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The phase III trial GEM05MENOS65 randomized 390 patients 65 years old or younger with newly diagnosed symptomatic multiple myeloma (MM) to receive induction with thalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone and Vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone bortezomib (VBMCP/VBAD/B) followed by autologous stem cell transplantation (ASCT) with MEL-200. After ASCT, a second randomization was performed to compare thalidomide/bortezomib (TV), thalidomide (T) and alfa-2b interferon (alfa2-IFN). Maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of intravenous bortezomib at 1.3 mg/m2on days 1, 4, 8 and 11 every 3 months) versus T (100 mg daily) versus alfa2-IFN (3 MU three times per week) for up to 3 years. A total of 271 patients were randomized (TV: 91; T: 88; alfa2-IFN: 92). The complete response (CR) rate with maintenance was improved by 21% with TV, 11% with T and 17% with alfa2-IFN (P, not significant). After a median follow-up of 58.6 months, the progression-free survival (PFS) was significantly longer with TV compared with T and alfa2-IFN (50.6 vs 40.3 vs 32.5 months, P=0.03). Overall survival was not significantly different among the three arms. Grade 2–3 peripheral neuropathy was observed in 48.8%, 34.4% and 1% of patients treated with TV, T and alfa2-IFN, respectively. In conclusion, bortezomib and thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide or alfa2-IFN. (no. EUDRA 2005-001110-41).

Summary Twelve patients with carpal tunnel syndrome were studied. Clinical and electrophysiological data were obtained and an estimation of vitamin B6 (pyridoxine) status by an assay of erythrocyte aspartate aminotransferase and coenzyme stimulation assay were done. None of the patients was found to have vitamin B6 deficiency. Patients were treated with 150 mg of pyridoxine daily for 3 months. Erythrocyte aspartate aminotransferase increased significantly (p<0.001) in all the patients. In 6 patients there were clinical and electrophysiological improvement and erythrocyte aspartate aminotransferase increased more than in the other 6 patients. The data obtained appear to indicate that although vitamin B6 deficiency is not common in carpal tunnel syndrome patients, pyridoxine supplementation can be recommended as adjuvant treatment in those patients undergoing surgery.

Several studies have demonstrated that both CD34+/CD38- and CD34+/HLA-DR- human hematopoietic progenitor cells have properties associated with hematopoietic stem cells. However, the kinetics of these two cell populations in human peripheral blood (PB) after priming with granulocyte colony-stimulating factor (rhG-CSF) has not been investigated. By using flow-cytometric analysis we have shown that administration of rhG-CSF to 14 patients eligible for peripheral blood progenitor cell (PBPC) transplantation led to an increment of CD34+/CD38+ and CD34+/HLA-DR+ cells in the PB that paralleled the increase of total CD34+ cells, indicating that such subpopulations are responsible for the major release of CD34+ cells. Furthermore, rhG-CSF priming led to a significant mobilization of fractions of more immature CD34+/CD38- and CD34+/HLA-DR- cells to the PB. In the leukapheresis preparations, the average frequency of CD34+ cells lacking the CD38 or HLA-DR antigens was low (5% and 30%, respectively), with little overlap between the CD38- and HLA-DR- subpopulations. In addition, the yield of each subset of CD34+ cells (CD34+/CD38± and CD34+/HLA-DR±) in the PB correlated with the numbers in the collected material. The results of the present study indicate that administration of rhG-CSF causes a significant increase of CD34+/CD38± and CD34+/HLA-DR± cells in PB, and that such cells can be then safely harvested by leukapheresis procedures.

The binding of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] to saponin-permeabilized blood-bank-outdated human platelets, 6 days old, has been characterized (Kd= 3.8 nM;Bmax= 1.7 pmol/mg protein) and used to develop a novel radioreceptor assay which allows the measurement of the Ins(1,4,5)P3content in resting or agonist-stimulated cells. This assay is as sensitive (0.25 pmol in a 0.25 ml volume), specific, and reproducible as previously proposed methods. In addition, obtaining large batches of the Ins(1,4,5)P3binding protein by treating outdated platelets with saponin is simple and quick and uses otherwise discarded material. Moreover, the assay is considerably cheaper than commercially available kits. Using this method we confirmed that thrombin evokes a rapid, transient, and dose-dependent increase in the platelet concentration of Ins(1,4,5)P3.

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.

