Hyper-CVAD Plus Epratuzumab As Salvage Regimen for Younger Relapsed/Refractory CD22+ B Acute Lymphoblastic Leukemia (ALL) Patients: Results of the Phase 2 Prospective Cheprall Study

Abstract Purpose: Hyper-CVAD developed by the MD Anderson group a few years ago, is one of the standard salvage regimen used for younger relapsed/refractory ALL patients. Recently, targeted therapies using monoclonal antibodies directed against such surface antigens as CD19, CD20 or CD22 have allowed to obtain complete remission (CR) in B ALL expressing these markers. We hypothesized that combining Hyper-CVAD and an anti-CD22 monoclonal antibody could improve the response of such patients. Materials and Methods: This study evaluated the Cheprall salvage regimen, where epratuzumab, a humanized therapeutic monoclonal antibody against CD22 with mainly ADCC property, was associated to Hyper-CVAD, in younger patients (18-59 years old) with relapsed/refractory CD22+ (>30% of expression) B-ALL. Cheprall consisted of epratuzumab 360 mg/m²/d iv on days 1, 8, 15 and 22, cyclophosphamide 300 mg/m²/12h iv on days 1 to 3, vincristine 2 mg iv on days +4 and +11, doxorubicin 50 mg/m² iv on day +4 and dexamethasone 40 mg po on days 1 to 4 and 11 to 14. The main objective of the study was the overall response rate (CR + CR with incomplete platelets recovery (<100 000/mm3, CRp) + partial response (PR, >=50% of bone marrow (BM) blasts decrease or CR with persistent extramedulladory disease) evaluated between 4 and 6 weeks from day+1. Secondary objectives were overall (OS) and leukemia free (LFS) survivals and minimal residual disease (MRD) evaluated by flow cytometry. Results: Between January 2011 and April 2016, 31 patients from 11 French centres were enrolled in the study. A combination of epratuzumab + vincristine and dexamethasone (EVD) only was given to one patient subsequently excluded from the analysis. Among the 30 patients ultimately considered for analyses, 19 were males and the median age was 35 years (range: 21-59). The median time between diagnosis and Cheprall was 14.5 months (range: 4-130) and 13 patients had been allotransplanted. Disease status at time of Cheprall was as follows: primary refractory n=3; first relapse non treated n=13; refractory first relapse n=6, second relapse non treated n=7 and fourth relapse n=1. Median percentage of white blood cells and BM blasts were 4525/mm3(range: 90-86790) and 60% (range: 15-100), respectively. The median CD22 expression of BM blasts was 100% (range: 36-100). Four patients had extramedullary disease: breast n=2, parotid n=1, nervous central system n=1 (deviation). Cheprall was overall well tolerated including mostly pancytopenia as grade ¾ toxicities. Three patients died during aplasia (septis n=1; cerebral haemorrhage n=1, fusariosis n=1) and were not evaluable for response. The overall response rate was 50% (n=15) including 9 CR (30%), 1 CRp (3%) and 5 PR (17%). The number of CR/CRp was higher for patients in first non-treated relapse (54% vs 18%) with an age below 36 years (50% vs 14%), with <=50% of BM blasts (57% vs 26%) and with a delay between diagnosis and Cheprall > 18 months (54% vs 17%). Four out of 9 evaluated CR/CRp patients (45%) were documented with negative MRD. All patients in CR/CRp and 1 patient in PR received a consolidation consisting of a second cycle of Cheprall n=5, EVD n=5 or blinatumomab n=1. At the time of analysis (July 2016), all patients have died (during aplasia n=3, progression n=23, multiple organ failure n=1), except three responders still in CR, but yet recently enrolled (2015 n=1, 2016 n=2). Six patients received allogeneic transplant after Cheprall: 4 in CR2, 1 as salvage treatment and 1 in CR3. The last patient included and who achieved CR2 should be allografted in August 2016. Median OS was 3 months (range: 0.2-34.8). Median LFS for those achieving CR/CRp was 4.5 months (range: 1-12). Conclusion: Hyper-CVAD + epratuzumab allowed to obtain 50% of response in this cohort of patients at high risk of failure with refractory/relapsed younger CD22+ B-ALL. Disease improvement was however short-lived, which could be explained either by an insufficient disease load decrease and/or by escape of the blast cells to epratuzumab. This partial efficacy in a population of poor prognosis may suggest that epratuzumab should be tested within first-line chemotherapies as it may participate to decrease MRD level, especially before transplantation. The trial was registered at http://clinicaltrials.gov/ct no.NCT01219816. This study was supported by a grant from the French National Cancer Institute (PHRC 2010). Disclosures Huguet: Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Thomas:Pfizer: Consultancy. Goldenberg:Immunomedics: Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Wegener:Immunomedics: Employment, Honoraria.

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D.C.E.P. in Patients with Quad- or Penta-Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-117713 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2021-2021

Author(s):

Scott Goldsmith ◽

Mark A. Fiala ◽

Brandon B. Wang ◽

Mark A. Schroeder ◽

Tanya M. Wildes ◽

...

