e13141 Background: Lynch Syndrome is associated with germline mutations in Mismatch Repair (MMR) genes ( MLH1, MSH2, MSH6, PMS2). CRC patients whose tumors exhibit high-level microsatellite instability (MSI-H) have an increased probability of LS. Although the diagnosis of LS has important implications for the patient and the family, germline genetic testing is not reimbursed by the Hellenic Public State Healthcare Services. To address this need HeSMO conducted a national program to screen and diagnose CRC patients with LS. Methods: All patients with CRC were eligible. Assessment for LS involved initially screening tumor tissue for the presence of MMR deficiency, either via molecular MSI testing or via immunohistochemistry (IHC) to detect the absence of one or more MMR proteins. Patients with an MMR-deficient tumor in the absence of a somatic cause (e.g. BRAF mutation or MLH1 promoter hypermethylation) underwent genetic counseling and germline testing to confirm a LS diagnosis. Results: From June 2017 to December 2018, 104 patients diagnosed with CRC were enrolled and tested. Median age of diagnosis was 58,5 years (range 32 - 89) and male-to-female ratio was 1.6:1. Fifty patients (48%) had tumors that exhibited the MSI-H phenotype. From the MSI-H tumors, 41 (82%) did not harbor the BRAF V600E mutation and 33 of them (80.5%) did not harbor an MLH1 promoter hypermethylation. Therefore, 33 patients were invited for genetic counseling and testing. Fifteen patients (45.45%) were diagnosed with LS: 6 ( 40 %) had a mutation in MLH1 (one of which had also a mutation in PMS2 gene), 4 (26.6%) in MSH6, 4 (26.6%) in MSH2 and 1 (6.6%) in PMS2. Conclusions: In our series, 30% of the CRC patients with MSI-H tumors were tested positive for LS. These results confirm the value of a universal screening program of CRC patients for LS. Hopefully, these results will convince the Hellenic Public State Healthcare Services to reimburse screening and germline genetic testing of CRC patients for LS.

e15521 Background: Bevacizumab (BEV) is an active antiangiogenic agent for the treatment of all patients (pts) with advanced colorectal cancer (CRC). We investigated the toxicity, compliance and survival of pts with locally advanced/inoperable or metastatic CRC treated with BEV-based treatment according to KRAS status. Methods: This phase IV study recorded prospectively (July 2009-June 2016) the clinicopathologic characteristics, safety and survival of pts receiving BEV with 1st line chemotherapy according to oncologist’s preference. Results: Of 682 pts providing consent for BEV-based therapy, 382pts completed treatment; 144pts had disease progression and 156pts discontinued treatment (adverse events: 58pts; toxic deaths: 2pts; consent withdrawn: 34pts; lost to follow up: 5pts; other reasons: 33pts whereas 24pts underwent curative metastasectomy/surgery). On treatment initiation KRAS status was recorded as mutant (mtKRAS) in 229pts (33.65%), wild type (wtKRAS) in 177pts (26%) and unknown (uKRAS) in 276pts (40.5%). Chemotherapy regimens included FOLFOX (243pts; 37%), FOLFIRI (197pts; 30%), XELOX (147pts; 22.5%) and XELIRI (69pts; 10.5%). The median follow up was 34.9m (0.4–66.3), the mPFS of the entire cohort was 10.8m (0.4-66.3) [mtKRAS 11.0m (1.0-55.7), wtKRAS 9.7m (0.9-61.9), uKRAS 11.3m (0.4-66.3); p = 0.033 (all three), p = 0.051 (mt vs u), p = 0.020 (wt vs u)] and the mOS was 26.4m (0.4-66.3) [mtKRAS 25.6m (1.4-61.3), wtKRAS 25.2m (2.2-63.7) and uKRAS 28.1m (1.4-66.3); p = 0.796 (all three)]. The ORR (CR+PR) in evaluable pts was 46.6% (104pts) in mtKRAS, 56.1% (97pt) in wtKRAS and 40.9% (112pt) in uKRAS [p = 0.007 (all three); p = 0.063 (mt vs wt); p = 0.002 (wt vs u)]. The ORR for FOLFOX/BEV was 48.3% (115pts), FOLFIRI/BEV 47.7% (92pts) and XELOX/BEV 45% (65pts) regardless the KRAS status. Toxicity profile was similar to previous BEV-investigating studies. BEV-related SAEs were myocardial infarction (1pt; G5), ileus (2pts; G4) and thromboembolism (8pts; G4). Conclusions: This phase IV study adds on evidence that BEV-based front line therapy is highly efficacious in pts with advanced CRC independently of mutant, wild or unknown KRAS status. Clinical trial information: NCT01811108.

