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Introduction: There remains no clear standard first-line therapy for MCL. VcR-CVAD is a novel, intermediate-intensity chemoimmunotherapy regimen which incorporates bortezomib into modified hyper-CVAD chemotherapy. We hypothesized that the addition of bortezomib would improve the complete response (CR) rate, and maintenance rituximab (MR) would improve the remission duration. The results of this study were previously reported (Chang JE, et al. Br J Haematol 2011), with an observed overall response rate (ORR) of 90% (CR/unconfirmed CR in 77%), and 3-year progression-free survival (PFS) and overall survival (OS) of 63% and 86%, respectively. Long-term follow-up (LTFU) is reported from this multicenter trial. Methods: The study enrolled patients ≥18 years of age with histologically confirmed MCL. Patients were previously untreated, with the exception of 1 cycle of CHOP/CHOP-like chemotherapy. Patients received VcR-CVAD induction chemotherapy every 21 days for 6 cycles: rituximab (R) 375 mg/m2 intravenously (IV) on day 1; bortezomib/Velcade® (Vc) 1.3 mg/m2 IV, days 1 & 4; cyclophosphamide 300 mg/m2 IV every 12 hours, days 1-3 (total of 6 doses); doxorubicin 50 mg/m2 IV continuous infusion days 1-2 (total dose over 48 hours equal to 50 mg/m2); vincristine 1 mg IV day 3; and dexamethasone 40 mg orally days 1-4. Patients received G-CSF support beginning day 5-6 of each induction cycle, and all appropriate supportive care measures were permitted throughout treatment including tumor lysis prophylaxis, transfusion support and antibiotics. Patients achieving at least a partial response to induction therapy received R consolidation (R 375 mg/m2 IV X 4 weekly doses) and MR (R 375 mg/m2 IV every 12 weeks for a total of 5 years; total of 20 doses). Restaging CT scans were performed after cycles 2, 4, and 6 of induction, 12 weeks after consolidation, every 6 months during maintenance, and yearly during LTFU. The primary endpoint was ORR and CR to induction chemotherapy; secondary endpoints were PFS and OS. Results: Thirty patients were enrolled from 7/2005-5/2008. Median age was 61 years (range 48-74), 80% male, all patients had advanced stage disease, and 60% had MIPI score of medium- or high-risk disease. Six patients had blastic morphology. Long-term results are reported after a median follow-up of 7.8 years in surviving patients. Twenty patients are alive, and 15 (50%) are alive in ongoing remission (Figure 1). Estimates of 6-year PFS and OS are 53.1% and 69.8%, respectively (Table 1). The observed PFS and OS differences between patients Conclusions: VcR-CVAD is a moderate intensity chemotherapy regimen that is tolerable for many older and less fit adult patients as first-line therapy of MCL. LTFU of patients receiving VcR-CVAD induction followed by 5 years of MR demonstrates high rates of durable remission that are comparable with more intensive chemotherapy and consolidative autologous stem cell transplant (ASCT). The highly promising activity of the VcR-CVAD regimen was recapitulated in ECOG-ACRIN protocol E1405 (Chang et al, Blood 2014). A randomized phase 3 trial has recently confirmed the beneficial effects of bortezomib incorporation into standard immunochemotherapy (Robak et al, NEJM 2015). VcR-CVAD remains an effective therapy choice for initial treatment of MCL, both in younger and older MCL populations. Disclosures Kahl: Celgene: Consultancy; Seattle Genetics: Consultancy; Infinity: Consultancy; Gilead: Consultancy; Juno: Consultancy; Pharmacyclics: Consultancy.