Keyword(s):

Multiple Myeloma ◽

Retrospective Study ◽

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Cell Transplant ◽

Advisory Committees ◽

Salvage Regimen ◽

Overall Response

Abstract Introduction: Despite the recent introduction of novel agents for multiple myeloma (MM), the disease remains incurable and invariably progresses through these new therapies. Patients with quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) and penta-refractory MM (refractory to an anti-CD38 monoclonal antibody as well) are left with few treatment options and poor prognoses. The chemotherapy regimen of dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) has demonstrated efficacy in the treatment of relapsed/refractory MM. We and others employ DCEP as a salvage regimen, however, few outcomes data exist in this heavily pretreated population. Methods: We conducted a retrospective study to identify all patients who received DCEP for quad- or penta-refractory MM at our institution between 2013 and 2018. Disease response and refractoriness were defined by IMWG criteria. The primary endpoint was overall response rate (ORR) defined as PR or better. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and duration of response (DOR). Results: We identified 31 patients who received DCEP, 8 (26%) for quad-refractory and 23 (74%) for penta-refractory MM (Table 1). Twenty-eight (90%) had at least one autologous stem cell transplant, and one had a prior allogeneic transplant. Sixteen (52%) were female, 27 (87%) were white, and median age at DCEP was 60. Median number of prior treatment regimens was 8. All patients received dexamethasone (40mg/day), cyclophosphamide (400mg/m2/day), etoposide (40mg/m2/day), and cisplatin (10mg/m2/day) on days 1-4 (Lazzarino et al. 2001). Cycles were generally 28 days in length, but doses were delayed in cases of cytopenias or other toxicities. Dose reductions occurred in cases of renal impairment or prolonged cytopenias. Twenty patients (65%) received more than one cycle (range: 1-5). The overall response rate was 35%. One patient achieved CR allowing him to proceed to a second autologous transplant. One patient achieved a VGPR, 9 (29%) a PR. Four of the 8 (50%) quad-refractory patients responded compared to 7 of the 23 (30%) of the penta-refractory patients. Eleven (35%) were primary refractory to DCEP, and two patients died after one cycle prior to response assessment. The overall median PFS was 2.7 months (95% CI 1.5-3.8) and median OS was 6.2 months (95% CI 4.4-7.8). For responders, median DOR was 4.2 months (95% CI 3.0-5.4) and median OS was 9.0 months (95% CI 7.2-10.9). Conclusion: Quad- and penta-refractory MM carry a grim prognosis. In our retrospective study, DCEP led to a notable ORR of 35% (95% CI 19%-55%) in this very heavily-treated population, and suggests that it remains a reasonable salvage therapy. Furthermore, it supports prospective study of this regimen, possibly in combination or in comparison with other agents effective in quad- or penta-refractory MM. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Bendamustine in Patients with Quad- and Penta-Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-112258 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5627-5627

Author(s):

Scott Goldsmith ◽

Mark A. Fiala ◽

Brandon B. Wang ◽

Mark A. Schroeder ◽

Tanya M. Wildes ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

Salvage Regimen ◽

Overall Response

Abstract Introduction: Despite significant advances in multiple myeloma (MM) therapy, disease progression through multiple novel treatments is often inevitable. Quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide), or penta-refractory MM (refractory to an anti-CD38 monoclonal antibody as well) portends a poor prognosis, with few subsequent lines of treatment currently available. We and others have used bendamustine combined with corticosteroids as a salvage regimen, but there is a paucity of outcomes data in this heavily pretreated population. Methods: We conducted a retrospective study to identify all patients who received bendamustine with corticosteroids for quad- or penta-refractory MM at our institution between 2013 and 2018. Disease response and refractoriness were defined by IMWG criteria. The primary endpoint was overall response rate (ORR) defined as PR or better. Secondary endpoints included overall survival (OS) and duration of response (DOR). Results: Twenty-seven patients were identified; 5 patients were quad-refractory, and 22 penta-refractory (Table 1). Twenty-two (81%) patients had at least one prior autologous stem cell transplant and 1 had a prior allogeneic. The median age at time of bendamustine was 61, 52% were female, and 85% were white. All patients received bendamustine at a dose of 90mg/m2 on days 1 and 2 of a 28 day cycle. Twelve patients (44%) received more than one cycle (range: 1-8). The overall response rate was 26%. While no patient achieved CR, 4 achieved VGPR and 3 a PR. Two of the 5 (40%) quad-refractory patients responded compared to 5 of the 22 (23%) penta-refractory. Sixteen (59%) were primary refractory to bendamustine and one patient went onto hospice prior to response evaluation. Overall the median PFS was 1.4 months (95% CI 1.1-1.6) and median OS was 8.7 months (95% CI 2.3-15.0). For responders (≥PR), median DOR was 6.6 months (95% CI 0.0-13.7) and median OS was 14.0 months (95% CI 0.6-27.4). Conclusion: The prognosis of quad- and penta-refractory MM remains poor. In this heavily pre-treated population, bendamustine demonstrates a 26% ORR (95% CI 11%-46%). The DOR and OS of the patients was poor but highly heterogeneous. Those who did respond to bendamustine had notably improved OS. Given the limited available options for quad- and penta-refractory MM, bendamustine remains a reasonable salvage therapy. Prospective trials are warranted perhaps including additional agents that are effective in penta-refractory patients. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase II Trial of the Oral mTOR Inhibitor Everolimus (RAD001) in Relapsed or Refractory Waldenstrom's Macroglobulinemia.

