy. The absolute probability of upgrading from less than CR before consolidation to CR after consolidation was 31% with VTD and 17% with TD (Pearson chi-square test: p=0.03). Ninety six percent of patients who upgraded from less than CR to CR after VTD consolidation were in nCR (44%) or VGPR (52%) before starting consolidation therapy. A landmark analysis (with the landmark set as the start of consolidation therapy) was performed to compare time to progression (TTP), PFS, and overall survival (OS) between treatment groups. With a median follow-up of 30 months, the estimated 3-year probability of relapse or progression was 38% with VTD and 52% with TD (p=0.039 by Kaplan-Meier analysis) (HR: 0.68, 95% CI: 0.47–0.98, p=0.041). PFS was significantly longer for patients receiving VTD consolidation than for those treated with TD (3-year estimates: 62% vs 46%; p=0.025) (HR: 0.66, 95% CI: 0.46–0.95, p=0.027), a gain particularly evident for patients who failed to achieve CR after ASCT (3-year PFS estimates: 66% vs 43%; HR: 0.54, 95% CI: 0.32–0.91, p=0.022). Superior PFS with VTD vs TD consolidation was retained across poor prognosis subgroups, including patients with t(4;14) and/or del(17q) (HR: 0.44, p=0.004), del(13q) (HR: 0.44, p=0.002), β 2 -microglobulin >3.5 mg/L (HR: 0.57, p=0.025), lactate dehydrogenase >190 U/L (HR: 0.57, p=0.005), or ISS stage 2 and 3 (HR: 0.57, p=0.021). In a multivariate regression analysis, the most important and independent variables positively correlated with PFS were VTD consolidation therapy (p=0.002), double ASCT (p=0.001), low β 2 -microglobulin (p Conclusions: In comparison with TD, post-ASCT consolidation therapy with the triplet VTD regimen significantly increased the rates of CR and CR/nCR, and extended landmarked TTP and PFS. Superior PFS with VTD consolidation was maintained across poor prognosis subgroups, including those with advanced ISS stage and/or high-risk cytogenetic profiles. In a multivariate regression analysis VTD consolidation was confirmed to be an independent variable favorably affecting PFS. The superior activity seen with VTD versus TD as induction therapy before ASCT was retained despite the same triplet regimen being used as post-ASCT consolidation. Disclosures: Cavo: Millennium: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Genzyme: Honoraria. Off Label Use: Bortezomib and Thalidomide as post autotransplantation consolidation therapy in myeloma. Patriarca: Schering-Plough: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Petrucci: Celgene: Honoraria; Janssen: Honoraria. Di Raimondo: Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Palumbo: Merck: Honoraria; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria. Offidani: Celgene: Honoraria; Janssen: Honoraria. Baccarani: Bristol-Meyers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Stratification Approach for Splenic Marginal Zone Lymphoma Based on Hemoglobin, Platelet Count, High LDH and Extrahilar Lymphadenopathy: The HPLL/ABC System

