ALBERT

Description: Abstract 2887 Poster Board II-863 Between November 2002 and April 2006, 72 patients with Waldenstrom's Macroglobulinemia (WM) were enrolled into this multicenter trial of primary treatment with DRC which consisted of dexamethasone 20 mg IV followed by rituximab 375mg/m2 IV on day 1 and oral cyclophosphamide 100 mg/m2 bid on days 1 to 5 (total dose 1000 mg/m2). DRC courses were repeated every 21 days for six courses and then patients without progressive disease were observed without treatment. Patient characteristics, toxicity and response data have been reported previously (Dimopoulos et al, J Clin Oncol 2007; 25:3344): 83% of patients achieved a response including 7% complete, 67% partial and 9% minor responses. In June 2009 we updated this study (minimum follow-up 〉3 years) in order to assess time to progression, time to next treatment, type of second-line treatment and response to this, overall survival (OS) and cause-specific survival (CSS) in which deaths unrelated to WM or complications of treatment were censored. Second line treatment was administered to patients who experienced progressive disease and also met criteria for treatment requirement based on consensus recommendations (Kyle et al, Sem Oncol 2003; 30:116). As of June 2009, 42 patients fulfilled the criteria for progressive disease (Kimby et al, Clin Lymphoma Myeloma 2006; 6:380) but 14 patients have not yet required second line treatment. The median time to progression was 35 months (95% Confidence Interval: 22-48 months) and the median time to next treatment requirement was 51 months. Among several factors who were analyzed for their possible correlation with shorter time to progression, only lymphadenopathy was significant (p

Description: Background. Bisphosphonates are widely used in the treatment of MM. ONJ can occur during treatment with bisphosphonates. We have shown that use of ZA and longer exposure are associated with higher frequency of ONJ in a series of patients with both MM and solid tumors. Dental problems or interventions are precipitating factors of ONJ. For this reason, since 2003, we have implemented assessment (and management if necessary) of all patients who are candidates for ZA or who are on treatment with ZA and have dental problems by specialists with particular experience on ONJ. In addition, we recommend improved oral hygiene and we avoid dental procedures during treatment with ZA. We have investigated whether the occurrence of ONJ decreased after the implementation of these measures. Patients and Methods. According to the policy of our center, all patients with MM who demonstrate lytic lesions or osteopenia receive ZA 4 mg i.v. every 4 weeks indefinitely. In our current analysis we included patients who received only ZA wheras patients who initially received pamidronate and were later switched to ZA were excluded. Patients were stratified into two groups depending on the date of initiation of treatment in relation to the start of implementation of the preventive measures (Group A: 26/8/1998–31/12/2002, Group B: 1/1/2003–1/12/2006). Occurrence of ONJ was studied as row percentages as well as incidence rate rates (IR: number of cases of osteonecrosis /person-months). The proportions of patients with ONJ between the two groups were compared with the Fisher’s exact test whereas the respective incidence rates were compared with the score test. The 95% confidence interval of the incidence rate ratio was also estimated. Results. One hundred twenty-eight patients with MM were included in the analysis (Group A: 35, Group B: 93; M/F: 66/62). Overall there were 10 cases of ONJ (8%): 8 cases in Group A (23%) and 2 cases in Group B (2%) (p

