PAD Induction Research Articles

PAD Induction Therapy Followed by Autologous Peripheral Blood Stem Cell Transplant (APBSCT) as Upfront Treatment for Myeloma (MM) in Chinese Patients.

Abstract 4367 IntroductionThe anti-myeloma effect of bortezomib, used as a single agent or in combination chemotherapy, is well recognized in various clinical studies. The aim of this study is to determine the feasibility of using the PAD combination (bortezomib, doxorubicin and dexamethasone) as upfront treatment in Chinese patients with newly diagnosed MM, followed by APBSCT. MethodPatients between the ages of 18 to 65 year-old with newly diagnosed MM were recruited. PAD (bortezomib 1.3 mg/m2 on days 1, 4, 8 & 11; doxorubicin 9 mg/m2 on days 1 & 4; dexamethasone 40 mg on days 1-4, 8-11 & 15-18 during cycle 1 and days 1-4 during cycles 2-4) induction therapy was administered for four 28-days cycles, followed by autologous peripheral blood stem cell mobilization with cyclophosphamide 3 g/m2 plus G-CSF 5 mg/kg/BD. Subsequently, APBSCT was performed with high dose melphalan 200 mg/m2 conditioning. ResultsA total of 25 patients has been recruited so far (male:female = 14:11). The age ranged from 44 to 65 year-old (median 53). Eleven patients were of IgG subtype, 6 were IgD, 4 were IgA and 4 were kappa light chain disease. By Durie-Salmon staging, 22 were stage III, 2 were stage II and 1 was stage I. Seventeen (68%) patients have completed the four cycles of PAD induction therapy, while 3 (12%) are still having on-going PAD induction. Five (20%) patients withdrew from the PAD therapy. One patient developed disease progression after 2 cycles of PAD, while the other 4 developed serious adverse events with the first cycle of PAD, including 1 patient each with severe bradycardia, atrial fibrillation, severe sensory neuropathy and pulmonary haemorrhage. Of the 18 patients who had evaluable response to PAD (i.e. 17 patients who completed four cycles of PAD and 1 who progressed on PAD induction), the results were 3 CR, 7 VGPR, 5 PR and 3 NR. Fourteen of the patients with at least PR received APBSCT. Post-APBSCT responses were so far evaluable in 11 patients with 6 CR, 4 VGPR and 1 PR. Hence, PAD is a feasible and effective upfront induction therapy for Chinese patients with MM resulting in a satisfactory response rate. Nevertheless, significant adverse events may occur even early on with the treatment. Subsequent APBSCT further improved the response rate but long-term survival rate remains to be established. Disclosures:No relevant conflicts of interest to declare.

Sequential Approach with Bortezomib as Induction Before Autologous Transplantation, Followed by Lenalidomide as Consolidation-Maintenance in Untreated Multiple Myeloma Patients.

Abstract 3419Poster Board III-307 BackgroundBortezomib induction before autologous stem cell transplantation (ASCT) has shown its efficacy in newly diagnosed multiple myeloma (MM) patients, both in association with dexamethasone alone (Harousseau JL, et al. Blood 110, 2007, abstr 450) and in combination with doxorubicin and dexamethasone (Popat R, et al. Br J Haematol 141:512-516, 2008). Lenalidomide, a less toxic and more potent thalidomide-derivative, lacks the neurotoxic effects of the parent drug and represents an optimal agent to include in maintenance regimens. AimsThese observations provided the rationale for investigating a sequential approach including bortezomib as induction and lenalidomide as consolidation-maintenance in MM patients undergoing ASCT. MethodsA hundred and two newly diagnosed patients aged 65–75 years were enrolled in 17 Italian centers. Induction (PAD) included four 21-day cycles of bortezomib (1.3 mg/m2 days 1,4,8,11), pegylated-liposomal-doxorubicin (30 mg/m2 day 4), and dexamethasone (40 mg/day: cycle 1, days 1–4, 8–11, 15–18; cycles 2–4, days 1–4). Autologous transplantation was tandem melphalan 100 mg/m2 (MEL100) followed by stem-cell support. After ASCT, patients received consolidation with four 28-day cycles of lenalidomide (25 mg/day days 1–21 every 28 days) plus prednisone (50 mg every other day) (LP), followed by maintenance (L) with lenalidomide alone (10 mg/day days 1–21 every 28 days) until relapse. Primary endpoints were safety (incidence of grade 3–4 adverse events [AEs]) and efficacy (response rate). Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Time-to-event estimates analysis was performed using the Kaplan-Meier method. ResultsVery good partial response (VGPR) or better was 58% after PAD induction and increased to 82% after MEL100 and to 86% during LP-L. Complete response (CR) rate was 13% after PAD induction, increased to 38% after MEL100 and to 66% during LP-L. After a median follow-up of 2 years, the 2-year PFS was 69%, the 2-year time-to-progression was 75% and the 2-year OS was 86%. During PAD induction, main grade 3–4 AEs were thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%); treatment-related mortality was 3%. During consolidation-maintenance grade 3–4 AEs included neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%). Consolidation-maintenance treatment was well tolerated: only 4% of patients required Granulocyte-colony stimulating factor support and no patient required platelet transfusion; dermatological toxicity was easily manageable with dose-reduction and supportive therapy; no treatment-related deaths were reported. Updated results will be presented at the meeting. ConclusionThis is the first phase II study in newly diagnosed MM patients to date, where a sequential approach including bortezomib as induction, and lenalidomide as post ASCT consolidation-maintenance was explored. Treatment was correlated with an increase in response rate and in the depth of response (CR rate) and was generally well tolerated. These data suggest that this is a safe and effective regimen for newly diagnosed MM patients. Randomized trials are needed to confirm these results. DisclosuresPatriarca:Celgene: Honoraria; Janssen Cilag: Honoraria. Bringhen:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Janssen Cilag : Consultant, advisory committee, Research Funding; Celgene: Consultant, advisory committee, Research Funding; Pharmion: Consultant, advisory committee, Research Funding. Palumbo:Celgene: Honoraria; Janssen Cilag: Honoraria.

PAD combination therapy (PS‐341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma

Bortezomib (formerly PS-341) has significant activity in patients with relapsed multiple myeloma (MM), its efficacy is increased with the addition of dexamethasone and it demonstrates synergy with doxorubicin, thus providing the rationale for combination therapy with bortezomib, doxorubicin and dexamethasone (PAD). Patients with untreated MM received four 21-d cycles of PAD, comprising bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11, along with dexamethasone 40 mg on days 1-4, 8-11 and 15-18 during cycle 1 and days 1-4 during cycles 2-4. During days 1-4, patients also received 0, 4.5 or 9 mg/m(2) of doxorubicin at dose levels 1, 2, and 3 respectively. Following peripheral blood stem cell (PBSC) collection, patients received high-dose melphalan (MEL200) with PBSC transplantation (PBSCT). After PAD induction alone, 20 of 21 patients (95%) achieved at least a partial response (PR), including complete response (CR) in five patients (24%). Twenty of 21 had PBSC mobilized, and 18 of 20 received MEL200/PBSCT. In an intention-to-treat analysis, response rates were: CR 43%, near CR 14%, very good PR 24%, PR 14% and stable disease 5%. PAD was effective, did not prejudice subsequent PBSC collection, and should be further evaluated in prospective randomized trials.