Abstract 1583Splenic Marginal Zone Lymphoma (SMZL) is a distinct lymphoma included in the WHO 2008 classification. Ann Arbor staging system is not adequate to stratify SMZL patients into risk groups, as blood and bone marrow are usually involved. Further, there are neither established criteria for starting treatment nor gold standard treatment. Herein we report an international retrospective study on 593 SMZL patients aimed to identify which factors could influence starting treatment and which could allow stratify risk categories.Logistic regression was used to identify the factors that have conditioned treatment in the whole series and Cox regression for factors influencing Lymphoma Specific Survival (LSS) in a training set of 336 patients. The variables used were age, hemoglobin level and platelet count (as continuous variables) and sex, low albumin serum level (<3 gr/dl), high LDH and β2microglobulin, serum monoclonal component, DAT positivity, active autoimmune anemia, HCV positivity, lymphadenopathy (other than in hepatic and splenic hila) and extranodal involvement. The final model for LSS was used to produce a prognostic index (PI) and allowed to divide the patients in three risk groups applying cutpoints at the 20th and 80th centiles in patients with events. The resulting stratification was validated in another set of 227 patients. Also, the stratification was compared with the Interguppo Italiano Linfomi (IIL) score in the set of 450 patients in whom the required data were available, using the extension net reclassification improvement (NRI).Hemoglobin (p=0.000), extrahilar lymphadenopathy (p=0.000), and HCV positivity (p=0.001), were the factors independently conditioning treatment. Untreated patients had a significant longer LSS than treated patients (p=0.000). In the treated group there were no differences in LSS according to the type of therapy (splenectomy, chemotherapy, rituximab or their combinations) (Figure A). The low number of rituximab treated patients (n=39) precluded statistically reliable conclusions. In the training set, haemoglobin (p=0.003), platelet count (p=0.043), high LDH (p=0.011) and extrahilar lymphadenopathy (p=0.020) were the factors independently influencing LSS. The resulting PI was: 0.6 × platelet count (in hundreds of thousands/mm3) + 0.2 × hemoglobin (g/dl) − 1 × high LDH (1 when LDH above normal, 0 when normal) – 0.75 × extrahilar lymphadenopathy (1 when present, 0 when absent). Applying the cut points a low, intermediate and high risk groups with significantly different 5 year LSS of 0.94, 0.78 and 0.67, respectively, were identified (Figure B). In the validation set the system also separated 3 groups with significant different 5 year LSS of 0.96, 0.88 and 0.44, respectively. This stratification was named HPLL after the determinant factors (H emoglobin, P latelet count, high L DH, L ymphadenopathy) and the resulting risk groups HPLLA, HPLLB and HPLLC. In the comparison HPLL/ABC system separated 3 groups with significantly different LSS, whereas in the IIL score there was no significant difference between the low and intermediate risk groups (p=0,102). Using as reclassification calibration statistics the Hosmer-Lemeshow test, HPLL/ABC (χ2 =1.48; p=0.475) showed a better fit than the IIL score (χ2= 3.339; p=0.118) indicating that HPLL/ABC discriminated better the risk groups.In this large SMZL series, haemoglobin, extrahilar lymphadenopathy and HCV positivity were the factors independently conditioning treatment. The combination of hemoglobin, platelet count, high LDH and extrahilar lymphadenopathy stratify the patients in three groups with significantly different outcome. This system may be helpful to select risk-tailored treatment approaches. [Display omitted] [Display omitted] Disclosures:Montalban:Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding. Mollejo:Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding. Piris:Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding.

CLLU1 Gene Expression Level As a Prognostic Parameter in Patients with Chronic Lymphocytic Leukemia

Abstract 4603 BackgroundChronic lymphocytic leukemia (CLL) is the most frequent leukemia in the Western world with an annual incidence of 5/100,000. The clinical course of the disease is highly variable; while some CLL patients experience a stable clinical course that will never affect their morbidity or mortality, some of them will eventually progress and require chemotherapy. In addition to the traditional prognostic markers (e.g. Rai and Binet staging systems), more recently, mutational status of the variable regions of the immunoglobulin heavy chains (IgVH), chromosomal aberrations, CD38 expression and Zeta-chain-associated protein kinase 70 (ZAP-70) expression are used to better determine the prognosis in CLL patients. A novel CLL-specific gene, CLL Up-regulated gene 1 (CLLU1) that uniquely overexpressed in CLL patients, was recently demonstrated. It has been shown that CLLU1 mRNA expression levels in CLL patients predict time to initiation of therapy as well as overall survival (OS), and CLLU1 is highly up-regulated in poor-risk groups. The aim of this study is to investigate the relationship between CLLU1 levels and well known prognostic parameters and, to determine the importance of CLLU1 gene on prognosis and clinical course in our CLL patients. Methods116 (46 female, 70 male) CLL patients who consecutively visited our outpatient clinic between May 2009 and March 2010 were enrolled in the study. Median age was 60 years (range, 30–87 years). Blood samples were drawn from the patients for CLLU1 determination, and CLLU1 levels were determined by RT-PCR method. CLLU1 expression level was counted both in CLL patients and healthy B cells as the difference between CLLU1 and abl (taken as an house keeping gene) gene. Then, they are transformed as folds which is the ratio between CLLU1 level in CLL patients and that in healthy B cells. Patients with CLLU1 expression exceeding the CLLU1 expression of normal (CD19+) B-cells were taken as positive. Each patient was followed for at least one year for survival data. For the statistical analysis, student's t-test, Mann-Whitney U test and Pearson correlation were used. p<0.05 was considered as statistical significant. The study was approved by the local research ethics committee, and written informed consent was obtained from the patients. ResultsThere was no relationship between CLLU1 levels and, sex, age, modified RAI and BINET stages, lymphocyte counts and LDH levels at the time of diagnosis. Patients with nodular bone marrow infiltration had lower CLLU1 levels than patients with non-nodular infiltration (57.6 vs 498). Patients with high β2 microglobulin levels had higher CLLU1 levels than the ones with low β2 microglobulin levels (356.7 vs 13.6, p<0.05). ZAP-70 positive patients had higher CLLU1 levels than ZAP-70 negative patients (217.2 vs 10.2, p=0.007) (Figure 1). Among the patients with CD38 levels studied (n=53) CLLU1 levels were higher in patients with CD38 levels above the median value than patients with CD38 levels below the median value (438.4 vs 42.2). CLLU1 levels were higher in cases who needed treatment than cases without treatment. Patients with a shorter time to treatment had higher CLLU1 levels than patients with a longer time to treatment (p=0.028) (Figure 2). [Display omitted] [Display omitted] ConclusionWith a limited number of patients we could demonstrate that CLLU1 levels correlated with β2 microglobulin levels and ZAP-70. Although there were similar findings also with CD38 levels; the association was not statistically significant due to the limited number of cases. Time to treatment was shorter in patients with CLLU1 levels above the median value than patients with CLLU1 levels below the median value. CLLU1 is a promising and specific new prognostic parameter in patients with CLL, and further studies in larger series are needed to define the impact of CLLU1 in the prognosis and clinical course of CLL patients. DisclosureThis study was supported by Istanbul University Research Fund. Disclosures:No relevant conflicts of interest to declare.