Introduction: Justification and Objectives

We have analysed the influence of age on survival after a tandem hematopoietic stem cell transplantation prospective protocol (GEM-2000) in patients diagnosed of multiple myeloma (MM). From 870 patients with symptomatic MM aged < 70 years and prospectively included in the GEM-2000 protocol, we have analysed the outcome of a group of 637 patients [351 males, median age of 59 (range, 32 – 70) years] and treated with at least one autologous stem cell transplantation (ASCT). Sixteen patients (2.5%) were between 31 and 40 years of age (group A), 96 patients (15%) between 41 and 50 years (group B), 244 patients (38%) between 51 and 60 years (group C) and the remaining 281 patients (44.5%), between 61 and 70 years (group D). In 325 patients the M component at diagnosis was an IgG (51%). Fifty three patients (8%) had stage I at diagnosis, 232 patients (37%) stage II and 352 patients (55%), stage III. One hundred and one patients (16%) presented with renal insufficiency at diagnosis. Significantly lower levels of serum albumin at diagnosis were observed in the older group of patients (3.88 g/L vs 4.46 g/L, p = 0.05). Most of the patients (612, 96%) were initially treated with the alternating protocol VBCMP/VBAD. The response rate to the first line therapy was of 84% (n = 533), without differences between group D and the rest of the groups. The BUMEL protocol (busulfan 10 mg/kg po plus melphalan 140 mg/m2 iv) and MEL200 (melphalan 200 mg/m2 iv) were the two conditioning regimens used for the first intensive procedure. Although the proportion of older patients (group D) who received MEL200 was higher than in the younger groups of patients (groups A – C) (35% vs 44%), these differences did not reach a statistical significance. At three months after the first ASCT, 30% of the patients had reached a complete remission with negative immunofixation (CR IF-); this percentage was significantly superior in the younger group of patients (groups A – C) with respect to group D (32% vs 27%, p = 0.02). Transplant related mortality (TRM) was also significantly superior in group D (8% vs 3%, p = 0.01). At the time of follow-up, 124 patients (19%) have received a second transplantation; a second intensive procedure was more frequently performed in the younger group with respect to group D (25% vs 12%, p = 0.0001). This second transplant was an ASCT in 73% of the patients (65% in groups A – C vs 94% in group D, p = 0.04). With a median follow-up of 24 months, 508 patients are alive. Actuarial 2-year overall survival (OS) and event free survival (EFS) for the whole population of patients are 75%±2% and 57%±2%, respectively, with statistically significant differences between groups A - C and group D (77%±3% vs 72%±3%, p = 0.05 and 62%±3% vs 52%±4%, p = 0.02, respectively). The overall benefit of the intensification procedure seems to be less in the older group of MM patients (61 – 70 years) included in the GEM-2000 protocol. These results could be related to the achievement of a significant lower rate of CR IF- after the first ASCT and a higher TRM in this older population of patients.

For more than 25 years, melphalan and prednisone has remained as the gold standard treatment for elderly multiple myeloma (MM) patients. Bortezomib has shown significant activity with manageable toxicity in refractory/relapse MM patients. Moreover, in vitro synergy has been reported when bortezomib is combined with cytotoxic agents such as melphalan.

