Pantoja, Mariela

Abstract Abstract 3861 Poster Board III-797 Previous studies have reported that multiple myeloma (MM) patients (pts) with t(4;14) identified by FISH who are treated with a single ASCT as part of first-line therapy have worse outcomes than those lacking this adverse cytogenetic marker; two trials have described a median progression-free survival (PFS) of only 8-9 months and median overall survival (OS) of 18 mos in this setting (Chang H, et al. Bone Marrow Transplant 2005; 36: 793; Gertz M, et al. Blood 2005; 106: 2837). Since the novel agent bortezomib appears to have efficacy in patients with t(4;14), we designed a phase II protocol in which pts receive induction with pegylated liposomal doxorubicin, bortezomib and dexamethasone (DBD) x 4 cycles, followed by post-induction therapy with oral cyclophosphamide 300 mg/m2 days 1,8 15, 22 with bortezomib 1.5 mg/m2 days 1,8,15 and prednisone 100 mg q 2 days of a 28-day cycle (CyBor-P) x 8 additional cycles. Maintenance therapy with dexamethasone (dex) 40 mg/month was then administered until progression. Although elective stem cell collection was recommended after induction, routine ASCT was not performed in the absence of disease progression. Between February 2008-August 2009, 153 newly diagnosed MM pts were screened for t(4;14) in 7 Canadian centers, and 14 (9%) were found to be positive by FISH. Four did not meet the critieria for symptomatic MM, 2 had received ≥ 2 mos of prior therapy while 8 were entered onto study. One of these was later determined to have a variant abnormality of chromosome 4 but not t(4;14) and underwent ASCT after induction; this pt is included in the safety analysis only. The median age was 56 (49-69) and 43% were male. The median percent nuclei positive for t(4;14) was 30% (10-41%), serum β2-microglobulin 394 nmol/L (190-1695) and albumin 34 g/L (28-39); one pt had ISS stage 1,3 had stage 2 and 3 had stage 3 MM. Immunoglobulin subtype included IgGκ in 2 and IgAκ in 2 and IgAλ in 3. All pts have completed DBD induction, with the best response in the 7 evaluable pts consisting of PR in 2 and VGPR in 5; one in PR progressed quickly after induction and has achieved nCR after D-PACE followed by ASCT and lenalidomide maintenance. Four are receiving post-induction therapy with CyBor-P currently, with VGPR in 3 and PR in 1. No SAEs or grade3/4 neutropenia or thrombocytopenia has occurred; other toxicities were mild, with grade 2 skin toxicity noted in 37.5% and grade 2 neurotoxicity observed in 7.4%. All pts are alive at a median follow-up (F/U) of 8 mos (2-11), and 6 (86%) are free of progression. We conclude: 1) the incidence of t(4;14) in newly diagnosed MM pts appears to be lower than the 15% anticipated; 2) 28% of newly diagnosed pts with this entity have asymptomatic MM; 3) preliminarily, DBD induction has resulted in ≥ PR in all pts although 1 progressed quickly; 4) this bortezomib-based regimen is very well-tolerated; 5) longer F/U is required to determine the PFS and OS with this approach. Disclosures: Reece: Ortho Biotech: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Use of bortezomib as part of initial therapy with pegylated liposomal doxorubicin and dexamethasone. Piza Rodriguez:Ortho Biotech: Honoraria. Belch:Ortho Biotech: Honoraria, Research Funding. Shustik:Ortho Biotech: Honoraria. Bahlis:Ortho Biotech: Honoraria; Celgene: Honoraria. White:Ortho Biotech: Honoraria, Research Funding. Chen:Ortho Biotech: Honoraria. Kukreti:Celgene: Honoraria. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Trudel:Ortho Biotech: Honoraria, Research Funding.

PurposeLenalidomide is an oral immunomodulatory drug with multiple effects on the immune system and tumor cell microenvironment leading to inhibition of malignant cell growth. Based on encouraging reports of lenalidomide in relapsed and refractory chronic lymphocytic leukemia (CLL), we investigated the first-line use of single-agent lenalidomide in CLL.Patients and MethodsUsing a starting dose of lenalidomide 10 mg/d for 21 days of a 28-day cycle and weekly 5-mg dose escalations to a target of 25 mg, we encountered severe toxicities (tumor lysis, fatal sepsis) in the first two patients enrolled. The study was halted and the protocol amended to a more conservative regimen: starting dose of lenalidomide 2.5 mg with monthly escalations to a target dose of 10 mg, and extended tumor lysis prophylaxis and monitoring. Gene expression profiles from patient samples before and after 7 days of lenalidomide were performed.ResultsTwenty-five patients were enrolled on the amended protocol. No further tumor lysis events were reported. Tumor flare was common (88%) but mild. Grade 3 to 4 neutropenia occurred in 72% of patients, with only five episodes of febrile neutropenia. The overall response rate was 56% (no complete responses). Although rapid peripheral lymphocyte reductions were observed, rebound lymphocytoses during the week off-therapy were common. Lenalidomide-induced molecular changes enriched for cytoskeletal and immune-related genes were identified.ConclusionLenalidomide is clinically active as first-line CLL therapy and is well-tolerated if a conservative approach with slow dose escalation is used. A lenalidomide-induced molecular signature provides insights into its immunomodulatory mechanisms of action in CLL.

Purpose The combination of oral weekly cyclophosphamide and alternate day prednisone is a convenient regimen for relapsed/refractory multiple myeloma (MM), and we sought to improve its efficacy by adding bortezomib, a proteasome inhibitor with proven antimyeloma activity. Patients and Methods We conducted a phase I-II trial evaluating six dose levels to define the maximum tolerated dose (MTD) of this combination in relapsed/refractory MM. An additional 10 patients were evaluated at the highest dose level reached. Results Thirty-seven patients were treated on this study. The MTD was not defined. Both of the highest dose levels of bortezomib tested (1.3 mg/m 2 on days 1, 4, 8, and 11 and 1.5 mg/m 2 on days 1, 8, and 15, each on a 28-day cycle) could be safely given with cyclophosphamide 300 mg/m 2 per week and prednisone. At these dose levels, the overall response rate was 95% (complete responses [CR] plus partial response plus minimal response), with CR observed in more than 50% of patients. The weekly bortezomib regimen resulted in fewer instances of grade 3 thrombocytopenia and grade 1 to 2 peripheral neuropathy; the 1-year progression-free and overall survival probabilities with this dose level were 83% (95% CI, 73% to 96%) and 100%, respectively. Conclusion Weekly bortezomib 1.5 mg/m 2 plus oral cyclophosphamide and prednisone produces an unprecedented response rate and encouraging 1-year survival in relapsed/refractory patients with MM. Further evaluation of this promising regimen is warranted both in relapsed and newly diagnosed disease.