Presenting features and outcome of chronic lymphocytic leukemia patients diagnosed at age 80 years or more. An ICLLSG study

Although the incidence of chronic lymphocytic leukemia (CLL) increases exponentially with age, data on patients 80 years or older at diagnosis are sparse. The records of patients diagnosed with CLL at age ≥80 years at seven medical centers in Israel during 1979-2009 were reviewed. Patients included 118 men and 96 women with a mean age of 84 years (range 80-94). Diagnosis was established in 56.5% due to routine blood count; 56% had Rai stage 0 disease and 25% of the patients received treatment. By June 2010, 72% had died. Mean survival was 67.7 months (median 56±5.4 months) and 5-year survival rate 47.2±3.6%. On univariate analysis, factors associated with better survival were age <84 years (p=0.002), early Rai and Binet stages (p=0.023, 0.003), low white blood cell count at time of diagnosis (p=0.015), low β2 microglobulin level (p=0.006), diagnosis by routine blood test (p<0.001), and low CD38 level (p=0.036). Multivariate analysis using Cox regression revealed that younger age, low white cell count, and diagnosis by routine blood test were independent predictors of good prognosis (hazards ratios 1.8, 1.6, and 1.9, respectively). Patients diagnosed with CLL at age ≥80 years may expect to live a long life. This study identifies several factors predicting good prognosis which are easy to obtain.

Chemoimmunotherapy with ofatumumab, fludarabine, and cyclophosphamide (O-FC) in previously untreated patients with chronic lymphocytic leukemia (CLL).