Introduction: We conducted a feasibility study on docetaxel/capecitabine/cisplatin (DCX) with chemoradiotherapy as adjuvant treatment for gastric cancer patients. Methods: Patients were scheduled to receive 2 cycles of DCX, followed by 50.4 Gy plus capecitabine as radiotherapy, followed by an additional 2-DCX cycles. Results: From the 40 enrolled patients, 26 (65%) completed treatment as per protocol and 14 (35%) discontinued with the treatment (patients’ refusal: n=6; adverse events: n=8). There were 2 toxic deaths. Grade >3 toxicity was 12.1% before and 13.3% after chemoradiotherapy. Disease progression was documented in 11 (27.5%) patients. Conclusions: No further development of this regimen is justified on the basis of poor tolerability in patients.

To estimate the safety and tolerability of azacitidine in those suffering from intermediate-2 and high risk Myelodysplastic Syndromes (MDS), in a real world setting in Greece. A nationwide, retrospective chart review study was conducted, based on 17 Hematology departments of Hospitals throughout the country. Eligible patients were analyzed concerning the frequency of Serious and Non-Serious-Adverse Drug Reactions (SADRs/NSADRs). By definition, a SADR could result death, life-threatening condition, significant disability, requires hospitalization or might be considered medically important. Any reaction which does not fulfill the above description is a NSADR. Patients were recruited if were >18 years and were alive at the time of their data collection, they have completed at least one evaluation after azacitidine treatment initiation and at least one cycle of azacitidine treatment regardless of the outcome. The study was conducted in accordance with the declaration of Helsinki. The incidence of NSADRs and SADR during treatment was 50% and 42%, respectively. The most commonly reported NSADRs were neutropenia (11.4%), thrombocytopenia (9.1%), pyrexia (8.0%) and constipation (8.0%). Regarding their intensity, 45.7% of NSADRs were grade I, 43.6% were grade II, and 10.6% were grade III. None of the NSADRs resulted in patient hospitalization. The most commonly reported SADRs were thrombocytopenia (13.6%), pyrexia (10.2%), neutropenia (9.1%), febrile neutropenia (4.5%), anaemia and respiratory tract infection (both 4.5%). 48.6% of all SADRs were grade III,while 18% were grade IV. In 20.8% of SARDs no action was taken, 1.4% resulted in permanent discontinuation, while temporary treatment interruption was required for 34.7% of patients. 30.7% of patients experienced any SADRs, required hospitalization. In this study, the safety and tolerability of azacitidine for intermediate-2 and high risk MDS patients was descriptively analyzed based on Greek data. A broader, real life, analysis is needed to reach more decisive conclusions in the local setting.