Blood ◽

10.1182/blood.v114.22.587.587 ◽

2009 ◽

Vol 114 (22) ◽

pp. 587-587

Author(s):

Irene M Ghobrial ◽

Morie A Gertz ◽

Betsy LaPlant ◽

John Camoriano ◽

Suzanne R. Hayman ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Single Agent ◽

Waldenström’S Macroglobulinemia ◽

Advisory Committees ◽

Overall Response ◽

Waldenstrom's Macroglobulinemia ◽

Waldenström's Macroglobulinemia

Abstract Abstract 587 Background: The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway controls cell proliferation and survival. Everolimus is an oral agent targeting raptor mTOR (mTORC1). The trial's goal was to determine the anti-tumor activity and safety of single-agent everolimus in patients with relapsed/refractory Waldenstrom's macroglobulinemia (WM). Patients and Methods: Eligible patients had measurable disease (IgM monoclonal protein >1000 mg/dL with >10% marrow involvement or nodal masses >2 cm), a platelet count ≥75,000 × 106/L, a neutrophil count ≥1,000 × 106/L, and a creatinine and bilirubin ≤2x laboratory upper limit of normal. Patients received everolimus 10 mg PO daily and were evaluated monthly. Tumor response was assessed after cycles 2 and 6 and then every 3 cycles until progression. Results: 50 pts were treated. The median age was 63 years (range, 43-85). The overall response rate (CR+PR+MR) was 70% (95% CI: 55-82%), with a PR of 42% and 28% MR. The median duration of response and median progression-free survival (PFS) has not been reached. The estimated PFS at 6 and 12 months is 75% (95%CI: 64-89%) and 62% (95%CI: 48-80%), respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematological toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients. Dose reductions due to toxicity occurred in 52% of patients. Conclusions: Everolimus has high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM, and offers a potential new therapeutic strategy for this patient group. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Treon:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Honoraria, Research Funding, Speakers Bureau. Witzig:Novartis: Research Funding.

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Interim Results of An Ongoing Clinical Study Suggests Efficacy and Improved Toxicity Profile with Once a Week Bortezomib with Dexamethasone In Newly Diagnosed Multiple Myeloma Patients with Older Age and Co-Morbidities

Blood ◽

10.1182/blood.v116.21.3061.3061 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3061-3061 ◽

Cited By ~ 1

Author(s):

Nikhil C. Munshi ◽

Saem Lee ◽

Suman Kambhampati ◽

Abid Mohiuddin ◽

Michal Rose ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Overall Response Rate ◽

Response Rate ◽

Previous History ◽

Cell Transplant ◽

Newly Diagnosed ◽

Advisory Committees ◽

Current Time ◽

Overall Response

Abstract Abstract 3061 The current bortezomib schedule involves administration of the drug twice a week at 1.3 mg/m2 for 2 weeks every 21 days. This regimen although effective is inconvenient and associated with side effects including neuropathy and gastrointestinal toxicities that limits its use in a proportion of patients. Therefore, to improve convenience and compliance, we have investigated efficacy and safety of a weekly regimen of bortezomib. In this one-stage phase II multi-center, open-label single-arm study bortezomib is administered once a week at 1.6 mg/m2 in combination with dexamethasone in newly-diagnosed multiple myeloma patients not considered for autologous stem cell transplant in participating Veterans Hospitals nationwide. The objective is to evaluate overall response rate and toxicity of this regimen. Patients received bortezomib at 1.6 mg/m2 IV weekly for 4 weeks followed by 1 week off and dexamethasone 40mg PO on the day of and day after each dose of bortezomib. Patients may receive 6 such 5-week cycles. At the current time 32 patients (median age - 73; range 50–88) have been enrolled at 11 Veterans Administration Hospital across the U.S. Patients had significant co-morbidities including 61% with cardiovascular problems, 58% with diabetes and/or hyperlipidemia, 58% with elevation of serum creatinine, 26% with respiratory problems and 23% with previous history of cancer. All patients were at least on 5 daily medications. Of the 32 patients enrolled, 25 patients have received at least one cycle of therapy and were evaluable for toxicity and efficacy, while 6 patients have received less than one cycle of therapy and one patient has inadequate data. With a median of 4 cycles administered, this regimen was well tolerated. None of the patients have developed grade 3 neuropathy, while grade 1 neuropathy was observed only in 2 patients and one patient with grade 1 neuropathy at diagnosis had increase to grade 2. Dexamethasone dose was reduced in 29% patients while 6% required reduction in bortezomib dose to 1.3 mg/m2. Additionally, Grade ≥1 asthenia was observed in 42%, diarrhea in 35%, and thrombocytopenia in 26%. Four patients have died of co-morbidities which were considered unrelated or probably unrelated to the treatment with bortezomib. The partial response or better was achieved in 68% patients receiving at least 1 cycle of therapy; 20% patients achieved CR/nCR and additional 12% achieved VGPR. Including MR in the analysis, overall response was observed in all evaluable patients. On intent to treat analysis including all 32 patients, overall response rate (≥ MR) was observed in 78% patients and PR or better in 53% patients. These preliminary results suggest that the once a week bortezomib regimen is effective and tolerable with reduced toxicity even in this older patient population with significant co-morbidities. Disclosures: Munshi: Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roodman:Millennium: Consultancy; Amgen: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria.