6520^ Background: Ofatumumab, a human monoclonal antibody targeting a unique epitope encompassing both large- and small-loop of CD20, demonstrated high overall response rates (ORR) in a pivotal study in refractory CLL. We conducted an international, randomized, phase II trial to assess efficacy and safety of two dose levels of O-FC in previously untreated patients (pts) with CLL. Methods: Pts with active CLL were randomized to ofatumumab 500 mg (Group A) or 1,000 mg (Group B) Day 1, with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 Days 2–4, Course 1; Days 1–3, Courses 2–6; every 4 weeks for 6 courses. First ofatumumab dose was 300 mg. The primary endpoint was complete response (CR) rate (1996 NCI-WG criteria) evaluated by an Independent Review Committee during treatment until 3 months after last dose. Results: 61 pts were randomized (Group A, n=31; Group B, n=30). CR rate was 32% and 50% for Group A and B; ORR was 77% and 73%, respectively. Responses by baseline and treatment parameters are shown (Table). Short median follow-up (8 months) currently does not permit analyses of time-to-event endpoints. Ofatumumab Cmax (426 vs. 201 mg/L) and Cmin (60 vs. 20 mg/L) at 6th infusion were higher in Group B vs. Group A. Based on exploratory univariable regression analyses, lower β2-microglobulin (as continuous variable), completion of 6 courses of O-FC, and higher ofatumumab Cmin prior to last infusion were significantly correlated with increased likelihood for response including CR, and decreased risk for progression. Additional pharmacokinetic analyses are ongoing. Conclusions: O-FC is highly active in previously untreated pts with CLL. β2-microglobulin level, number of O-FC courses completed, and Cmin prior to last course correlated with outcomes with O-FC Parameters N % CR % ORR All pts 61 41 75 Age <65 50 44 76 ≥65 yrs 11 27 73 ALC <30 × 109/L 11 64 82 ≥30 × 109/L 50 36 74 Lymph nodes ≤5 cm 51 39 78 >5 cm 10 50 60 Rai stage 0-II 33 36 73 III- IV 28 46 79 β2-M <4 mg/L 32 53 84 ≥4 mg/L 28 29 68 CD38+ <30% 48 44 77 ≥30% 12 33 67 IGHV mutated 28 46 75 IGHV unmutated 25 36 84 17p del 8 13 63 11q del 10 40 70 Trisomy 12q 9 56 56 No FISH abn. 7 71 100 13q del (sole) 25 32 80 No. of O-FC courses received: 6 39 56 92 4–5 9 33 78 1–3 13 0 23 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Genomic Health, sanofi-aventis Amgen, Genomic Health, sanofi-aventis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.

Drug induction apoptosis assay as predictive value of chemotherapy response in patients with B-cell chronic lymphocytic leukemia

A large number of prognostic factors are available to help predict the course of the disease for patients with B-cell chronic lymphocytic leukemia (B-CLL). However, it is not clear the involvement of these well established prognostic factors in the clinical response of the patients with B-CLL to the chemotherapy. The possible association of the patient clinical–biological characteristics and the in vitro response to chemotherapic agents may serve to provide powerful predictive information to identify optimum treatment for patients. An apoptosis induction assay displays the patient in vitro responses to chemotherapy and the possible association with their clinical–biological characteristics. In this study, patients showed a significant better in vitro response to drugs when they were in the initial stages of the disease or with low β2 microglobulin serum level. Response to purine analogues was significantly higher in patients with long lymphocyte doubling time (LDT), few cells expressing CD38, normal karyotype or no p53 deletion, whereas there was no correspondence with ZAP-70 expression. Furthermore, a good correlation was shown between in vitro apoptosis induction assay and the patient clinical response to purine analogues. In conclusion, association between in vitro drug sensitivity and some of the markers considered as prognostic factors could help to develop personalised therapeutic regimens for patients with B-CLL.

Serum Adiponectin Compared with ZAP-70, CD38 and Immunoglobulin Heavy-Chain Mutation Status as a Predictor of Time to First Treatment in Early B-Cell Chronic Lymphocytic Leukemia.

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70- and CD38-expression) and serum levels of adiponectin by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 69 previously untreated Binet stage A B-cell CLL patients. Higher levels of adiponectin inversely correlated with peripheral blood lymphocytosis (r=−0.254; P=0.03), male gender (P=0.0002), percentage of ZAP−70-positive (r=− 0.285; P=0.04) and CD38-positive (r=−0.294; P=0.04) B-CLL cells.After a median follow-up time of 32 months (range, 2–120 months) 28 (40.5%) out of 69 patients experienced a need for chemotherapy. Kaplan-Meier estimates of patients' TFT, plotted after searching the best cut-off for adiponectin (i.e., 5.88 μg/mL ), demonstrated that low adiponectin concentration was associated with a shorter TFT (median TFT 32 months; P=0.01). The relationship among the various bio-pathological parameters, analyzed by the multiple correspondence analysis (MCA), showed two different clinico-biological profiles. The first, characterized by higher adiponectin serum levels (i.e., > 5.88 μg/mL), higher platelet count (> 174 x 109/L), lower β2-microglobulin [β2-m] (< 2.35 mg/L), presence of mutation in the IgVH and low percentage of either CD38-positive (< 20%) or ZAP-70-positive (< 20%) B-CLL cells, was associated with a stable pattern of disease generally not requiring therapy. The second, defined by lower adiponectin levels, lower platelet count, high β2-m concentration, absence of mutation in the IgVH, high percentage of CD38- and ZAP-70 positive B-cells, was associated with a more progressive pattern of disease and a shorter TFT. The univariate Cox proportional hazard model demonstrated that in addition with lower serum levels of adiponectin (Hazard Ratio [HR], 2.936; P=0.01), the absence of IgVH mutational status (HR, 6.378; P=0.002) and ZAP-70-positivity (HR, 3.314; P=0.02) were associated with a shorter TFT. However, in multivariate analysis only ZAP-70 positivity emerged as predictor of the TFT (HR, 5.187; P=0.008).Our results indicate that in early B-cell CLL clinico-biological profile including among other parameters adiponectin may provide a useful insight into the complex interrelationship of prognostic variables and semplify their interpretation. However, adiponectin may not replace the need for the determination of ZAP-70 and IgVH mutational status.