Oral topotecan has been recently brought into clinical practice at a dose of 2.3 mg/m(2) for 5 days, every 3 weeks. Published data show quite high myelotoxicity. The aim of this trial was to define the daily dose and treatment duration, which permits safe toxicity. The study was designed to begin at a low daily dosage of 1.5 mg/m(2) and was escalated by increasing the topotecan dose and the day-treatment duration. The plan was to end up with 2.3 mg/m(2) daily for 5 days. In cases of tolerability with the last dosage given, we would then continue testing a higher daily dosage. Treatment repetition was planned to be every 21 days. Dosage levels were 1.5, 2.0 and 2.3 mg/m(2) for 3 days, 2.0 and 2.3 mg/m(2) for 4 days, and 2.3 mg/m(2) for 5 days. Toxicity was scored according to the Common Toxicity Criteria. Thirty-two patients (27 male, five female, median age 60 years, range 46-77 years) with small-cell lung cancer were included. The patients on 1.5 and 2 mg/m(2) for 3 days showed no myelotoxicity. Four (25%) patients on 2.3 mg/m(2) 3-day treatment developed grade 3-4 neutropenia. Three of five patients (60%) treated for 4 days at a dose of 2.3 mg/m(2) developed grade 3-4 neutropenia and less than half (two of five, 40%) of these patients had thrombocytopenia. Eight patients (66.7%) on the 5-day treatment presented with serious grade 3-4 myelotoxicity. Two treatment-related deaths were observed in the 5-day group and one in the 4-day group. Granulocyte growth factor was applied in over 60% of the patients. In conclusion, a dose of 2.3 mg/m(2) for 5 days was intolerable. Dose-limiting toxicity was 2.3 mg/m(2) for 4 days without prophylactic granulocyte colony-stimulating factor administration. The safe duration of oral topotecan treatment and the maximum tolerated dose seem to be not longer than 3 days at a dose of 2.3 mg/m(2). Anti-Cancer Drugs 21:202-205 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

The majority of patients with indolent lymphomas relapse due to minimal residual disease (MRD). In the present study, we sought to determine whether by using rituximab consolidation, for eradication of MRD, following induction chemotherapy with fludarabine and mitoxantrone (FN) combination could improve the outcome of indolent lymphomas. Patients with indolent lymphoma received fludarabine 25 mg/m2 Day 1 – 3 and mitoxantrone 10 mg/m2 on Day 1 every 28 days. Patients who attained a response (complete response, CR or partial response, PR) received four weekly doses of Rituximab 375 mg/m2 1 month and 3 months after completion of treatment. Forty-five patients were entered into this Phase II trial. The median follow-up time was 39 months. The median number of delivered cycles was 6. Fifty-three percent of patients attained a CR and 38% a PR for an overall response rate of 91%. One patient had stable disease, one had progression of the disease, whereas 2 were non-evaluable. After a median follow-up of 39 months, 32 of 46 patients (74%) are alive and disease-free. Grade III and IV toxicities included leucopenia (37%), neutropenia (28%), thrombocytopenia (7%), anemia (4%), and diarrhea (2%). Grade V toxicities included septic death in one patient and death due to hepatititis B reactivation 6 months after the last Rituximab dose in another patient. FN followed by R consolidation is a well-tolerated and active regimen in the treatment of patients with indolent lymphomas. Further follow-up is required to determine if these remissions are maintained.

Background: Small cell carcinomas (SCC) originate mainly from bronchial tissue. Several extrapulmonary sites of origin have been described, including the genitourinary and gastrointestinal tracts, the ear, nose and throat and lymph nodes. SCC of the lung may be associated with paraneoplastic neurologic syndromes.Case Report: We report an oat cell histological variant of SCC found in the thymus gland of a 53-year-old woman who presented with subacute cerebellar dysfunction.Conclusions: SCC of the thymus gland, which is a rare extrapulmonary site of origin of SCC, accompanied by cerebellar dysfunction, is rarely reported.

