ALBERT

Beschreibung: Background: Although clearly unsatisfactory, melphalan and prednisone remains the gold standard for elderly MM patients. Therefore new treatment strategies are needed for these patients. The proteasome inhibitor bortezomib (VELCADE) has shown significant activity in refractory/relapsed MM patients. Moreover, in vitro synergy has been reported when bortezomib is combined with cytotoxic agents such as melphalan. Aim: To define the appropriate dose of bortezomib in combination with MP and to analyse the toxicity and efficacy of V-MP (in terms of response) in untreated MM pts ≥ 65 years old. Methods: Treatment schedule consisting of four 6-week cycles followed by five 5-week cycles. First, two sequential dose levels of bortezomib (1.0 and 1.3 mg/m2) (6 pts each) were explored, administered on days 1,4,8,11,22,25,29 and 32 in combination with oral melphalan, 9 mg/m2 and prednisone, 60mg/m2 once daily on days 1 to 4. When maximum tolerated dose (MTD) of bortezomib in combination with MP was defined, the cohort of pts at the MTD was expanded to up to 60 patients to further refine estimates of efficacy and toxicity (PhaseII). Results: Median age of the 60 enrolled pts was 74(65–85) and the median number of cycles so far received is 3(1–9). During PhaseI, no dose limiting toxicity(DLT) was observed in the two cohorts of pts, and the recommended dose for phaseII was 1.3 mg/m2 of bortezomib in combination with MP. 53pts are evaluable for efficacy since they have already completed at least the first cycle. Analysis of response after cycle 1 revealed a Response Rate(RR) of 72%(6%CR with Immunofixation negative(CRIF-), 2%CRIF+ and 64%Partial Response(PR)). Analysis of best response after a median of 3 cycles revealed a RR of 85%(28%CRIF-, 11%CRIF+ and 45%PR); an additional pt(2%) achieved Minor Response(MR) and 7(13%) stable disease. The toxicity was manageable. Adverse events G3-4 reported for 60 pts included: Gastrointestinal toxicity, such as nauseas(2%), vomiting(2%), diarrhoea(15%) and constipation(8%); haematological toxicity, such as anemia(12%), neutropenia(G3 in 26% and G4 in 13%) and thrombocytopenia(G3 in 33% and G4 in 13%); infection(G3 en 12% and G4 in 2%) and peripheral neuropathy(G3 in 13% and G4 in 2%). Bortezomib and melphalan dose modification was required in 6 and 2 pts, respectively. Eight pts so far have been discontinued due to toxicity related to study medication: peripheral neuropathy in 5(G2 in 1, G3 in 2 and G4 in 2), diarrhoea in 1(G3), infection in 1(G3) and prolonged thrombocytopenia in 1(G4). With a median follow up of 7 months (range:3–15), two responding pts have progressed (months +9and+10), 54(90%) are alive and 6(10%) have died. Cause of death was lung cancer diagnosed 1 month after start of study treatment(1), progressive disease(1), septic shock(2), pulmonary thromboembolism (1) and pulmonary hypertension with right ventricular insufficiency and multiorganic failure(1). Conclusion: V-MP shows a high response rate(85% with 28%CRIF-) and manageable toxicities and could replace MP as the standard of care for elderly MM pts. An international phase 3 randomized trial is in progress to examine this.