Description: Introduction: An ISSWM was recently proposed (Morel et al, ASH 2006), which was based on a large number of patients treated primarily with alkylating agents and /or nucleoside analogues. The ISSWM based on 5 adverse covariates wich defined 3 risk groups: low, intermediate and high risk with 5-years survival rates of 87%, 68% and 36% respectively. In our current analysis, we assessed the impact of this system in patients with WM who received primary treatment with rituximab-based regimens. Patients and methods: Ninety-three previously untreated, symptomatic patients who received treatment either with single agent rituximab (21 patients) or with the combination of dexamethasone, rituximab, and cyclophosphamide (72 patients) were classified according to the ISSWM, which is based on 5 adverse covariates: age〉 65 years, hemoglobin ≤11.5 g/dl, platelet count ≤ 100 x 109/L, β2- microglobulin 70g/L. Low risk is defined by the presence of ≤ 1 adverse characteristics except age, high risk by the presence of 〉2 adverse characteristics and intermediate risk by the presence of 2 adverse characteristics or age 〉65 years. Results: The disease features of the 93 patients were typical of symptomatic WM: age 〉 65 years in 63%, males 65%, B-symptoms in 22%, splenomegaly in 29%, lymphadenopathy in 34%. 15% of patients were rated as low risk, 65% as intermediate risk and 20% as high risk. Criteria for initiation of therapy included cytopenia, hyperviscosity, constitutional symptoms, organomegaly or IgM-related disorders. Overall, 62% of patients were alive at 6 years. Median survival was not reached for low and intermediate risk and was 38 months for high risk patients (p=0.006). There was a clear separation of the survival curves in the three groups. At the time of last follow-up the percentage of patients alive was 100%, 82% and 58% for patients classified as low, intermediate and high-risk group respectively. Conclusions: The recently proposed ISSWM is applicable in patients with WM who receive primary treatment with rituximab-based regimens and may serve as a basis to compare outcomes in different studies.

Description: 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. Patients and methods: Over the last decade 41 patients with RF, defined as a serum creatinine ≥2 mg/dL at the time of diagnosis, received primary treatment with high dose dexamethasone-based regimens in our Department. All patients were eligible fore assessment of reversibility of RF which was defined as a sustained decrease of serum creatinine to

Description: Purpose: We have previously reported that diffuse pattern of bone marrow involvement as determined by MRI imaging of the spine, in newly diagnosed patients with MM is associated with features of advanced disease and with shorter survival compared to patients with normal, focal or variegated pattern of BM involvment. Purpose of the study was to determine the prognostic value of spinal bone MRI in the outcome of MM patients undergoing treatment with HDM and ASCT. Materials and methods: Between October 1995 and June 2006, 63 MM patients for whom a MRI of the spine before first line therapy was available, received treatment with HDM (200mg/m2 iv) and ASCT, in our Department. Four patterns of BM involvement in MRI were identified: normal pattern which required no evidence of abnormal signal, focal pattern, which consists of localized areas of abnormal marrow (on T1-weighted images, focal lesions are darker than yellow marrow and slightly darker or isointense to red marrow; on T2-weighted images they are brighter than both red and yellow marrow), diffuse pattern of abnormal marrow, where the normal bone marrow is completely replaced by the abnormal process and the intervertebral discs appear brighter or are isointense to the diseased marrow, and variegated pattern, which consists of innumerable small foci of disease on a background of intact marrow. MRI pattern of BM involvement and multiple clinical and laboratory parameters were evaluated for their possible correlation with progression free survival (PFS) after HDM. Results: Patients’ median age was 55years (range: 23 to 74 years), 60% of patients had ISS 2 or 3 before initial treatment, 54% of patients were transplanted during remission and 46% of patients had active myeloma at the time of HDM (primary refractory: 34%, resistant relapse: 12%). Nine patients (14%) had a normal MRI pattern, 33 (53%) had focal, 4 (6%) variegated and 17 (27%) diffuse MRI pattern of BM involvement. The median PFS for all patients was 20 months. Significant adverse prognostic factors for PFS included elevated creatinine and LDH serum levels, and ISS stage 3 at diagnosis. Furthermore the pattern of BM involvement by MRI correlated strongly with PFS: median PFS of 72 months for normal pattern, 20 months for focal pattern, 16 months for variegated and 9 months for diffuse pattern (p=0.016). Patients with both ISS stage 3 and diffuse MRI pattern had a median PFS of only 6 months. Conclusion: MRI of the spine before treatment provides prognostic information for the outcome of MM patients with myeloma after HDM and ASCT. Diffuse marrow replacement on MRI of the spine identifies patients with advanced MM who have a poor prognosis even after intensive therapy. Such patients are candidates for innovative treatments.