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A Multi-Center, Open-Label Phase II Study of Lenalidomide Plus Low-Dose Dexamethasone in Chinese Patients with Relapsed/Refractory Multiple Myeloma - the MM-021 Trial

Blood ◽

10.1182/blood.v120.21.1864.1864 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1864-1864

Author(s):

Jian Hou ◽

Jie Jin ◽

Zhen Cai ◽

Fangping Chen ◽

Li Yu ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Chinese Patients ◽

Open Label ◽

Advisory Committees ◽

Overall Response ◽

Best Response

Abstract Abstract 1864 Background: Previous studies (i.e. ECOG E4A03) have shown that lenalidomide plus low-dose dexamethasone (Rd) has a better safety profile compared with lenalidomide plus high-dose dexamethasone (RD) in newly diagnosed MM patients. It is hypothesized that Rd may also provide benefits in patients with relapsed/refractory multiple myeloma (RRMM). The MM-021 trial is the largest study in Chinese patients with RRMM aimed to assess the efficacy, safety, and pharmacokinetics (PK) of Rd in patients who had progressed or were refractory to previous treatment. Methods: This was a phase II, multi-center, single arm, open-label study, RRMM patients received lenalidomide (25 mg/day on days 1–21) and dexamethasone (40 mg on days 1, 8, 15 and 22) in 28-day treatment cycles until disease progression. Thromboembolic prophylaxis with aspirin or other anti-thrombotic medication was required. The primary endpoint was the best overall response rate (partial response [PR] or better) based on the investigator's assessment. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), safety, and PK parameters. Results: As of April 23, 2012 (median follow-up of 10.8 months), 199 patients have completed at least 1 cycle, 134 patients have completed at least 6 cycles, and 187 patients were evaluable for efficacy. Median age was 59 years (range 35–81) and 63% were male. The majority of patients (86%) had Durie-Salmon stage III disease and 57% had received ≥4 prior anti-myeloma regimens including bortezomib (64%), thalidomide (69%), or both bortezomib and thalidomide (45%). After median treatment duration of 8 months (range 1–18) or 8 cycles (range 1–19), best overall response rate (≥PR) was 54% (100 patients); including 8% (14 patients) with a best response of complete response (CR). Overall disease control (≥stable disease [SD] or better) was 95%, including 42% (78 patients) with best response of SD. Nine patients (5%) had best response of disease progression. Best overall response rates were consistent across subgroups when analyzed according to baseline renal function (creatinine clearance ≥60 mL/min: 68 patients [54%], 330 to <60 mL/min: 26 patients [52%], <30 mL/min: 6 patients [50%]) and number of prior therapies (64% if ≤2 prior regimens, 50% if >2 prior regimens). Responses were also consistent regardless of prior therapy received; 50%, 52%, and 47% for patients who previously received bortezomib, thalidomide, or both, respectively. Of the 5% (10 patients) presenting with IgD at baseline, 7 patients achieved ≥PR. Median time to first response was 2 months (range 1–12) and median duration of response was 7 months (range 0–16). The median PFS was 8 months (95% CI: 6–9) and the OS rate was 86% at 6 months and 73% at 1 year. Among the 199 patients evaluable for safety, the most common grade 3–4 adverse events (AEs) were anemia (25%), neutropenia (24%), thrombocytopenia (15%), and pneumonia (13%). Only 1 patient experienced febrile neutropenia. AEs led to dose reduction/interruption of lenalidomide in 40% of patients, 41% for dexamethasone; and 6.5% discontinued treatment due to one or more AEs. No patient discontinued due to anemia or neutropenia. Sixty-one patients (31%) died on study and the most common cause of death was disease progression (15 patients, 8%). Conclusions: Based on a median follow-up of nearly 11 months, the Rd regimen achieved a substantial best overall response rate (54%) in heavily pretreated RRMM Chinese patients. Response rates were consistent across subgroups including patients with renal impairment. The combination of Rd regimen was generally well tolerated. Disclosures: Hou: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Xian: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jensen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mei:Celgene Corporation: Employment. Zhang:Celgene Corporation: Employment. Wortman-Vayn:Celgene Corporation: Employment.

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Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and Refractory Myeloma: Results of a Multicenter Randomized Phase II Study

Blood ◽

10.1182/blood.v124.21.303.303 ◽

2014 ◽

Vol 124 (21) ◽

pp. 303-303 ◽

Cited By ~ 6

Author(s):

Rachid Baz ◽

Thomas G. Martin ◽

Melissa Alsina ◽

Kenneth H. Shain ◽

Hearn J. Cho ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Advisory Committees ◽