Beschreibung: Introduction: Justification and Objectives There are little epidemiologic data about Myeloma Multiple in Spain. The heterogeneity and complexity of this pathology, and the several sociodemographic factors, justify the interest of this type of studies. On the other hand, this disease needs a high assignement of welfare and therapeutic resources, and besides new strategies have arisen for its treatment. The Spanish Leukaemia and Lymphoma Foundation (FLL)has analyzed the actual situation of Myeloma Multiple in Spain, compiling several epidemiologic and welfare parameters about the disease in a Multiple Myeloma “White Book” for Spain. Patients and Methods The period of analysis was 10 years, from 1.991 to 2.001. The information was compiled from a Hospital Based Survey about MM and the following official sources: International Agency for Research on Cancer (IARC): “Cancer incidence in Five continents” and “Incidence and Mortaliity for Cancer In Spain, Patterns and Tendences” Data Base of EUCAN and GLOBOCAN (Cancer Incidence, Mortality and Prevalence Worldwide) EUROCARE III study, (IARC Cancer Base Number 5, Lyon, IARCPress). “Natural Changes of Population and Demography. Spanish National Statistic Institute (INE) and National Spanish Center for Epidemiology (CNE.) Official Records for Mortality Rates by MM in Spain in Spanish Regions (CCAA) (death records Demograhy Records of INE). INE Hospital Case Rate Inquest. CMBD Data Base of Department of Health (Inmunoproliferative Neoplasm and Multiple Myeloma, CIE-9 Diagnosis Code: 203.0)The indicators used were: Deaths number, median of age, proportional mortality, mortality rates, mortality rates adjusted by age, gender and potential years of life lost due to multiple myeloma, (item 203 of ICD-10, OMS) during the last ten years in Spain. Results The incidence rates of MM, adjusted to the European population were: 3,54 cases by 100.000/year for men and 2,54 cases by 100.000/year for women. The global incidence rate were 4,44 cases by 100.000/year for men and 4,22 cases by 100.000/year for women. These rates were similar in all geographic regions. Performed predictions show a prevalence increase during the following five years, which means more than 2.400 cases in men and more than 2.100 in women MM cases per year. Regarding mortality, rates, myeloma is a very slightly frequent cause of death: 3.23 cases by 100.000/years of men and 2.3 cases of women. A whole an increase of mortality of 45.2 per cent was observed for the period of time between 1992 and 2001. Comments and Conclusions The MM incidence and mortality rates in Spain for this period were lower than expected in comparison with other European epidemiology studies. Nevertheless we observed that the MM mortality and prevalence rates present a continuous and uniform increment in the last years. Part of these increases can be due to the incorporation of new technologies, more sensitive for diagnosis, and to the increase of aging of the population. Furthermore certain occupational and chemical exposures and other environmental changes could explain these trends.

Beschreibung: Introduction and objectives : Plitidepsin is a cyclic depsipeptide originally isolated from the marine tunicate, Aplidium albicans. It appears very potent against multiple myeloma (MM) cells. Specifically, it was observed that it was active against a broad panel of 35 human MM cell lines, which included MM cells resistant to conventional anti-MM agents and novel agents (i.e. thalidomide, bortezomib). Plitidepsin also induced cell death in primary MM tumor cells freshly isolated from patients resistant to thalidomide or its analogs and/or proteasome inhibitors. Phase I has been completed exploring 4 different schedules of administration. Muscle and liver (transaminases and/or alkaline phosphatase) toxicities were the main DLTs. Hematological toxicity was not observed at the recommended dose. The aim of this trial was to explore the activity of plitidepsin in patients with previously treated refractory/relapsed MM. Material and Methods: This is a non-randomized two-stage Phase II, multicenter, clinical and pharmacokinetic trial, with Aplidin® (APLD) 5 mg/m2 as a 3 h intravenous infusion every 2 weeks, with antiemetic and antihistaminic prophylaxis. In the first stage 16 patients evaluable for efficacy were included. At least one response was requested in order to proceed with the second stage, in which a total of 37 patients will be included. Results: Between June’04 and June’05, 19 patients have been enrolled and data are available for 18 patient (7 men and 11 women, median age was 65.7y, range 48–82). Patients were previously relapsed/refractory. Prior treatments included: stem cell transplantation 64.7%, thalidomide 35.28% and bortezomib 17.64%. The median previous chemotherapy lines received were 3, range 1–6. The APLD median number of cycles received 4, range 1–16. Thirteen patients are currently evaluable for efficacy. One patient (7.7%) achieved a partial response (PR) with a 70% reduction in M-component lasting 8 months. Stable disease lasting between 3–5 months was observed in 3 patients (23.0%). In 2 patients (15.38%) a stabilization lasting 2.5 months was stated and the remaining 7 patients (53.8%) progressed. NCI-CTC grade 3–4 related toxicities were reported for n=17 patients and were mainly fatigue in 2 patients (11.8%), myalgia in 1 patient (5.9%), elevation of CPK in 1 patient (5.9%) and transient transaminases increase in 9 patients (52.9%). Significant hematological toxicity did not occurred in spite of 2 patients included and treated with thrombopenia grade 3–4 and 2 patient with neutropenia grade 3. Conclusions: First stage data shows that APLD presents hints of activity in patients with refractory/relapsed MM, with acceptable toxicity profile, thus meeting the criteria for proceeding to second stage recruitment. The absence of significant hematological toxicity is a well known feature of this drug and is being confirmed in this trial.