Monokine Induced by Interferon-γ (MIG) Serum Levels Are a Marker of Disease Load and Correlate with Prognosis in Multiple Myeloma.

Background and Aims: Monokine-induced by interferon-γ (MIG) is a chemokine that is produced by monocytes and macrophages in response to interferon-γ and acts as a chemoattractant mainly to T-lymphocytes in inflammatory processes. MIG has also been suggested to act in an autocrine loop to stimulate tumour cells through its receptor CXCR3, which is known to be expressed in myeloma cells. However, it is presently unclear if MIG is of biologic significance in myeloma in vivo. We have recently shown that multiple myeloma oncogene 1 (MUM1) expression in myeloma cells correlates with prognosis in this disease (Heintel D et al., ASH 2005), and MUM1 was found to upregulate MIG gene expression in B cell malignancies (Uranishi M et al., Leukemia 2005). This led us to evaluate the potential prognostic significance of MIG serum levels in a series of well characterized myeloma patients.Methods: 105 newly diagnosed multiple myeloma patients (median age 69.3 years, range 39.4–90.5) were enrolled. 18 patients presented with Durie/Salmon stage I disease, 9 had stage II and 78 had stage III. MIG serum levels were determined by a commercially available ELISA (R&D Systems). Serum samples from 17 MGUS patients and 37 age-matched healthy volunteers were used as controls.Results: MIG serum levels were elevated in multiple myeloma patients (median 161.3 pg/ml, range 9.37–1966.0) compared to MGUS patients (median 92.7 pg/ml, range 6.29–1303.1) and healthy controls (median 106.2 pg/ml, range 51.0–390.6). For analysis of myeloma cases, a cut-off level for MIG of 200pg/ml (=95th percentile of MIG in controls) was chosen to identify low and high MIG expressers. Using the cut-off as defined above, 63 patients with low MIG serum levels and 42 high MIG expressers were identified in a population of 105 myeloma patients. MIG serum levels in myeloma patients showed strong correlations with several markers of tumour load including low albumin and high β2-microglobulin. Interestingly, no correlation was found with C-reactive protein levels, indicating that MIG is not associated with an inflammatory response in myeloma. Median survival was significantly shorter in patients with high MIG serum levels compared to patients with low MIG expression (median not reached vs. 17.0 months, p<0.001; see figure).Conclusions: MIG serum levels correlate with markers of disease burden in myeloma and high MIG levels are associated with a poor outcome in this disease. [Display omitted]

Recovery of Polyclonal Immunoglobulin Synthesis after Autologous Stem Cell Transplantation in Multiple Myeloma Patients as a Prognostic Factor for Event-Free Survival.