Overall Response ◽

Best Response ◽

Randomized Phase Ii ◽

Grade 3

Abstract Background: Pomalidomide-dexamethasone results in an overall response rate of 33% and median PFS of 4.2 months in patients with prior lenalidomide and bortezomib (Richardson et al. Blood 2014). In this randomized phase II trial, we compared pomalidomide-dexamethasone (arm B) versus the addition of oral weekly cyclophosphamide to pomalidomide-dexamethasone (arm C) in patients with lenalidomide-refractory multiple myeloma (MM). We have previously reported that the recommended phase II dose of cyclophosphamide with standard-dose pomalidomide + dexamethasone was 400 mg PO D1, 8, 15. Patients and Methods: Eligible patients had relapsed and refractory MM after at least 2 prior therapies and were lenalidomide refractory. Patients had a platelet count ≥ 50,000/mm3 and ANC ≥ 1,000/mm3 (patients with ≥50% bone marrow plasmacytosis were allowed if platelet count was ≥ 30,000/mm3and ANC could be supported with GCSF during screening and therapy). Patients were randomized (1:1) to receive pomalidomide 4 mg PO D1-21 and dexamethasone 40 mg PO D1, 8, 15, 22 (20 mg if older than 75 years) (arm B) with or without oral cyclophosphamide 400 mg PO D1, 8, 15 of a 28-day cycle (arm C). Patients randomized to arm B were allowed to cross over to arm C in the event of disease progression. Thromboprophylaxis was mandated with aspirin, warfarin, or LMWH. The primary endpoint was overall response rate using IMWG criteria. Secondary endpoints included an evaluation of PFS, OS and safety of the two arms. Results: Between 7/2012 and 3/2014, 36 patients were randomized to arm B and 34 to arm C. Patients characteristics were not different between the 2 arms (table below). The median number of prior therapies was 4 (2-12). All patients were lenalidomide refractory and none received prior pomalidomide. After a median follow up of 15 months, the overall response rate (partial response or better) was 39% and 65% (p=0.03) for arm B and C, respectively. The clinical benefit rate (minimal response or better) was 64% and 79% (p=0.2) for arm B and C, respectively. The median PFS was 4.4 months (95% CI 2.3-5.9) for arm B and 9.2 months (95% CI 4.6-16) for arm C (log rank p=0.04). As of July 2014, 28 patients had died (16 arm B, 12 arm C) with median overall survival of 10.5 versus 16.4 months (p=0.08) for arm B and C, respectively. Hematologic grade 3/4 adverse events were more frequent in arm C, although this was not statistically significant (see table). Thirteen patients crossed over and oral weekly cyclophosphamide was added to their tolerated dose of pomalidomide dexamethasone. For those patients, the best response was as follows: 2 PR, 2 MR, and 6 SD, 3 PD. Conclusions: Pomalidomide-dexamethasone in combination with oral weekly cyclophosphamide resulted in a superior response rate and PFS compared to pomalidomide-dexamethasone alone in patients with relapsed and refractory MM. The increased hematologic toxicities, as a result of the addition of oral cyclophosphamide, were manageable. Table Arm B (N=36) Arm C (N=34) P value Age, years, median (range) 63 (50-78) 64 (47-80) 0.7 Male, n (%) 23 (64) 18 (53) 0.3 Number of prior therapies, median (range) 4 (2-12) 4 (2-9) 0.5 Bortezomib refractory, n (%) 28 (78) 24 (71) 0.3 Carfilzomib refractory, n (%) 16 (44) 13 (38) 0.5 Prior high-dose therapy, n (%) 27 (75) 28 (82) 0.6 Prior alkylating agent, n (%) 32 (89) 32 (94) 1 B2-microglobulin, median (range) 3.2 (1.6-10) 3.6 (1.5-13.9) 0.5 Serum creatinine, median (range) 1 (0.5-2.3) 0.9 (0.6-2.1) 0.6 High-risk cytogenetics, n (%) 5 (24) 6 (28) 0.8 Deletion 17p, n (%) 3 (14) 4 (20) 0.8 t(4;14), n (%) 3 (14) 3 (14) 0.9 Trisomy or tetrasomy 1q, n (%) 11 (55) 6 (33) 0.4 Best response (partial response or better), n (%) 14 (39) 22 (65) 0.03 Clinical benefit rate (MR or better), n (%) 23 (64) 27 (79) 0.2 Grade 3/4 neutropenia, n (%) 12 (33) 17 (50) 0.2 Grade 3/4 febrile neutropenia, n (%) 4 (11) 6 (18) 0.5 Grade 3/4 thrombocytopenia, n (%) 2 (5) 5 (15) 0.2 Grade 3/4 anemia, n (%) 3 (8) 7 (20) 0.2 Grade 3/4 pneumonia, n (%) 4 (11) 3 (9) 1 Grade 3/4 fatigue, n (%) 2 (5) 4 (12) 0.4 Number of serious adverse events 17 20 Disclosures Baz: Celgene: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Karypharm: Research Funding; Sanofi: Research Funding. Off Label Use: Pomalidomide cyclophosphamide dexamethasone in relapsed refractory myeloma. Martin:Sanofi: Research Funding; Novartis: Speakers Bureau. Alsina:Triphase: Research Funding; Millenium: Research Funding. Shain:Onyx / Amgen: Research Funding; Treshold: Research Funding. Chari:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Honoraria; Millennium: Honoraria; Sanofi: Honoraria.

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Phase 1/1b Study of the Efficacy and Safety of the Combination of Panobinostat + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.4081.4081 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4081-4081 ◽

Cited By ~ 6

Author(s):

Jatin J. Shah ◽

Sheeba K. Thomas ◽

Donna M. Weber ◽

Michael Wang ◽

Raymond Alexanian ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Single Agent ◽

