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

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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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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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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Belinostat Induces High Overall Response Rate (ORR) in Patients with Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL)

Blood ◽

10.1182/blood-2019-127155 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4050-4050

Author(s):

Ahmed Sawas ◽

Helen Ma ◽

Andrei Shustov ◽

Pamela Hsu ◽

Gajanan Bhat ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Cell Lymphoma ◽

Single Agent ◽

T Cell Lymphoma ◽

Advisory Committees ◽

Overall Response

Background: Angioimmunoblastic T-cell lymphoma (AITL) is a relatively common subtype of peripheral T-cell lymphoma (PTCL) that typically presents with lymphadenopathy, extranodal disease, including rash, and is associated with frequent infections due to immune dysregulation. Patients with AITL generally have a poor prognosis, even with aggressive chemotherapy as responses to standard chemotherapy are often suboptimal. Recent advances in cancer biology suggest that AITL is derived from T-follicular helper cells and is often characterized by gross epigenetic dysregulation. Histone deacetylase (HDAC) inhibitors have demonstrated significant activity in T-cell neoplasms. The BELIEF trial established an overall response rate of 25% in patients with relapsed/refractory PTCL who were treated with belinostat, with a duration of response of about 1 year, leading to accelerated approval. Herein, we present a subset analysis of the data for patients with AITL. Methods: Patients with histologically confirmed PTCL (N = 129) who experienced failure with or refractory to ≥ 1 prior systemic therapy received belinostat 1,000 mg/m(2) as daily 30-minute infusions on days 1 to 5 every 21 days. Central assessment of response used International Working Group criteria. Primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DoR) and progression-free and overall survival (PFS). Results: Of 129 patients, 22 patients had AITL; most had advanced disease (91% stage III/IV; 36% with bone marrow involvement). The median number of prior therapies was 2 (range, 1-5), and 3 (14%) patients were refractory to their last line of therapy. The ORR for patients with AITL was 46% (10/22; 95%CI: 24 - 68%), with a complete response (CR) in 4 of 22 patients (18%). Of the ten responders, the median time to response of 11.3 weeks (range, 4.7 - 24.4 weeks) in the AITL subgroup. After a median follow up of 21.5 months, the median PFS was 4.2 months (95%CI: 1.5 -13.9) and the median DOR was 13.6 months (95%CI: 1.4 - 29.4) as shown in Figure 1. For all patients with AITL treated with belinostat, the median OS was 9.2 months (95%CI: 6.8 - 21.5). The most common grade 3 to 4 adverse events were asthenia (n=2), fatigue (n=2), anemia (n=2), thrombocytopenia (n=2), neutropenia (n=2), and septic shock (n=2). Conclusions: Single-agent belinostat induced rapid and durable responses in patients with relapsed/refractory AITL. At the end of the study, there were 37% patients with ongoing responses at 2 years. Patients with clinical benefit from belinostat continued treatment until progression of disease. These results support the use of belinostat in relapsed/refractory AITL as a single agent and provide rationale for combination therapies in clinical trials. Disclosures Sawas: Seattle Genetics, Gilead, Daiichi Sanko: Consultancy; Affimed: Research Funding. Shustov:Spectrum Pharmaceuticals: Consultancy, Research Funding. Hsu:Spectrum Pharmaceuticals: Employment. Bhat:Spectrum Pharmaceuticals: Employment. Acosta:Acrotech Biopharma: Employment. Horwitz:Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Kura: Consultancy; ADCT Therapeutics: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Aileron: Research Funding; Trillium: Research Funding; Miragen: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Forty-Seven: Research Funding; Millennium/Takeda: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Mundipharma: Consultancy; Kura: Consultancy; Miragen: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Astex: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astex: Consultancy; Portola: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron: Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Miragen: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Mundipharma: Consultancy; Portola: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Affimed: Consultancy; Millennium/Takeda: Consultancy, Research Funding. O'Connor:Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADCT Therapeutics, Affimed, Agensys, Merck, Seattle Genetics, Spectrum, Trillium, and Verastem Oncology.: Research Funding; TG Therapeutics: Other: Travel Support, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Twice Weekly Induction with Ixazomib-Lenalidomide-Dexamethasone (IRd) Combination Followed By Extended IRD Consolidation and Lenalidomide Maintenance in Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM): A Phase 2 Study from the Intergroupe Francophone Du Myelome (IFM 2014-03)

Blood ◽

10.1182/blood-2019-123184 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3159-3159 ◽

Cited By ~ 2

Author(s):

