ALBERT

Description: Dexamethasone-based combinations have been the standard induction regimens in younger patients with multiple myeloma (MM) prior to stem cell transplantation. Bortezomib alone or in association with dexamethasone has shown significant activity in patients with both refractory/relapsed and newly diagnosed MM. We investigated the efficacy of bortezomib and dexamethasone administered on an alternating basis, the end-points of the study being response rate, kinetics of response, safety, stem cell mobilization and response postransplant. Patients with newly diagnosed MM under the age of 66 years and with adequate organ and function status were eligible. Patients were treated with bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 (cycles 1, 3, 5) and dexamethasone 40 mg p.o. on days 1–4, 9–12 and 17–20 (cycles 2, 4 and 6), followed by high dose-therapy intensification (HDT) with melphalan -200. Responses were evaluated by the EBMT criteria but a near-CR (n-CR) response category was included. Stem cell mobilization was performed after G-CSF priming. Between August, 2005 and March, 2006, 40 patients (18 M, 22F, median age 57 yrs) were enrolled. The M-protein type was IgG in 26 patients, IgA in 11 and light chain in 3. Six patients had extramedullary plasmacytomas. At the time of this analysis response data after the 6 cycles were available for 26 of the 40 patients. The overall response rate was 76% and the CR rate 15% (4 CR, 5 n-CR, 7 PR, 4 MR, 2 stable disease, 3 progressive disease, 1 non-evaluable because of treatment discontinuation due to toxicity after cycle 1). In patients who achieved at least PR the mean M-protein decrease was 84% (48% associated with bortezomib cycles and 36% with dexamethasone). Two responding patients showed disease progression immediately before HDT. In all thirteen patients mobilized to date stem cells could be adequately collected (median CD34+ cells: 4.85 x106/Kg; range 2–10.6) with only one apheresis. Toxicity was low and mainly consisted of grade 1 and 2 neutropenia, fever, GI symptoms, fatigue, peripheral neuropathy and thrombocytopenia. Ten (25%) patients developed mild peripheral neuropathy (grade 1=9 cases; grade 2=1 case) and 11 patients grade 1 thrombocytopenia. Grade 3 toxicity was only observed in 7 patients (neutropenia 6, skin/liver 1 case) and no patient developed grade 4 toxicity. Updated results on all patients along with cytogenetic data will be presented at the meeting. In conclusion, bortezomib alternating with dexamethasone is highly effective as up-front therapy in patients with MM, is associated with an extremely low toxicity and results in an excellent stem cell harvesting. The results of this trial support a short program of alternating bortezomib and dexamethasone as an effective and safe induction regimen for newly diagnosed younger myeloma patients.

Description: Introduction Plitidepsin is a cyclic depsipeptide isolated from the marine tunicate, Aplidium albicans with promising antitumor activity. This work represents a comprehensive study (in vitro, in vivo and clinical) of its antimyeloma efficacy. Material & Methods In vitro studies were performed in 23 multiple myeloma (MM) cell lines and in cells from 16 MM patients. For the in vivo analysis a human plasmocytoma model in CB17-SCID mouse was used. Mice were randomized to receive Aplidin® 100 μg/Kg ip x 7 days/week (n=9), Aplidin® 140 μg/Kg ip x 5 days/week (n=7) or vehicle alone (n=9). The clinical efficacy of Aplidin® in relapsed/refractory patients was evaluated in a non-randomized two-stage Phase II, multicenter, clinical trial. Dosage of Aplidin® was 5 mg/m2 every 2 weeks. Results Aplidin® showed clear in vitro efficacy (IC50:1–10 nM) in the 23 cell lines tested including those resistant to dexamethasone, melphalan or doxorubicin. It was also active in the presence of microenvironment (IL-6, IGF-1 and BMSCs). Thirteen out of the 16 patient samples were sensitive to Aplidin® with 〉80% cell death in 8 cases and 60–80% in the remaining ones without significant toxicity in non tumor cells. Combination of Aplidin® with dexamethasone, bortezomib or lenalidomide showed clear potentiation. Aplidin® acts by inducing apoptosis with caspase−3, −7, −8, −9 and PARP cleavage. It also involves the activation of p38 and JNK signalling, Fas/CD95 translocation to lipid rafts and downregulation of Mcl-1 and myc. In mice studies, both schedules of treatment reduced tumor growth and increased survival with statistical differences in the group receiving 140 μg/Kg x 5d/week (p=0.04, Log Rank p=0.02). No significant toxicity was observed. These data provided the rationale for a clinical trial that has included 31 patients with relapsed/refractory MM. Median age was 65 years (47–82) and the median number of prior lines of therapy was 4 (range: 1–9) including autologous stem cell transplant (60%), thalidomide (58%) and bortezomib (48%). Out of the 26 evaluable patients, 2 (8%) achieved PR and 3 (12%) MR. Eight patients (31%) remained in stable disease (SD). Due to the synergism with dexamethasone observed in the in vitro studies, the protocol was amended to allow the addition of this agent in pts progressing after 3 cycles or with SD after 4 cycles. With a median follow-up of 14 months (range: 6.8–16.3), the time to progression in responding pts was 5.8 months (4.9–7.6). The most common G3-4 adverse events were fatigue (7%), serum creatine phosphokinase increase (7%), muscle toxicity (10%) and hepatic toxicity (10%). No significant hematologic toxicity or neuropathy was observed. Conclusion Aplidin® is effective both as a single agent and in combination with dexamethasone in the in vitro and in vivo settings. Its activity in relapsed/refractory MM patients is promising with an acceptable toxicity profile.