Advisory Committees ◽

Overall Response ◽

Elevated Creatinine

Abstract Abstract 4081 Background: Carfilzomib, a novel irreversible proteasome inhibitor (PI), has demonstrated single agent activity in, and was recently FDA approved for relapsed and refractory myeloma. Panobinostat, a potent histone deacetylase inhibitor (HDACi), has been studied as a single agent and in combination with bortezomib, demonstrating promising response rates and a favorable safety profile in bortezomib-refractory patients. Our hypothesis proposed that the combination of carfilzomib and panobinostat (Car-Pan) would also be highly active, and we therefore aimed to combine these two agents for the first time. We report the initial findings from the phase I dose-escalation and expansion portions of our phase I/II trial of this novel combination regimen. Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of Car-Pan in patients with relapsed or refractory multiple myeloma. Secondary objectives included determination of the overall response rate, time to progression, progression free survival, and time to next therapy. Panobinostat was administered orally on days 1, 3, 5, 8, 10, 12 of every 28-day cycle, while carfilzomib was given intravenously over 30 minutes on days 1, 2, 8, 9, 15, and 16. Dose level 1 started carfilzomib at 20 mg/m2 with 15 mg of panobinostat, and escalated from there using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. An amendment was later introduced to allow carfilzomib to be given at 20 mg/m2for days 1 and 2 of cycle 1, followed by an increase to the full dose level for that cohort. Adverse events (AEs) were graded using the NCI-CTCAE v4, and responses were assessed with the modified International Uniform Response Criteria. Results: To date, 20 patients have been enrolled, 3 of whom are still in their first cycle, leaving 17 evaluable patients who are described herein, who have received a median of 4 cycles (range 1–8). The median age was 62 years (range 46–73), 11/17 (70%) were male, and the median number of prior regimens was 5 (range 2–15). Patients were very heavily pretreated, with 16/17 (94%) having undergone stem cell transplantation, 16/17 (94%) having prior bortezomib, including 8/17 (47%) who were bortezomib-refractory, and 17/17 (100%) having prior lenalidomide, including 12/17 (70%) who were lenalidomide-refractory. Cytogenetic abnormalities were common, including: 4 with del(17p), 4 with t(4;14), 2 with t(11;14), 9 with del(13), of whom 7 had additional mutations. Grade 1–4 AEs regardless of causality occurring in >20% of patients included anemia (14/17), thrombocytopenia (17/17), neutropenia (8/17), diarrhea (9/17), nausea/emesis (7/17), fatigue (10/17), elevated creatinine (8/17), and pneumonia (5/17). Grade ≥3 AEs regardless of causality included anemia (7/17), thrombocytopenia (10/17), neutropenia (6/17), diarrhea (2/17), nausea/emesis (1/17), fatigue (4/17), elevated creatinine (2/17), and pneumonia (4/17). An MTD has not been established, and dosing is ongoing in cohort 4, with Carfilzomib at 45mg/m2and 20 mg of Panobinostat. Of the 17 evaluable patients, the overall response rate was 35% (6/17) who achieved at least a partial response (PR); including 2 with very good PR (VGPR). In addition, one patient had a minor response, and 65% overall achieved stable disease or better. Conclusions: The combination of Carfilzomib + Panobinostat is well tolerated with a manageable side effect profile. Importantly, the combination achieves a promising response rate in a very heavily pre-treated, lenalidomide/bortezomib/high dose melphalan-refractory population, with an overall response (≥PR) rate of 35%. Updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about panobinostat, which is not yet approved for use in patients with multiple myeloma. Thomas:Celgene: Research Funding; Millenium: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Johnson & Johnson: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees. Wang:Onyx Pharmaceuticals: Honoraria, Research Funding. Orlowski:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Final Results of the Phase I/II Trial of Weekly Bortezomib In Combination with Temsirolimus (CCI-779) In Relapsed or Relapsed/Refractory Multiple Myeloma Specifically In Patients Refractory to Bortezomib

Blood ◽

10.1182/blood.v116.21.990.990 ◽

2010 ◽

Vol 116 (21) ◽

pp. 990-990 ◽

Cited By ~ 5

Author(s):

Irene M. Ghobrial ◽

Edie Weller ◽

Ravi Vij ◽

Nikhil C. Munshi ◽

Ranjit Banwait ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Phase I Study ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Advisory Committees ◽