Murielle Roussel ◽

Benjamin Hebraud ◽

Cyrille Hulin ◽

Xavier Leleu ◽

Thierry Facon ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Single Agent ◽

Dose Intensity ◽

Phase 2 ◽

Open Label ◽

Advisory Committees ◽

Overall Response

Background: triplet combinations comprising a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) are current standard induction and consolidation regimens in NDMM. The all-oral combination of weekly ixazomib plus lenalidomide-dexamethasone (IRd) has been evaluated by several groups in NDMM and is approved in relapsed-refractory MM. The IFM 2014-01 phase 2 trial previously studied the weekly IRd regimen as induction and extended consolidation followed by single-agent ixazomib maintenance in frontline transplant eligible patients (Moreau et al ASH meeting 2016): IRd was well tolerated and overall response rate was 81%, including 38% very good partial response or better (≥VGPR) at the completion of induction (3 cycles). Responses further increased at each step of the program and 76% of patients (per protocole analysis) achieved ≥VGPR before maintenance with 6% CR and 38% sCR. To stay in line with current RVd regimen, and to increase dose intensity, we examined the efficacy and safety of twice-weekly ixazomib +Rd as induction prior to transplant, followed by weekly IRd consolidation and single-agent lenalidomide maintenance (NCT02897830). Methods: This is a phase II, single-arm, open-label, multicenter study. During induction, patients received three 21-day cycles of twice-weekly oral IRd: ixazomib (3 mg on days 1, 4, 8 and 11), lenalidomide (25 mg daily, days 1-14), and dexamethasone (40 mg on days 1, 4, 8 and 11) followed by transplant. Patients then received two 28-day cycles of weekly IRd early consolidation followed by 6 additional cycles of IR (no dexamethasone) as late consolidation (ixazomib 4mg on days 1-8 and 15; lenalidomide 25mg daily, days 1-21). Single-agent lenalidomide maintenance was administered for up to 1 year (10 mg daily, days 1-21). The primary endpoint was the stringent complete response (sCR) rate at the completion of consolidation. The secondary endpoints included assessments of overall response rate (ORR) and rates of response categories at each step of the program, progression-free survival (PFS), feasibility and safety. Responses were assessed in accordance with the IMWG uniform criteria. Toxicity was evaluated according to NCI CTCAE, version 4.03. Results Between 07/2016 and 08/2017, 50 patients with NDMM were screened at 10 IFM centers, 46 were enrolled with a median age of 59 years, and 59% were male. The percentages of patients with ISS stage I, II, and III were 41.5%, 41.5%, and 17%, respectively. High-risk cytogenetics, defined as t (4; 14), or del17p (central Lab, H. Avet-Loiseau), was observed in 9% of patients (6.5% FISH failure). As of July 1st 2019 (data cut-off), 10 patients prematurely discontinued therapy. Considering efficacy, 43/46 patients (94%) completed consolidation and 9 achieved sCR (20.9%; 90% CI [11.4 to 33.7]). This result did not meet the minimum efficacy threshold (40%) for the primary efficacy endpoint (p=0.998). Overall, at the completion of consolidation, ORR was 91% including 21% sCR, 30% ≥CR and 58%≥VGPR. Responses at each step of the program are described in the table 1. If we focus on twice-weekly IRd induction, at the completion of 3 cycles, ORR was 74%, including 33% ≥VGPR. The feasibility of the program was good and overall, 39/46 patients (85%) were able to receive maintenance therapy with single-agent lenalidomide. After a median follow-up of 22 months, 7 patients progressed and 3 patients died. Concerning safety: 31 serious treatment emergent AEs were reported in 20 patients (43.5%) comprising infections (8 patients), cardiac disorders (2 patients: ischemic heart disease and aortic valve incompetence), psychiatric, renal and respiratory disorders (2 cases each). No grade 3-4 peripheral neuropathy was described. Conclusions The all-oral Ixazomib-Lenalidomide-Dexamethasone (IRd) induction/consolidation regimen in the transplant setting is convenient, well tolerated, leading to 21% sCR before maintenance. Twice-weekly IRd induction does not seem superior to weekly IRd induction Results on response rates following maintenance and MRD data will be presented during the meeting. Table Disclosures Roussel: Celgene Corporation: Consultancy, Other: travel fees, lecture fees, Research Funding; takeda: Other: travel fees, lecture fees, Research Funding; Amgen: Other: travel fees, lecture fees, Research Funding; Janssen: Honoraria, Other: travel fees, lecture fees, Research Funding. Hebraud:celgene: Other: travel fees, lecture fees; takeda: Other: travel fees, lecture fees. Hulin:Janssen, AbbVie, Celgene, Amgen: Honoraria; celgene: Consultancy, Honoraria. Leleu:Oncopeptide: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria. Facon:Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Touzeau:celgene: Other: travel fees, lecture fees, Research Funding; takeda: Other: travel fees, lecture fees. Perrot:jannsen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; takeda: Honoraria. Stoppa:celgene: Other: travel fees, lecture fees; takeda: Other: travel fees. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Avet-Loiseau:takeda: Consultancy, Other: travel fees, lecture fees, Research Funding; celgene: Consultancy, Other: travel fees, lecture fees, Research Funding. Attal:celgene: Consultancy, Other: travel fees, lecture fees, Research Funding; takeda: Consultancy, Other: travel fees, lecture fees, Research Funding. OffLabel Disclosure: Ixazomib is indicated in RRMM in association with Rd