Abstract 5041 Introduction: Angiogenesis as an important feature of malignant propagation in MM and other malignancies. This had led to the development of treatment strategies focused on inhibition of vascular growth. Bevacizumab (B) has previously been reported to increase response rate as well as time to progression when combined with standard therapies in several tumor types. Bone marrow biopsy samples from pts with MM consistently demonstrate increased blood vessel density and drugs such as lenalidomide are thought to work in part due to antiangiogenic affects. We therefore investigated the combination of the VEGF inhibitor bevacizumab with L and D in patients with relapsed or refractory MM. Eligibility: Relapsed or refractory MM patients (pts), failing >1 therapy, with no previous exposure to lenalidomide, with measurable M protein in serum and/or urine, no current history of unstable cardiovascular disease or uncontrolled thrombosis, without therapy for 28 days, and no contraindication to aspirin. Methods: Each 4 week cycle consisted of lenalidomide (L) 25 mg PO d1–21, bevacizumab (B) 10 mg/kg IV over 2 hours every two weeks, and dexamethasone (D) 40 mg PO q week. All pts received aspirin 325 mg PO daily. Plasma levels of VEGF, VEGFR1, VEGFR2, and MIP-1α were measured by ELISA prior to, after 1 and 4 cycles of therapy. Clinical responses were assessed using IBMTR criteria. Results: 39 subjects were enrolled; 36 evaluable for response. Median age of pts was 69; 62% of pts were male, median time from diagnosis to study treatment was 26 months. Ten pts (25%) had high risk cytogenetics at time of enrollment. Median number of previous treatments was 2 (range 1–7), 23% had undergone auto transplant, 59% had received thalidomide. Patients received a median of 5 cycles (range 0–28). The combined complete and partial remission rate (CR+PR) were 64. 1 % (95% confidence interval 47–79%). For the entire group, the median PFS and median OS were 9 and 36 months, respectively. Grade 3–4 AEs occurred in 72% of patients. Common adverse events (AE) included DVT/PE in 5 pts, neutropenia 6 pts, infection (5 pts.). Specific Gr3–4 AE likely attributable to inclusion of B were GI perforation (3), cardiac events (4) and mucositis (4pts) Fifteen pts (39%) discontinued therapy early due to toxicity or withdrawal of consent. Patients with MIP-1α and VEGFR-1 levels below the median were more likely to achieve CR or PR (p=. 053). No correlation was seen with previous thalidomide exposure, previous transplant, lytic bone disease or standard vs high risk myeloma. Conclusions: The addition of bevacizumab did not translate to either increased response rate or prolongation of PFS. While the incidence of AE was lower than previously reported with L and high dose D, the increased GI and cardiac toxicity and the expected increase cost would not justify further exploration of this combination. Bevacizumab and lenalidomide were generously supplied by Genentech, Celgene and by the NCI. Disclosures: No relevant conflicts of interest to declare.

Introduction: There is no standard treatment for Mantle cell lymphoma (MCL). Intensive treatment strategies such as conventional R-hyperCVAD with alternating R-cytarabine/methotrexate or autologous stem cell transplant appear to improve PFS but the effect on OS is unclear. In addition, approximately 50% of newly diagnosed patients are not candidates for intensive therapies. Novel treatment strategies are needed. We have published the results of a study using a modified R-hyperCVAD induction followed by maintenance rituximab (Kahl et al, Ann Oncol 2006). This induction strategy yielded a complete response (CR) rate of 64% and the entire treatment program yielded a median PFS of 37 months. Bortezomib (Velcade) has demonstrated promising activity in relapsed MCL (Fisher et al, J Clin Onc, 2006). We hypothesized that the incorporation of Velcade (Vc) into the induction regimen would improve the CR rate. The new regimen, VcRCVAD, was tested for safety and efficacy in a phase II study at the University of Wisconsin and within the Wisconsin Oncology Network. Methods: Eligible patients had histologically confirmed mantle cell lymphoma, PS 0–2, and adequate end organ function. The final treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1–3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1–2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1–4. Due to excessive painful peripheral neuropathy (PN), 2 dose modifications were required during the course of the study. Patients 1–7 received 1.5 mg/m2 Velcade and 2 mg vincristine. Patients 8–14 received 1.3 mg/m2 Velcade and 2 mg vincristine. Patients 15–30 received 1.3 mg/m2 Velcade and 1 mg vincristine. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF cytokine support. Patients achieving at least a PR receive maintenance rituximab therapy for 5 years. Results: Enrollment is complete and all 30 patients are evaluable for response to VcRCVAD induction. Baseline characteristics include median age 60.5 (48–74), 24M:6F, 26/30 (87%) stage IV, and 12 (40%) low-risk, 8 (27%) int-risk, and 10 (33%) high-risk by MIPI. 3 patients (10%) experienced PD during induction therapy and 27 (90%) responded with 23 CR/CRu (77%) and 4 PR (13%). With a median follow up of approximately 18 months, the 18-month PFS and OS are 73% and 97%, respectively. The major toxicity of this treatment regimen is painful PN and expected hematologic toxicity. 5/7 patients in cohort 1 and 3/7 patients in cohort 2 developed grade 3 painful PN and 1 patient in cohort 2 developed grade 4 painful PN. Only 1/16 patients in the final cohort experienced grade 3 painful PN. All neuropathy eventually improved to ≤ grade 2, but 10 patients require chronic medication for symptom relief. 13/167 (8%) of the treatment cycles were complicated by neutropenic fever/infection. There were no treatment related deaths. Conclusion: The VcR-CVAD induction has produced high overall response (90%) and CR rate (77%) in a very representative MCL patient population. Comparing these data to our previous frontline MCL study, the CR rate appears to be enhanced (77% vs 64%) by the addition of Velcade. Longer follow up is needed before determining if the higher CR rate will translate into an improved PFS and OS. Because of the risk for painful PN, caution must be exercised when using vincristine and Velcade in combination. The MTD for this combination was 1 mg vincristine and 1.3 mg/m2 Velcade. The encouraging complete response rate provided the rationale for ECOG study E1405, which is testing the safety and efficacy of this induction regimen in a cooperative group setting.

The interaction between malignant plasma cells and non malignant bone marrow microenvironment has been recognized as both an important feature of MM propagation and a therapeutic target. One critical interaction appears to involve angiogenesis as evidenced by increased blood vessel density in areas of myeloma cell proliferation. The potent anti MM compound lenalidomide may work partly through down regulation of VEGF expression by bone marrow stromal cells. We hypothesized that the addition of the VEGF-A receptor inhibitor, bevacizumab, in combination with low dose weekly dexamethasone, would provide more complete blockade of VEGF activation and translate to increased activity in MM patients with relapsed or refractory disease. ELIGIBILTY: relapsed or refractory MM patients (pts), failing >1 therapy, with no previous exposure to lenalidomide, measurable M protein in serum and/or urine, no current history of unstable cardiovascular disease or uncontrolled thrombosis, no therapy for ≥28 days, and no contraindication to aspirin. METHODS: Each 4 week cycle consisted of lenalidomide 25 mg PO d1–21, bevacizumab 10 mg/kg IV over 2 hours every two weeks, and dexamethasone 40 mg PO q week. All pts received aspirin 325 mg PO daily. Prior to therapy pts underwent bone marrow biopsy and aspirate. MM and stromal cells were isolated for analysis of STAT 3 activation to assess the treatment’s effect on stromal/MM cell interactions. Clinical responses were assessed using IBMTR criteria. RESULTS: 17 pts have been enrolled, ages 53––89, with median number of previous regimens 3 (range 1–6). Two pts were taken off study during the first cycle, one due to GI perforation occurring d 6 of therapy, and one pt due to rapidly progressive disease during first week of therapy. Ten pts have completed ≥ 4 cycles and can be evaluated for response. Seven of 10 pts achieved a PR after a median of two cycles and have maintained that response. One pt progressed after completing one cycle, one pt progressed after 5 cycles, and one pt had stable disease after 6 cycles. Expected grade 3 toxicities included DVT in 2 patients (both of whom were on aspirin but received erythropoiesis stimulating agents) and 2 pts developed shortness of breath attributed to bevacizumab, with resolved after discontinuation of the drug; one patient developed atrial fibrillation which spontaneously converted. No patient developed hypertension or proteinuria. Most required a dose reduction of lenalidomide due to fatigue. Analysis of STAT3 DNA-binding in MM cells alone or in co-culture with MM-BMSCs revealed variable low levels of constitutive STAT3 activity and enhanced activity in co-culture. No additional effect of bevacizumab + revlimid on constitutive STAT3 activity was observed. CONCLUSIONS: the combination of lenalidomide, bevacizumab and low dose dexamethasone has activity in relapsed and refractory myeloma. The initial 70% response rate compares favorably with the 58% response rate reported by Stadtmauer et al (Blood 108:3552) in previously treated MM pts receiving lenalidomide and high dose dexamethasone. Toxicities of this regimen are predictable but manageable. The use of ESAs may contribute to the development of DVT and the protocol has been modified to preclude their use.