Description: Abstract 2886 Poster Board II-862 Rituximab and bortezomib are active single agents in the treatment of WM. Based on preclinical studies in lymphoproliferative disorders which indicated synergism between bortezomib and rituximab, in 2006 we designed a large phase II multicenter trial to assess the toxicity and activity of the combination of these agents in previously untreated patients with WM requiring therapy based on consensus recommendations (Kyle et al, Sem Oncol 2003;30:116). This trial is being conducted within the European Myeloma Network and has been activated in 6 Centers so far. In order to prevent the “IgM flare effect” seen with rituximab-based regimens, one course of single agent bortezomib is first administered at a standard dose of 1.3 mg/m2 IV on days 1, 4, 8 and 11. Ten days later, the patients receive four courses of 35 days duration each. In courses 2 to 5, bortezomib is administered weekly at a dose of 1.6 mg/m2 on days 1, 8, 15 and 22. During courses 2 and 5, immediately after the administration of bortezomib, patients receive dexamethasone 40 mg IV followed by rituximab 375 mg/m2 IV. Patients receive a total of 8 infusions of rituximab. Bortezomib is being administered weekly in order to reduce the incidence of neurotoxicity which can be significant in WM patients treated with standard schedule bortezomib (Treon et al, Clin Cancer Res 2007;13:3320). During treatment, valacyclovir prophylaxis for herpes zoster is given to all patients. A single dose of dexamethasone is given before each dose or rituximab in order to take advantage of potential synergism with rituximab and to reduce allergic reactions but to avoid steroid-induced complications. After completion of treatment, patients with CR, PR, MR or SD according to consensus criteria (Kimby et al, Clin Lymphoma Myeloma 2006;3:380) are being followed without further therapy until there is evidence of progressive disease. The main endpoint was the best response observed after BDR. Dose modifications for toxicity were allowed and bortezomib could be reduced from 1.6 mg/m2 to 1.3 mg/m2 to 1.0 mg/m2. The trial was initiated in March 2007 and 61 patients are scheduled to be enrolled. As of June 2009, 38 patients have started treatment with BDR. Patients characteristics include: age 〉65 years in 42% of patients, hemoglobin 7 g/dL in 6%, lymphadenopathy in 37%, splenomegaly in 37%, and B-symptoms in 43% of patients. According to the International Prognostic Index Scoring System (IPSS) for WM, 23% of patients were rated as low-risk, 31% of patients as intermediate risk and 46% as high-risk. The main reasons which prompted initiation of treatment include cytopenia in 43% of patients, hyperviscosity syndrome in 22%, presence of B-symptoms in 16% and lymphadenopathy in 14%. So far, 31 patients are evaluable for response, which include CR in 1 (3%), PR in 16 (52%), MR in 5 (16%), SD in 4 (13%) and PD in 5 (16%) patients. In responding patients, at least MR has occurred within 2 months of treatment. Plasmapheresis was not required in any patient before or after treatment with BDR. An “IgM flaire phenomenon” was not seen in any patient and this was attributed to the initial course of simple agent bortezomib. Toxicities include: neutropenia (grade 3,4) in 26% of patients; thrombocytopenia (grade 3,4) in 11%; peripheral neuropathy, grade 1,2 in 44%, but grade 3,4 in only 7%; gastrointestinal toxicity (grade 3: 11%); and infections (grade 1,2: 19%, grade 3,4: 11%). One patient died of septic shock in absence of neutropenia. Three patients experienced pulmonary toxicity (grade 3,4) which was attributed to bortezomib and consisted of dyspnea, decrease of O2 saturation and diffuse pulmonary infiltrates on CT scan of the chest. This toxicity resolved completely after administration of steroids and 2 of 3 patients continued treatment as per protocol. Only one patient (who had discontinued valacylovir prophylaxis) developed herpes zoster. The dose of bortezomib was reduced in 30% of patients primarily because of peripheral neuropathy. Our ongoing study indicates that the BDR regimen is active in patients with symptomatic WM most of whom had intermediate or high risk disease. Another update on response, toxicity and time to progression will be performed in November 2009. Disclosures: Dimopoulos: Janssen-Cilag: Honoraria. García-Sanz:Janssen-Cilag: Honoraria. Sonneveld:Janssen-Cilag: Honoraria.