Overall Response ◽

Phase I And Ii

Abstract Abstract 990 Introduction: This study aimed to determine activity and safety of weekly bortezomib (Takeda Inc) and temsirolimus (Pfizer Inc) in patients with relapsed/refractory Multiple Myeloma (MM). Methods: Eligibility criteria included: 1) patients with relapsed or relapsed/refractory MM with any prior lines of therapy including bortezomib, 2) no chemotherapy within 3 weeks, or biological/novel therapy within 2 weeks. Primary endpoint was the percent of patients with at least a minimal response (MR). Results: Twenty patients were enrolled on the phase I study and 43 on the phase II study. The MTD was determined at 1.6 mg/m2 bortezomib Days 1, 8, 15, and 22 every 35 days in combination with 25 mg IV temsirolimus Days 1, 8, 15, 22, and 29 every 35 days. Twenty % were stage III by ISS staging system in the phase I, and 21% in the phase II. The overall response rate of MR or better in the Phase II study was 20/43 (47%, 95%CI: 33,60), with 5% CR, 9% VGPR, 19% PR and 14% MR. Progression without any response occurred in just 1 patient (3%). One patient had an unconfirmed PR, but was included in the stable disease category. An additional 3 (6%) patients were unevaluable in the phase II trial because they did not complete their first cycle of therapy and had no follow up laboratory results for response. If these patients are excluded, the ORR including MR improves to 50% (95% CI: 36,64). The overall response rate in the phase I study was 20% with responses occurring in all the stages of the dose escalation. If three patients who were unevaluable in the phase I trial are excluded, then the response rate of evaluable phase I patients is 24% (95% CI: 9,46). Response was also evaluated by whether patients were bortezomib-refractory or not. These were defined as progressing while on therapy or progressing within 60 days of completing bortezomib therapy. Fifty-one patients had received bortezomib as part of prior treatment. Of these patients, 32 were refractory to bortezomib therapy immediately prior to study entry, and an additional 2 pts were refractory at prior time points. Responses observed among the 32 patients refractory to their most recent bortezomib therapy include 3 PR and 3 MR (ORR: 19%, 95% CI: 9,34). Another 21 patients had SD, 2 PD and 3 patients were unevaluable. Of the evaluable patients, the ORR was 6/29 (21%). Responses observed among the 19 patients who were not refractory to their last bortezomib treatment include 2 VGPR, 5 PR and 3 MR with 6 patients with SD, 0 PD and 3 unevaluable. The ORR among the evaluable patients who received bortezomib but were not refractory was 62%. Median time to response of MR or better (min, max) among all patients was 1.7 months (0.5,14.2) and among phase II patients 1.3 months (0.5,8.0). Median duration of MR or better (min, max) among all patients is 5.2 months (0.5,15.8) and among phase II patients is 4.6 months (0.5,10.8). Median duration of PR or better response (min, max) among all patients is 6.0 months (1.8,15.8) and among phase II patients is 5.2 months (1.8,10.8). The median time to progression for all patients in the phase I and II studies was 7.3 months (95% CI: 5.7 –17.2) and the median progression free survival was 6.4 months (95% CI: 4.8–7.4). The median overall survival in all phase I and II patients was 11.4 months (95%CI: 8.6-undetermined). Three deaths occurred during therapy in the phase I and II studies, 1 of septic shock, 1 with H1N1 infection, and 1 with cardiac amyloid and ventricular arrhythmia. The most common G1-4 toxicities that occurred in > 25% of patients included cytopenias, hypertrigyceridemia and diarrhea. Grade 3 and 4 thrombocytopenia occurred in 48% of patients in the phase I and II studies, G3 and 4 neutropenia occurred in 36%, and anemia in 26% of phase I and II patients. G3 and 4 hypertriglyceridemia occurred in 5% and diarrhea in 9%. Peripheral neuropathy (PN) was rare with no G3 or 4 neuropathy reported. Overall, there was 34% grade 1 and 2 PN seen. Conclusions: The combination of weekly bortezomib and temsirolimus showed an encouraging response rate in heavily pretreated patients with relapsed or refractory MM, with an overall response rate in evaluable patients as part of the phase II portion of the trial of 50%, and a 21% ORR including MR or better in evaluable bortezomib refractory patients. Cytopenias were the most common toxicities, specifically thrombocytopenia, as well as GI toxicity, with side effects proving manageable. Significant PN was rare in this study. Disclosures: Ghobrial: Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Vij:Novartis: Honoraria; Eisai: Speakers Bureau. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.

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Management of Post-Transplant Lymphoproliferative Disorders in the Real Life: The French Attitude Between 2010 and 2013

Blood ◽

10.1182/blood.v128.22.4230.4230 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4230-4230

Author(s):

Inès Boussen ◽

Caroline Algrin ◽

Julien Rossignol ◽

Eric Durot ◽

Sarah Guenounou ◽

...

Keyword(s):

Board Of Directors ◽

Overall Response Rate ◽

Response Rate ◽

Chop Chemotherapy ◽

First Line ◽

Advisory Committees ◽

Overall Response ◽

National Expert ◽

Expert Network

Abstract Introduction Post-transplant lymphoproliferative disorders (PTLD) are a rare but severe complication occurring after organ transplantation as a result of immunosuppressive therapy (IST). Until recently, there was no consensus regarding best treatment practice. In 2006, a phase 2 trial using a monotherapy with rituximab showed an overall response rate of 44%, with a complete response (CR) rate of 28%. In 2012, the PTLD-1 international multicenter trial evaluating rituximab followed by CHOP chemotherapy proved an efficacy of 90% and an overall survival of 6.6 years in PTLD treatment. K-virogref is a French national expert network created in 2011 to structure and improve the management of viro-induced cancers, occurring in adult after transplantation, including PTLD. Within this network, an epidemiological observational study has been set up in September 2013. The aim of our study was to analyze the management of PTLD in France before the creation of the national database of K-virogref. Patients and methods We included solid organ or allogeneic stem cell recipients, aged 18 years and above, with a histologically proven PTLD, diagnosed between January 2010 and September 2013 in 19 French hematology departments. We collected from clinical charts data regarding transplant characteristics, PTLD presentation, first-line treatment and outcomes. Results The study population consisted of 94 patients, 67% were men and median age was 53 years (ranging 18 - 81 years). The majority of patients received kidney transplantation (54%), followed in almost equal proportion by heart (13%), liver (13%) and allogeneic stem cell transplantation (10%). Most of the time (80% of patients), PTLD occurred more than one year after organ transplantation with a median delay of 7.8 years. Histologically, mainly monomorphic PTLD were observed with 66% of diffuse large B cell lymphoma and PTLD was EBV associated in 54%. At the time of diagnosis, 80% were classified as stage IV according to Ann Arbor. The median follow-up time was 28.3 months (ranging 0.2 - 78 months). As far as treatment is concerned, modification of IST was performed in 68% of patients but response was rarely evaluable because a specific treatment was often started at the same time. Surprisingly, first line treatment consisted in rituximab alone or rituximab followed by CHOP chemotherapy in only 32% of the patients. Among these patients, the overall response rate was 81% with 55% of CR. Most patients (56%) received chemotherapy (n=11) or immunochemotherapy (n=46) without previous rituximab therapy. For these patients the overall response rate was 71% with a CR rate of 53%. At 1 and 3 years of follow-up, the relapse-free rates were 56% (95% confidence interval (CI) 46% - 68%) and 47% (95% CI 37% - 60%), respectively. Overall, 49% of patients died during follow-up of which 37% due to infectious complications and 32% due to PTLD progression. Conclusion This is one of the largest cohort study of PTLD in the literature, providing an overview of epidemiological features, treatments and outcomes of this rare disease. The lag between the management of PTLD and literature data emphasizes the usefulness of a national expert network such as K-virogref in order to generalize a less toxic and more powerful attitude. Disclosures Leblond: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Choquet:Celgene: Consultancy; Janssen: Consultancy.