Introduction: Mantle cell lymphoma has the poorest 5-year survival of all the non-Hodgkin’s lymphoma subtypes and appears incurable with standard therapies. High response rates are seen with CHOP plus rituximab (R), but the progression free survival (PFS) is disappointingly short (median 16–20 months). Favorable results have been reported for hyper-CVAD + R with midcycle high dose methotrexate and cytarabine, but this regimen can be prohibitively toxic for some patients. We hypothesized that eliminating methotrexate and cytarabine while adding R to the induction hyper-CVAD would produce high response rates with acceptable toxicity. We further hypothesized that adding R maintenance would prolong the PFS. Methods: Eligible patients had histologically confirmed CD20+ mantle cell lymphoma and could not have received more than 1 cycle of CHOP-like therapy for their disease prior to study entry. PS 0-2 was allowed. The treatment plan included rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1–3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1–2, vincristine 2 mg IV day 3, dexamethasone 40 mg po days 1–4, and G-CSF 5mg/kg/day starting after therapy until ANC ≥ 4000/mm3. Cycles were repeated every 28 days, up to 6 cycles. Patients achieving at least a PR received R maintenance therapy (375 mg/m2 IV weekly X 4 doses) every 6 months for 2 years. The accrual goal was 20 patients evaluable for response. Results: Enrollment is completed. All 22 patients are evaluable for toxicity, PFS, and OS and 20 patients evaluable for response rate (2 patients died before any restaging). Patient characteristics include 20/22 male, median age 63 (40–81), median IPI 3 (1–5), and 19/22 stage IV. All patients have completed the induction chemotherapy. Six patients have completed the R maintenance, 10 remain on R maintenance, and 6 patients came off study due to progressive disease (4) or death (2). The ORR is 85% (17/20) with 3 PR, 14 CR/CRu. With a median follow up of 22.5 months (range 4–45), the median PFS and OS have not been reached. The 2-year PFS is 73% (95% CI 50–89%) and the 2-year OS is 82% (95% CI 60–95%). Responses are ongoing in 16 patients, with response duration ranging from 2+ to 39+ months. The most common grade 3–4 toxicities in the 22 patients included neutropenia (10), anemia (5), thrombocytopenia (5), and infection (4). To date, five patients who participated in this study have died (1 treatment-related neutropenic fever, 1 post-surgical infection, 3 progressive disease). The major toxicity of this treatment regimen is expected hematologic toxicity. Conclusion: Modified hyper-CVAD with rituximab maintenance demonstrates ORR comparable to conventional hyper-CVAD (85% vs. 93%) and is less toxic, especially in patients over 60. Compared with published reports for R-CHOP, we observed higher CR rates (70% vs 34–48%) and considerably longer median PFS (not yet reached vs. 16–20 months). Longer follow up will better define the effectiveness of this regimen, but the encouraging results of this pilot study provide the basis for additional study in a larger setting.