Description: Introduction: WM is a disease of the elderly with a median age of 70 years in most series. Advanced age is recognized as an adverse prognostic feature and age 〉 65 years has been included among the 5 adverse covariates in the recently reported International prognostic Scoring System for WM (Morel et al, ASH 2006). There is little information regarding the incidence of disease features and outcomes after treatment of young patients (≤ 50 years of age) with symptomatic WM. Patients and methods: Our database includes 220 patients with previously untreated, symptomatic WM. These patients were separated in two groups according to age ≤ 50 years and 〉50 years at the time of initiation of treatment. Clinical and laboratory characteristics, response to treatment, overall survival (OS) and disease-specific survival (DSS) were compared among the two groups. Results: Twenty-two patients (10%) were ≤ 50 years of age at the time of initiation of treatment. The incidence of clinical and laboratory features was similar among young and older patients: gender (p=0.3), B-symptoms (p=0.3), splenomegaly (p=0.9), lymphadenopathy (p=0.1), anemia (p=0.3), median serum IgM level (p=0.6), hyperviscosity syndrome (p=0.7), elevated β2-microglobulin (p=0.3) and IgM related disorders (p=0.6). primary treatment consisted of chlorambucil, nucleoside analogs or rituximab-based regimens with equal distribution among young and older patients. At least partial response was observed in 73% of young patients and in 57% of older patients (p=0.16). The median OS was not reached in young patients and it was 106 months in older patients (p=0.07). The median DSS was not reached in young patients and it was 116 months in older patients (p=0.2). Conclusion: 10% of patients with WM are ≤50 years at the time of treatment initiation. Their clinical and laboratory features and response to treatment are similar to those of older patients. Overall survival tend to be longer in young patients, but when deaths unrelated to WM or complications of treatment are excluded, survival times among young and older patients are similar.

Description: Since the 1960s the survival of patients with MM had remained rather stable, until the introduction of high-dose melphalan with autologous stem cell transplant (ASCT) in the early 90s which improved the survival of younger patients. In 1999, thalidomide was introduced in the treatment of relapsed/refractory MM, followed by two other novel drugs: bortezomib and lenalidomide. Clinical trials have indicated that novel agent-based treatment are associated with improvement of response and survival in both relapsed/refractory and newly diagnosed patients. A recent report from Mayo Clinic (Kumar et al Blood2008, 111, 1516–20) has indicated that the survival of patients with MM treated at this major referral center, has improved significantly over the last decade. The purpose of our analysis was to confirm this observation in a large number of unselected patients who were treated in several hospitals throughout Greece and to assess the current applicability of ISS, a staging system that has been developed from a large database of patients who were treated with conventional or high-dose therapy before the introduction of novel drugs. Therefore we compared the outcome of two patient cohorts who started treatment before or after the introduction of the first novel drug, thalidomide: since January 1985, 1376 patients were entered in to the database of GMSG: 859 patients started treatment before 31/12/1999 (Group A) and 517 patients after 1/1/2000 (Group B), when thalidomide became available in Greece. Patients in group A were younger (p