For more than 25 years, melphalan and prednisone has remained as the gold standard treatment for elderly multiple myeloma (MM) patients. Bortezomib has shown significant activity with manageable toxicity in refractory/relapse 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 efficacy of V-MP in untreated MM patients ≥ 65 years old. Methods: This is a dose escalation study with two sequential dose levels (Ph 1) and expansion of the cohort at the MTD by 60 patients to further refine estimates of efficacy (Ph 2). In the first cohort, bortezomib (1mg/m2) was administered as a iv bolus to 6 consecutive patients on days 1,4,8,11,22,25,29 and 32 followed by a 10 day rest period in combination with oral melphalan, 9 mg/m2, and prednisone, 60mg/m2, once daily on days 1 to 4. In the 2nd cohort, bortezomib was administered at 1.3mg/m2. MTD was defined as that dose level below which 2/6 patients had a DLT. Patients: 12 patients have been enrolled to date - 6 in cohort 1 and 6 in cohort 2. Results: Toxicity has been manageable. The first cohort at 1 mg/m2 has completed at least two 6-week treatment cycles. There was no DLT in the first cycle. The 2nd cohort has enrolled 6-patients at a dose of 1.3 mg/m2 but none has completed the first cycle yet. In the first cohort, there was one patient with grade 3 neutropenia (ANC = 0,668) observed at Cycle 1 Day 25. During the second cycle, there were no patients with grade 4 therapy-related toxicity and only one grade 3 adverse event (neutropenia) was observed. The most common grade1 or 2 toxicities were nausea, vomiting, rash, constipation, diarrhea, fever, herpes zoster infection, anorexia, neutropenia, anemia and thrombocytopenia. Ocular neuropathic pain (grade 2) developed de novo in 1 patient during the first cycle; one dose of bortezomib was held and the adverse event resolved with analgesic treatment in 4 days. Treatment was continued at a dose of 0,5 mg/m2 at D11 and D22. After this date, bortezomib at 1.0 mg/m2 was restarted. The second cohort is in the first 6-week cycle at present, so observations are limited. One serious adverse event (pulmonary embolism and probably septic shock with death) was observed in this cohort in a patient at day +11. He had normal WBC. Two grade 3 adverse events (leucopenia and neutropenia) were observed in one patient. Other grade 1 or 2 toxicities are similar to those observed in the first cohort. Regarding response, after two cycles of treatment, in the first cohort, 3 out of the 6 patients have experienced >50% reduction in M-protein (two with > 75% reduction) and the others three have experienced either a minor response (1) or stable disease (2). In the second cohort, response data are not available at this time. Conclusion:The combination of V-MP is well tolerated at standard doses of MP with bortezomib 1 mg/m2 with no DLTs in 6-patients. Bortezomib (1.3 mg/m2) is being explored in the second 6-patient cohort in order to define the MTD. So far, no patient has developed DLT. Rapid M-protein responses have been seen. Results will be updated and presented for the 2nd cohort.

We have analysed the influence of age on survival after a tandem hematopoietic stem cell transplantation prospective protocol (GEM-2000) in patients diagnosed of multiple myeloma (MM). From 870 patients with symptomatic MM aged < 70 years and prospectively included in the GEM-2000 protocol, we have analysed the outcome of a group of 637 patients [351 males, median age of 59 (range, 32 – 70) years] and treated with at least one autologous stem cell transplantation (ASCT). Sixteen patients (2.5%) were between 31 and 40 years of age (group A), 96 patients (15%) between 41 and 50 years (group B), 244 patients (38%) between 51 and 60 years (group C) and the remaining 281 patients (44.5%), between 61 and 70 years (group D). In 325 patients the M component at diagnosis was an IgG (51%). Fifty three patients (8%) had stage I at diagnosis, 232 patients (37%) stage II and 352 patients (55%), stage III. One hundred and one patients (16%) presented with renal insufficiency at diagnosis. Significantly lower levels of serum albumin at diagnosis were observed in the older group of patients (3.88 g/L vs4.46 g/L, p = 0.05). Most of the patients (612, 96%) were initially treated with the alternating protocol VBCMP/VBAD. The response rate to the first line therapy was of 84% (n = 533), without differences between group D and the rest of the groups. The BUMEL protocol (busulfan 10 mg/kg po plus melphalan 140 mg/m2iv) and MEL200 (melphalan 200 mg/m2iv) were the two conditioning regimens used for the first intensive procedure. Although the proportion of older patients (group D) who received MEL200 was higher than in the younger groups of patients (groups A – C) (35% vs44%), these differences did not reach a statistical significance. At three months after the first ASCT, 30% of the patients had reached a complete remission with negative immunofixation (CR IF-); this percentage was significantly superior in the younger group of patients (groups A – C) with respect to group D (32% vs27%, p = 0.02). Transplant related mortality (TRM) was also significantly superior in group D (8% vs3%, p = 0.01). At the time of follow-up, 124 patients (19%) have received a second transplantation; a second intensive procedure was more frequently performed in the younger group with respect to group D (25% vs12%, p = 0.0001). This second transplant was an ASCT in 73% of the patients (65% in groups A – C vs94% in group D, p = 0.04). With a median follow-up of 24 months, 508 patients are alive. Actuarial 2-year overall survival (OS) and event free survival (EFS) for the whole population of patients are 75%±2% and 57%±2%, respectively, with statistically significant differences between groups A - C and group D (77%±3% vs72%±3%, p = 0.05 and 62%±3% vs52%±4%, p = 0.02, respectively). The overall benefit of the intensification procedure seems to be less in the older group of MM patients (61 – 70 years) included in the GEM-2000 protocol. These results could be related to the achievement of a significant lower rate of CR IF- after the first ASCT and a higher TRM in this older population of patients.