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Lenalidomide, Bortezomib, and Dexamethasone (RVD) in Combination with Vorinostat As Front-Line Therapy for Patients with Multiple Myeloma (MM): Results of a Phase 1 Study

Blood ◽

10.1182/blood.v120.21.336.336 ◽

2012 ◽

Vol 120 (21) ◽

pp. 336-336 ◽

Cited By ~ 6

Author(s):

Jonathan L. Kaufman ◽

Jatin J. Shah ◽

Jacob P. Laubach ◽

Alaina R. Mitchell ◽

Cathy Sharp ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Cardiopulmonary Arrest ◽

Hematologic Toxicity ◽

Cell Transplant ◽

Newly Diagnosed ◽

Advisory Committees ◽

Overall Response

Abstract Abstract 336 Background: The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate (Richardson et al, Blood 2010; Kumar et al, Blood 2012). The addition of a novel targeted agent to RVD may improve depth of response as reflected by an increase in complete remission (CR) rate. Preclinical studies have demonstrated that vorinostat (Vor), a histone deacetylase inhibitor, is synergistic with bortezomib, immunomodulatory compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study was to determine the tolerability and activity of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM. Methods: Patients (pts) received the classical RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5–8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. Dose limiting toxicity (DLT) (Grade (G) 3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of neutrophils to 1,000/μL or platelets to 50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified European Group for Blood and Marrow Transplantation and Uniform Criteria. Pts with partial remission (PR) or better could proceed to autologous transplant after 4 cycles. After completion of 8 cycles, patients could continue maintenance with lenalidomide +/− bortezomib, with Vor not administered during maintenance therapy. Results: Thirty pts (median age 56 years [range 40–76], 63% men) were enrolled with 4 pts in cohort 1 (Vor 100mg), 15 pts in cohort 2 (Vor 200mg), 8 pts in cohort 3 (Vor 300 mg) and 3 pts in cohort 4 (Vor 400mg). The maximum tolerated dose was determined to be 200 mg Vor with RVD. Including maintenance, the median number of cycles completed was 4 (range <1 to 41) with 5 pts completing less than 4 cycles, 4 because of toxicity and one for non-compliance. Ten patients completed 4 cycles and discontinued study therapy and proceeded to autologous stem cell transplant. Eleven pts completed 8 cycles with 8 pts remaining on study having completed between 4 and 41 cycles. Five DLTs have occurred, one in cohort 1 (syncope), one in cohort 2 (venous thromboembolism [VTE]) and 3 in cohort 4 (reversible G4 thrombocytopenia without bleeding; G3 reversible, asymptomatic elevated transaminases and G5 cardiopulmonary arrest, suspected to be due to VTE but not confirmed). The most common G1 or higher toxicities included thrombocytopenia (n=30), constipation (n=25), diarrhea (n=20), fatigue (n=19), nausea (n=16), and neuropathy (n=8). Grade 3 toxicities that occurred in 10% or more of pts were thrombocytopenia (n=8), fatigue (n=5), neutropenia (n=3), cardiovascular (n=3) and neuropathy (n=3). The overall response rate (PR or better) was 100% for the 29 evaluable pts, with a very good PR (VGPR) or better of 52% and a CR rate of 28%. For those pts who completed 4 cycles, VGPR and CR rates were 60% and 32% respectively and for pts who completed 8 cycles, the rates were 64% (VGPR) and 55% (CR). At a median follow up of 11.5 months (range 1 – 31 months) there has been only one pt with progressive disease (asymptomatic relapse from CR). Conclusion: The combination of RVD with vorinostat using the classical dose and schedule proved most tolerable at 200mg Vor dosing D1-14 every 21 days. The remarkably high VGPR/CR rate after 4 cycles and favorable progression free survival suggest that this combination is very effective. Alternative dosing and schedule of Vor may improve tolerability and so enhance clinical benefit, thus warranting further study. Disclosures: Kaufman: Onyx: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Merck: Research Funding. Off Label Use: use of vorinostat in myeloma; use of lenalidomide as induction. Shah:Novartis: Honoraria, Research Funding, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harvey:Celgene: Research Funding. Heffner:Millenium: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Orlowski:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck; all < $10,000 per year and disclosed to my institution: Consultancy.

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