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A Phase I/II Study of Bortezomib and Low Dose Intravenous Melphalan (BM) for Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.2555.2555 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2555-2555 ◽

Cited By ~ 8

Author(s):

Rakesh Popat ◽

Heather E. Oakervee ◽

Nicola Foot ◽

Samir Agrawal ◽

Patricia Smith ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Progressive Disease ◽

Overall Response Rate ◽

Response Rate ◽

Single Agent ◽

Median Number ◽

Overall Response ◽

Grade 3 ◽

Number Of Cycles

Abstract Background: Bortezomib as a single agent has known efficacy in the treatment of relapsed multiple myeloma. The overall response rate (CR+PR+MR) was 35% in the SUMMIT study and 46% in the APEX study. In-vitro studies including our own have demonstrated potent synergy with other chemotherapeutic agents such as melphalan. It therefore follows that responses to bortezomib may be further improved by the combination of such drugs. Aims: The primary objectives of this Phase I/II study was to assess the safety, tolerability and response rates in patients with relapsed multiple myeloma; secondary objectives being time to progression (TTP) and overall surival (OS). Methods: This was a multi-centre, non-randomised trial for patients with relapsed myeloma. Patients received bortezomib 1.3mg/m2 on days 1,4,8 and 11 of each 28 day cycle with melphalan on day 2 at increasing dose levels. This was initially at 10mg/m2, but due to cytopenias subsequently at 2.5 and 5mg/m2 (levels 1a, 1 and 2) and we plan to escalate to 7.5mg/m2. Up to 8 cycles were given with dexamethasone added for stable or progressive disease after 4 or 2 cycles respectively. Responses were determined by EBMT criteria. Results: To date, 18 patients have been enrolled (12 male 6 female; median age 60 [range 44–73]; median number of prior therapies 3 [range 1–5] of which 17 have had at least one autologous stem cell procedure with high dose melphalan; 10 prior thalidomide and 2 prior bortezomib). 12 patients received melphalan at 10mg/m2 but due to unacceptable delays predominantly due to thrombocytopaenia, subsequent treatment levels commenced at 2.5mg/m2. The median number of cycles completed thus far is 4 (range 0–8) and of the 16 evaluable, the overall response rate (CR+PR+MR) across all treatment levels was 50% rising to 75% following the addition of dexamethasone as per protocol. At level 1a (melphalan 10mg/m2 ,N=12, median number of cycles completed =5) the best responses (with dexamethasone as indicated) were: 1CR, 1 VGPR, 5 PR, 2 MR; at level 1 (melphalan 2.5mg/m2, N=4) 1 PR, 2 MR (after 2 cycles only). The median time to any response was 1 cycle (range 1–3 ). Three patients have progressive disease, but the median TTP and OS have not yet been reached (median follow-up 3 months). Non-haematological toxicities have been modest with 7 SAEs reported of which only 1 was possibly drug related (myocardial infarction), and 4 episodes of Grade 3 neuropathy (2 resulting in study withdrawal). The commonest grade 3–4 haematological toxicity was thrombocytopaenia (N=10) complicated by bleeding in one patient, followed by neutropenia (N=6). Summary: The combination of bortezomib and intravenous melphalan can be given safely to patients with relapsed multiple myeloma and dose escalation is ongoing. Myelosupression was the commonest grade 3–4 adverse event. A response rate of 50% was seen, which was further improved to 75% with the addition of dexamethasone. This combination may therefore result in higher responses than single agent bortezomib in heavily pretreated patients.