Reduced-intensity conditioning has extended the use of allogeneic hematopoietic stem cell transplantation (HSCT) to patients otherwise not eligible for this treatment due to older age or frailty. One hundred twelve acute myelogenous leukemia/myelodysplastic syndromes patients received fludarabine and melphalan (FM) conditioning with allogeneic HSCT. Most patients (73%) were not in remission. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate. Median age was 55 years (range, 22-74). Donors were related (53%) and unrelated (47%). Median follow-up of surviving patients (n = 43) was 29.4 months (range, 13.1-87.7). The complete remission (CR) rate was 82%. Estimates of 2-year survival were 66%, 40%, and 23% for patients in CR, with active disease without and with circulating blasts at HSCT, respectively. In multivariate analysis, survival was negatively influenced by active disease at HSCT and development of grade II-IV acute GVHD. Presence of circulating blasts at HSCT negatively influenced freedom from disease progression. Incidence of nonrelapse mortality (NRM) was significantly higher for patients with active disease, but was not influenced by patient age. Patients in CR had a day-100 and 2-year NRM of 0% and 20%, respectively. Use of unrelated donors increased the risk of NRM only among patients with active disease. FM and HSCT elicited long-term disease control in a significant fraction of this high-risk cohort.

Renal failure is a common feature of multiple myeloma and a major management problem. However there is limited data regarding the reversibility of renal failure, the kinetics of serum creatinine and the safety of novel agents such as bortezomib when administered to newly diagnosed or relapsed/refractory patients with renal failure. Patients and Methods. We evaluated 20 consecutive patients with newly diagnosed or relapsed/refractory multiple myeloma and renal failure, defined as a serum creatinine ≥ 2 mg/dl. All patients received bortezomib with dexamethasone or in combination with other agents (thalidomide, doxorubicin or melphalan). Results. Reversal of renal failure was documented in 40% of all patients and the median time to reversal was 17 days. Moreover 10 patients (50%) had 50% decrease in serum creatinine and the median time to decrease was 35 days. Some decrease of creatinine was documented in 85% of patients. The objective response rate was 65%. Toxicities were similar to those seen in myeloma patients without renal failure. Conclusions. Bortezomib based regimens can be administered to myeloma patients with renal impairment and their toxicity and efficacy are similar to those observed in patients without renal impairment. Moreover, bortezomib-based regimens induce improvement of serum creatinine in most patients and reversal of renal failure in approximately one-third.

We have recently shown that serum free light chain ratio (sFLCR) provides independent prognostic information in patients with newly diagnosed MM (Kyrtsonis et al, Br J Haematol, 137: 240–243, 2007). The aim of the present study was to extend our previous observations in a multicenter setting and to investigate the potential additive effect of sFLCR to the ISS system, in determining the prognosis of patients with MM. We analyzed 214 newly diagnosed MM patients (125 kappa-, 89 lambda-). Serum free light chain levels were measured in sera drawn at diagnosis, using a latex-enhanced immunoassay (The Binding Site, Birmingham, UK). Then, the sFLCR was calculated, accordingly as kappa/lambda or lambda/kappa, depending on the monoclonal light chain type of the patient. Based on our previous study “high” sFLCR was defined as ratios ≥3.57 and ≥45.09 for kappa- and lambda- MM respectively. The median age of the patients was 68 years (33–92), 51% were males, 28%, 30%, and 42% had Durie-Salmon stages I, II, and III, 14% creatinine >2 mg/dl, and 13% had Bence-Jones MM. ISS stage was 1, 2, or 3 in 33%, 33%, and 34% of the patients, 48% had CRP ≥4 mg/l, 18% elevated LDH, 31% hemoglobin

The impact of high dose dexamethasone containing regimens with or without the novel agents thalidomide and bortezomib on the reversal of renal failure (RF) was evaluated in 41 consecutive newly diagnosed patients with multiple myeloma (MM) treated in a single institution. RF was reversed in 73% of all patients within a median of 1.9 months. In patients treated with dexamethasone and novel agents (thalidomide and/or bortezomib) the reversibility rate was 80% within a median of 0.8 months. Severe RF and significant Bence Jones proteinuria were associated with a lower probability of RF reversal. Patients who responded to treatment achieved RF reversal more often than in those who did not (85% versus 56%, p=0.046). In conclusion, RF is reversible in the majority of newly diagnosed MM patients treated with high-dose dexamethasone containing regimens. The addition of novel agents induces a more rapid RF reversal.