Description: Abstract 2845 Poster Board II-821 Recently, the IPSS has been proposed as a staging system for patients with WM who require treatment. This system is based on five adverse covariates: age 〉65 years, hemoglobin '11.5 g/dL, platelet count '100×109/L, beta2-microglobulin 〉3 mg/L and serum monoclonal protein concentration 〉7 g/dL. Low risk is defined by the presence of ' 1 adverse characteristic and age '65 years, intermediate risk by the presence of 2 adverse characteristics or only age 〉65 years and high risk by the presence of 〉2 adverse characteristics. The aim of our analysis was to independently validate the significance of IPSS not only for overall survival (OS) but also for cause-specific survival (CSS) (i.e deaths unrelated to WM or to complications of treatment are censored). Furthermore, we wanted to assess whether elevated serum LDH may add to the strength of IPSS. From the data base of the Greek Myeloma Study Group, we identified 335 patients with clearly defined criteria for diagnosis and for initiation of treatment who were treated over the last 20 years. Main primary therapies included alkylating agents (43%), CHOP (3%), nucleoside analogues (3%) and rituximab either alone (3%) or in combination with conventional chemotherapy (44%). Before the initiation of treatment the median age of patients was 68 years (range 28 to 89 years). Fifty-nine percent of patients were 〉65 years, while 75% of patients had hemoglobin levels of 3 mg/L, 33% had lymphadenopathy, 32% splenomegaly, 23% presence of B-symptoms, 12% platelet count of 7 g/dL. Among 152 patients who had died by the time of this analysis, 33 patients (22%) had died due to causes not related to WM, to disease transformation, to myelodysplasia or to complications of treatment. Most frequent causes were second primary solid tumors, celebrovascular accidents, coronary artery disease and congestive heart failure. For the whole group of patients median OS was 105 months and median CSS was 116 months. Patients were divided into low risk (23%), intermediate risk (38%) and high risk (39%), according to IPSS. Median OS was 161 months, 105 months and 64 months respectively (p

Description: Purpose: Biphosphonates have been approved for the treatment of bone lesions in patients with multiple myeloma. Although these agents are usually well tolerated, osteonecrosis of the jaw (ONJ) has been recently associated with the use of pamidronate and zoledronic acid. Nevertheless, the true incidence of this complication is not clearly defined. Therefore, we studied the incidence, characteristics and risk factors for the development of ONJ among patients with multiple myeloma treated with biphosphonates in our institution. Patients and Methods: One hundred and thirty-seven patients who received biphosphonates (zoledronic acid: 50 pts, pamidronate: 29 patients, bondronate: 2 pts, pamidronate and zoledronic acid: 50 pts, zoledronic acid and bondronate: 5 pts) since January 1995 and had a minimum exposure of 6 months to the drug were included in this analysis. Since the first reports, which associated ONJ with biphosphonate treatment, we prospectively evaluated this complication (first patient diagnosed in July 2003): all patients complaining of symptoms suggestive of ONJ were referred to a maxillofascial surgeon who confirmed the diagnosis and managed the patients for this complication. The medical records of all patients who were included in the analysis were reviewed in order to exclude symptoms and signs of ONJ, which might have not been formally diagnosed. From this retrospective review, no patient with a highly probable diagnosis of ONJ was identified. Results: Ten patients (6.7%) developed ONJ. The median number of treatment cycles and time of exposure to biphosphonates were 26 infusions and 42 months for patients with ONJ compared to19 infusions (p=0.2) and 27 months (p=0.05) for patients with no ONJ. The cumulative hazard of ONJ increased with time to exposure from 0% for exposure 6–12 months to 13% (95% CI: 3–23) for exposure of 5 years. The use of thalidomide was not associated with the development of ONJ. No case of ONJ was observed among patients treated with pamidronate or pamidronate and ibandronate. In patients who received sequential pamidronate and zoledronic acid, all cases of ONJ occurred during the use of zoledronic acid. The cumulative hazard was significantly higher with zoledronic acid compared to pamidronate alone or sequential administration of pamidronate and zoledronic acid (p=0.022). Among the 10 patients, who developed ONJ, 7 had had dental extraction prior to the development of the complication, 2 had dentures and only one had not had either. In spite of the discontinuation of biphosphonate treatment, only one patient experienced improvement of osteonecrosis, in 7 cases it remained stable and in 2 cases osteonecrosis progressed. Conclusions: The use of biphosphonates in patients with multiple myeloma seems to be associated with the development of ONJ. Our cohort study is the first one which provides a fairly accurate estimate of the incidence of documented ONJ after treatment with biphosphonates. Length of exposure and the type of biphosphonate used appear to be the most important risk factor for this complication. The risk of developing osteonecrosis appears to be higher with zoledronic acid than with pamidronate and may be precipitated by dental extraction.