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A Phase I Study of Vorinostat, Lenalidomide, and Dexamethasone In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Excellent Tolerability and Promising Activity In a Heavily Pretreated Population

Blood ◽

10.1182/blood.v116.21.1951.1951 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1951-1951 ◽

Cited By ~ 4

Author(s):

Paul Richardson ◽

Donna Weber ◽

Constantine S. Mitsiades ◽

Meletios A. Dimopoulos ◽

Jean-Luc Harousseau ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Phase I Study ◽

Response Rate ◽

Advisory Board ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 1951 Background: Although novel treatment combinations for multiple myeloma (MM) have improved outcomes, the disease remains incurable and new drug combinations are urgently needed. Vorinostat is an oral histone deacetylase inhibitor approved in the United States for treatment of patients (pts) with advanced cutaneous T-cell lymphoma who failed prior therapies. Vorinostat alters gene expression and protein activity, promoting MM cell death through multiple pathways, and has been shown in preclinical studies to synergistically enhance the anti-MM activity of bortezomib and immunomodulatory drugs, including lenalidomide, with or without dexamethasone. Aims: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) of vorinostat plus lenalidomide and dexamethasone in pts with relapsed or relapsed and refractory MM. Secondary objectives included overall safety, tolerability, response rate, duration of response, and time to progression (TTP). Methods: Pts in this Phase I multicenter open-label study were sequentially enrolled into 1 of 5 escalating doses of the combination regimen using a standard 3 + 3 design for ≤8 cycles. Pts who tolerated treatment and experienced clinical benefit were eligible for enrollment in an extension phase. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria (version 3.0). Response was assessed using the modified European Group for Blood and Marrow Transplantation criteria and International Myeloma Working Group Uniform Criteria. Safety and efficacy data were analyzed using summary statistics, except for TTP, which was estimated by the Kaplan-Meier method. Results: As of July 15, 2010, 31 pts were treated and evaluable for toxicity; 4 pts remain on study. Most pts had received prior thalidomide (n=22; 71%), bortezomib (n=20; 65%), or lenalidomide (n=14; 45%), with a median of 4 prior therapies (range, 1–10). The patient population contained both high-risk and low-risk pts, based on cytogenetic and/or fluorescence in situ hybridization analyses. Most adverse events (AEs) were mild or moderate in severity. The most common grade ≥3 treatment-related AEs, experienced by 19 (61%) pts, were neutropenia (26%), thrombocytopenia (16%), diarrhea (13%), anemia (10%), and fatigue (10%); 8 pts discontinued due to toxicity. One dose-limiting toxicity (grade 3 diarrhea lasting >48 h) was observed at the maximum assessed dose (level 5), but MTD was not reached (Table) and there were no treatment-related deaths. Among 30 pts evaluable for response, the median TTP was 32 weeks (5 mo), and 4 pts remain on study as of the data cutoff date; 26 of 30 pts (87%) have achieved at least stable disease (SD). Best single responses included 2 complete responses, 3 very good partial responses (VGPR), 11 partial responses (PR), and 5 minimal responses (MR), with 5 pts achieving SD and 4 developing progressive disease, resulting in an overall response rate (ORR; PR or better) of 53%. Of 13 evaluable pts who had previously received lenalidomide, a best single response of SD or better was observed in 9 (69%; 2 VGPR, 3 PR, 1 MR, 3 SD), resulting in a 38% ORR. Notably, SD or better (2 PR, 1 MR, 3 SD) was observed in 60% of 10 evaluable pts who were relapsed, refractory, or intolerant to previous lenalidomide-containing regimens. Conclusions: Preliminary data from this Phase I study suggest that vorinostat plus lenalidomide and dexamethasone is a convenient and generally well-tolerated regimen with promising activity for relapsed or relapsed and refractory MM. The MTD for this combination was not reached. Importantly, responses were observed in pts who had received prior lenalidomide, bortezomib, and thalidomide. Further evaluation of this regimen is planned in future trials. Disclosures: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Vorinostat, Lenalidomide, and Dexamethasone for treatment in Multiple Myeloma. Weber:Novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; Celgene- none for at least 2 years: Honoraria; Millenium-none for 2 years: Honoraria; Celgene, Millenium, Merck: Research Funding. Mitsiades:Millennium: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck & Co.: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centrocor: Consultancy, Honoraria; PharmaMar: Patents & Royalties; OSI Pharmaceuticals: Research Funding; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding. Dimopoulos:MSD: 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. Harousseau:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Houp:Merck Research Laboratories: Employment. Graef:Merck Research Laboratories: Employment. Gause:Merck Research Laboratories: Employment. Byrne:Celgene Corporation: Employment, Equity Ownership. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board.

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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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