Waldenstrom’s macroglobulinemia is defined by bone marrow lymphoplasmacytic infiltration and by production of monoclonal IgM. Treatment is employed only to symptomatic patients. Alkylating agents (chlorambucil), nucleoside analogues and rituximab are reasonable choices for primary therapy. Combination therapy either with nucleoside analogues with alkylating agents and/or rituximab or rituximab with chemotherapy such as CHOP or cyclophosphamide are also reasonable frontline treatment options for WM patients. Several factors should be taken into account when choosing the most appropriate primary treatment. These factors include the age of the patient and possible co-morbidities, the presence of cytopenias and especially thrombocytopenia, the presence of symptoms and signs indicative of hyperviscosity, the need for rapid disease control due to severe symptoms, significant splenomegaly or lymphadenopathy, symptomatic peripheral neuropathy and whether the patient is candidate for autologous stem cell transplantation. For patients with refractory or relapsing disease, the use of an alternate first-line agent is reasonable. Outside the setting of a clinical trial, the administration of high-dose therapy should be reserved only for patients refractory to alkylating agents, purine nucleoside and rituximab. For patients who develop resistance to all three classes of agents, alemtuzumab, thalidomide with or without dexamethasone or bortezomib could be tried.

There are limited data regarding the long term follow up after thalidomide based regimen and the outcome of patients when they progress and they receive further treatment. We reassessed our original series of 43 patients with previously treated multiple myeloma who had received a pulsed cyclophosphamide, thalidomide, dexamethasone (CTD) regimen. Among the 43 patients, 14 did not respond to pulsed CTD and 29 (67%) achieved at least a partial response. The median PFS for all patients was 10 months. After a median follow up of 24 months (range 1 - 62), the 3 year PFS is 14% and 3 patients remain off treatment and without progression for 55+, 55+ and 56+ months respectively. Moreover, 28% of patients who progressed after CTD achieved a partial response after subsequent treatment which included thalidomide, bortezomib or lenalidomide. The median PFS of these patients was 5 months and the 1 year PFS was 20%. Furthermore, 31% of patients who had responded to CTD and then progressed (CTD sensitive) responded to subsequent treatment. We conclude that some patients enjoy long responses after CTD and that several patients who progress after CTD may respond to treatment with a novel agent-based regimen.

PURPOSE:Alkylating agents and the anti-CD20 monoclonal antibody rituximab are among appropriate choices for the primary treatment of symptomatic patients with Waldenström macroglobulinemia (WM), and they induce at least a partial response in 30% to 50% of patients. To improve these results, we designed a phase II study that included previously untreated symptomatic patients with WM who received a combination of dexamethasone, rituximab, and cyclophosphamide (DRC).PATIENTS AND METHODS:Seventy-two patients were treated with dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5 (total dose, 1,000 mg/m2). This regimen was repeated every 21 days for 6 months. Patients' median age was 69 years and many had features of advanced disease such as anemia (57%), hypoalbuminemia (40%), and elevated serum beta2-microglobulin (43%).RESULTS:On an intent-to-treat basis, 83% of patients (95% CI, 73% to 91%) achieved a response, including 7% complete, 67% partial, and 9% minor responses. The median time to response was 4.1 months. The 2-year progression-free survival rate for all patients was 67%; for patients who responded to DRC, it was 80%. The 2-year disease-specific survival rate was 90%. Treatment with DRC was well tolerated, with 9% of patients experiencing grade 3 or 4 neutropenia and approximately 20% of patients experiencing some form of toxicity related to rituximab.CONCLUSION:Our large, multicenter trial showed that the non-stem-cell toxic DRC regimen is an active, well-tolerated treatment for symptomatic patients with WM.