Suppression of polyclonal immunoglobulin (Ig) synthesis is one feature of multiple myeloma (MM). To evaluate if recovery of polyclonal Ig synthesis after autologous stem cell transplantation (ABSCT) influences prognosis, we have retrospectively analyzed the prognostic value of clinical and laboratory variables of 348 multiple myeloma patients who underwent their first autologous stem cell transplantation between 06.1992 and 10.2002 at the University Hospital of Heidelberg. The median follow-up was 34 months (range, 3 to 136 months). The median number of chemotherapy courses prior to first ABSCT was 5 (range, 3 to 30). Twenty-two of 348 patients underwent altogether three ABSCTs (including 18 patients with tandem transplantations), 141 had two ABSCTs (including 87 tandem transplantations) and 29 patients were treated with allogeneic transplantation as second line treatment. Recovery of polyclonal Ig synthesis was studied by serumelectrophoresis on day 100 after first ABSCT (±30 days). Full polyclonal Ig recovery was observed in 93 of 348 patients (28%), partial recovery (reduced polyclonal Ig, no monoclonal Ig) in 58 (17%), no recovery (almost no polyclonal Ig and no monoclonal Ig) in 16 (5%), polyclonal Ig recovery associated with monoclonal Ig in 95 (27%) and monoclonal Ig without polyclonal Ig in 72 patients (21%) (data missing in 14 patients (4%)). On multivariate analysis (333 patients), using Cox proportional hazards regression model stratified with respect to tandem transplantation, superior event-free survival was observed with recovery of polyclonal Ig synthesis, low beta2-microglobulin at diagnosis (<2.5mg/L) and a high haemoglobin at diagnosis, whereas MM type IgA and a high number of chemotherapy courses prior to first ABSCT were identified as adverse prognostic factors. Regarding polyclonal recovery, patients with polyclonal Ig recovery associated with monoclonal Ig had a superior event-free survival compared to patients with only monoclonal Ig without any polyclonal Ig recovery. Overall survival was superior in patients with a low β2-microglobulin at diagnosis (<2.5mg/L) and a high haemoglobin at diagnosis, and worse in patients with a high number of chemotherapy courses prior to first ABSCT. We conclude that any recovery of polyclonal Ig synthesis even when associated with monoclonal Ig, improves event-free survival, and therefore can be used as a predictor of prognosis in the follow-up of multiple myeloma patients who underwent ABSCT.

Long-Term Survival in Patients Receiving Conventional Therapy for Newly Diagnosed Multiple Myeloma; Results from United Kingdom Medical Research Council Trials 1980–1997.

Introduction: With conventional therapy, the median survival for patients following diagnosis of multiple myeloma (MM) is 31 months. Prior to 1985 2–4% of patients survived up to 10 years, subsequently this figure has improved to around 10%. We have analysed the United Kingdom Medical Research Council (MRC) trial records to identify the proportion, presentation features and outcome of patients who have survived greater than 7.5 years.Methods: Patients selected were those randomised to conventional (melphalan and ABCM based) therapy who survived greater than 7.5 years; all of these patients had achieved a plateau phase. Their presenting clinical and laboratory features were compared to a group of patients (matched by trial and treatment) who also reached plateau but were the first of the cohort to die directly from MM. Time to response and absolute response was calculated. Clinical course and performance status were assessed from 3 month follow-up clinical data forms and central laboratory paraprotein analysis.Results: 239/2781 (8.5%) of eligible patients survived greater than 7.5 years. 170 patients had died (median and interquartile range (IQR) 9.5 years and 8.3–11.7 years) and 69 patients were still alive at the time of the analysis, median follow-up of 11.4 years (IQR 9.2–14.1 years). Compared to the matched short-lived control group, these long term survivors had lower β2-microglobulin, preserved albumin, lower marrow plasmacytosis, less renal impairment, better performance status, fewer fractures, less bone pain and fewer lytic lesions at presentation. There were no differences in age, lymphocytes, or depth of serological response, however, median time to reach plateau was delayed for the long term survivors {0.77 years (IQR 0.41–1.05) versus 0.42 years (0.26–0.73 for controls)}. 35 patients remain in first plateau with no progression, 28 patients died in first plateau most commonly of vascular disease (25%) or cancer (21%). 176 patients relapsed and 11 (6%) died of myeloma in first relapse, however the majority (140/176, 80%) achieved a second plateau and having relapsed a second time 53/114 (46%) achieved a third plateau. 43 of these 140 patients died in second plateau or beyond of a cause other than myeloma - (vascular 7/43 (16%), cancer 5/43 (12%), renal 5/43 (12%), infection 6/43 (14%), other 4/43 (9%). 30/239 patients (13%) died with no information on disease status or cause of death. Following second relapse 73/114 (64%) patients died directly as a result of myeloma. Time spent in performance status 1 and 2 was 96% for plateau 1, 83% for relapse 1 and 63% beyond relapse 2.Conclusions: 8.5% of MRC trial patients receiving conventional non-intensive therapy survive greater than 7.5 years. Factors associated with long survival include low disease burden, better performance status and less end organ damage. Absolute serological response had no bearing on overall outcome; however rapid response is associated with poorer survival. The existence of second and subsequent plateau phases of MM, have rarely been documented in the literature. A large proportion of time following relapse is spent with good performance status, suggesting that patients experience a good quality of life during much of this period.