Opinion statement Waldenstrom’s macroglobulinemia is defined by bone marrow lymphoplasmacytic infiltration and by production of monoclonal IgM. Treatment is employed only to symptomatic patients. Alkylating agents (chlorambucil), nucleoside analogues and rituximab are reasonable choices for primary therapy. Combination therapy either with nucleoside analogues with alkylating agents and/or rituximab or rituximab with chemotherapy such as CHOP or cyclophosphamide are also reasonable frontline treatment options for WM patients. Several factors should be taken into account when choosing the most appropriate primary treatment. These factors include the age of the patient and possible co-morbidities, the presence of cytopenias and especially thrombocytopenia, the presence of symptoms and signs indicative of hyperviscosity, the need for rapid disease control due to severe symptoms, significant splenomegaly or lymphadenopathy, symptomatic peripheral neuropathy and whether the patient is candidate for autologous stem cell transplantation. For patients with refractory or relapsing disease, the use of an alternate first-line agent is reasonable. Outside the setting of a clinical trial, the administration of high-dose therapy should be reserved only for patients refractory to alkylating agents, purine nucleoside and rituximab. For patients who develop resistance to all three classes of agents, alemtuzumab, thalidomide with or without dexamethasone or bortezomib could be tried.

Introduction: The effectiveness of thalidomide based regimens (TBR) in patients with relapsed/refractory multiple myeloma is well established. However, there are still limited data regarding the long term follow up after such regimens and the outcome of patients when they progress and they receive further treatment. In order to answer these questions we evaluated a series of 114 patients with relapsed/refractory multiple myeloma who were treated with TBR. None of these patients had previously received thalidomide, bortezomib or lenalidomide. Patients and Methods: All patients were treated with thalidomide and dexamethasone with or without other oral agents. More specifically 41 patients had received continuous thalidomide and pulse dexamethasone, 25 patients clarithromycin, continuous thalidomide and pulse dexamethasone, 43 patients intermittent thalidomide, pulse dexamethasone and cyclophosphamide and 5 patients continuous thalidomide, pulse dexamethasone and cyclophosphamide. Type of treatment at the time of progression after TBR, response to this treatment and progression free survival were recorded for each patient. Moreover, patients who received novel agents after progression to TBR, were divided into 2 subgroups, according to their resistance to thalidomide. In group A, patients had refractory or progressive myeloma while on TBR or within 2 months after discontinuation of TBR. In group B, myeloma progressed more than 2 months after discontinuation of TBR. Results: Among the 114 patients, 41 had not responded to TBR and 73 (64%) had achieved at least a partial response. The median PFS for all patients was 8 months. As of June 2007, 10 patients remain without progression from 28 to 81 months (median 54 months). Eight patients remain off treatment and without progression for a median of 56 months (range 28–81). Patients who did not respond to or progressed after TBR were analyzed for further treatment and outcome. Thirty eight patients (37%) died before receiving further treatment, 23 patients (23%) received conventional chemotherapy and 41 patients (40%) received continuous thalidomide and dexamethasone +/− clarithromycin or cyclophosphamide (17 patients), bortezomib and dexamethasone (7 patients), melphalan-bortezomib-dexamethasone and intermittent thalidomide (12 patients) or lenalidomide with dexamethasone (5 patients). Among these 41 patients, 24 were classified in group A (thalidomide resistant) and 17 in group B. Overall 17 (41%) achieved at least partial response after retreatment with novel agent-based regimens. A response was observed in 46% of patients in group A and in 35% of patients in group B. The median progression free survival of the 41 patients who received retreatment with novel agents was 9.2 months and the median survival was 17 months. Among the 23 patients who received conventional chemotherapy only five (21%) patients responded and the progression free survival and the median survival were 5.3 and 10.2 months, respectively. Conclusions: After an oral TBR regimen 6 (5%) patients remain without treatment and free of progression for more than 4 years. A significant number of patients who progressed after TBR and who received further treatment which included a novel agent achieved a response, including several patients who were resistant to TBR.

Background: Primary (AL) amyloidosis and light chain deposition disease (LCDD) are clonal plasma cells disorders characterized by deposition of either amyloid fibrils (in AL) or amorphous nodular non-congophilic deposits (in LCDD) derived from abnormal light chains, that cause failure of affected organs. Treatment of AL is based on steroids and standard dose or high dose melphalan with ASCT. Data on treatment of LCDD are limited. Bortezomib, a proteasome inhibitor, has significant activity in myeloma, which is enhanced by the addition of dexamethasone (BD) and can be given in myeloma patients with renal impairment. We evaluated this combination in patients with AL and LCDD.

The cause of the polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes (POEMS) syndrome is currently unknown, but increased levels of vascular endothelial growth factor (VEGF) appear to play a pathogenetic role. Osteosclerotic bone lesions are a characteristic finding in POEMS, but there are no data about the specific role of various molecules that control bone remodeling in patients with POEMS. Serum levels of angiogenic cytokines (VEGF, angiogenin, angiopoietin-2, and basic fibroblast growth factor) along with a series of bone remodeling indices (C-telopeptide of type I collagen, bone-alkaline phosphatase [bALP], osteocalcin [OC], soluble receptor activator of nuclear factor-kappaB ligand [RANKL], osteoprotegerin [OPG], and macrophage inflammatory protein-1alpha) were measured in 2 patients with POEMS before and after high-dose therapy (HDT) with autologous stem cell transplantation and in age- and sex-matched controls. Increased VEGF levels before HDT were reduced significantly after treatment, although levels of the other angiogenetic factors did not differ from that of controls and were less influenced by HDT. Serum RANKL levels were increased before HDT, whereas OPG levels were within the levels of healthy controls, resulting in an abnormal soluble RANKL to OPG ratio. Levels of bone resorption markers (C-telopeptide of type I collagen) were very low or undetectable before HDT, although bALP and OC levels were similar to that of controls. After HDT, soluble RANKL levels decreased, OPG remained rather stable, bone resorption markers increased to levels of normal individuals, bALP levels were rather unchanged, and OC levels increased. Decreasing VEGF levels parallel clinical improvement, and the restoration of normal bone metabolism follows HDT.

BACKGROUND AND OBJECTIVES:As new therapeutic options for multiple myeloma (MM) emerge, identification of biological markers which could predict clinical response to standard treatment with high-dose melphalan (HDM) supported by autologous stem cell transplantation (ASCT) becomes more important.DESIGN AND METHODS:Melphalan-induced damage formation and repair of monoadducts and interstrand cross-links in the p53 gene were studied in peripheral blood mononuclear cells obtained from 32 patients prior to therapy. The same studies were performed in the peripheral blood cells of these patients immediately after subsequent HDM administration. Clinical response and time to progression were correlated with molecular endpoints obtained in vitro.RESULTS:Values for all molecular end-points examined in vitro were highly correlated with the respective in vivo results within individual patients. All in vitro end-points indicative of increased DNA damage and slower repair capacity were predictive of a favorable response to HDM; the area under the curve of total adducts (AUC-TA) had the highest predictive ability. Using the cut-off value of 736 adducts/10(6) nucleotides x h for the AUC-TA, the positive predictive value for clinical response to HDM was 100%. Moreover, patients with an AUC-TA equal to or higher than this cut-off value had significantly longer times to progression than had patients with an AUC-TA lower than the cut-off value (hazard ratio 0.19; 95% confidence intervals 0.06 to 0.60).INTERPRETATION AND CONCLUSIONS:An in vitro assay to quantify melphalan-induced p53-specific damage formation/repair can be used to select those patients with MM who are more likely to benefit from HDM supported by ASCT.

Introduction: Approximately 20% of patients with multiple myeloma present with renal failure (RF). It has been reported that with supportive measures and with antimyeloma treatment RF is reversible in 25 to 58% of patients. However, the impact of specific antimyeloma therapies on RF reversibility has not been clarified. Because high dose dexamethasone containing regimens are associated with a rapid myeloma control we performed a study to assess the impact of such regimens on RF reversibility.