ALBERT

Description: Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) after myeloablative AuSCT in pts with MM. Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAM F7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of MM pts who have received 1-3 prior therapies. The objective of this phase 2 trial is to evaluate the efficacy and safety of adding ELO to LEN as maintenance therapy post-myeloablative AuSCT. We report updated results of the primary (PFS) and secondary (overall survival [OS] and toxicity) endpoints. Patients and Methods: Between 4/15/2015-1/27/2016, 27 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2, q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=57 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until disease progression (PD). LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity 〉 grade 1 and significant cytopenias (ANC 〈 1000/mL, platelet count 〈 100,000/ml). For the 1st 8 weeks, pts

Description: Abstract 1227 Poster Board I-249 Background In comparison with single autologous hematopoietic stem cell transplantation (auto HCT), tandem autologous HCT has resulted in longer event-free and overall survival in randomized trials for patients with newly diagnosed multiple myeloma (MM). Most myeloma patients, however, only receive a single auto HCT. Many of these patients are eligible for a second auto HCT as salvage at the time of relapse. We evaluated the outcome of salvage auto HCT for MM patients treated at our institution. Methods We performed a retrospective chart review and identified 62 MM patients (38 males, 24 females) who received a second auto HCT as salvage between 1/3/1992 and 11/4/2008.. Preparative regimen was high-dose melphalan alone or in combination with other chemotherapy agents, including busulfan, topotecan and bortezomib. Three patients received a combination of thiotepa, busulfan and cyclophosphamide. Results Median interval between the first and salvage auto HCT was 21 months (range 2-81). Median age at salvage HCT was 55 years (37-73) and median prior treatment regimens were 4 (range 2-16). Twelve patients had chromosomal abnormalities on conventional cytogenetic studies. Patients received a median CD34 cell dose of 4 ×106 / kg (range 2.3-11.2). Fourteen patients (22%) experienced grade 3 or higher toxicity after the salvage auto HCT. Two patients died within 100 days with a TRM of 3%. Median time to neutrophil engraftment was 10 days (8-38). Responses after salvage auto HCT were as follows: CR+ near CR 15%, PR 48%, with an overall response rate of 63%. Twenty-seven (44%) patients received post auto HCT maintenance therapy. Median follow-up from salvage HCT was 25 months. Kaplan-Meier estimates of median progression-free survival and overall survival (OS) were 15.5 and 43.3 months, respectively. Median time to progression after the first and salvage auto HCT was 20 and 12 months, respectively, with total remission duration of 32 months from two HCTs. Median OS from the time of diagnosis was 72 months, comparable to reported results with tandem auto HCT. At last follow up, 20 patients were alive and in remission. Conclusions In selected MM patients a second auto HCT for salvage therapy is well tolerated with acceptable toxicity. The combined remission duration and overall survival are comparable to outcomes with tandem autotransplants. Disclosures Qazilbash: Cephalon: Speakers Bureau.

Description: Backround: Arsenic trioxide (ATO) has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a phase I/II trial to determine the safety and efficacy of a combination of arsenic trioxide, melphalan and ascorbic acid (AA) as preparative regimen in patients undergoing high-dose therapy (HDT) and autologous hematopoietic progenitor cell transplantation for multiple myeloma (MM). We also assessed the impact ATO levels on melphalan pharmacokinetics (PK), engraftment and toxicity. Methods: Forty-eight patients with secretory myeloma (23 females, 25 males; median age: 54, range: 3570) were treated between 4/04 and 8/05. All patient received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days -9 to -3. Patients were randomized to 3 arms; no ATO (arm 1), ATO 0.15 mg/kg IV on days -9 to -3 (arm 2) and ATO 0.25 mg/kg IV on days -9 to -3 (arm 3). Twelve patients had disease progression or relapse after a prior autograft. Median CD34 cells dose infused was 4.5 x 106/kg (range 2.3–10.9). Results: Patients in all 3 arms were evenly matched. With a median F/U of 14.0 months (range 6–25) post autograft, no dose-limiting toxicity or non-relapse mortality was seen. Toxicity was limited to grade I or II nausea, vomiting and diarrhea. Median ATO levels on day 0 in arms 1, 2 and 3 were 0.2, 26.3 and 46.2 ng/ml, respectively. Melphalan PK was not altered by ATO pretreatment. Median time to neutrophil engraftment (ANC 〉500/ dl) was 9 days. There were no engraftment failures or delays in the ATO arms. CR rate for the entire group was 23%, and total response rate (CR + PR) was 75%. 1-year Progression-free survival (PFS) and overall survival (OS) were 75% and 95%, respectively. There was no significant difference in CR, RR, PFS or OS between the 3 arms (p = 0.9, 0.9, 0.4 and 0.6, respectively). A prior autologous transplant (p = 0.02) and abnormal cytogenetics at transplant (p = 0.04) were associated with a significantly shorter remission. Conclusions: ATO + melphalan + ascorbic acid is a safe, effective and well tolerated preparative regimen for patients with multiple myeloma undergoing an autotransplant. A longer follow up is needed to assess the impact of ATO on progression-free and overall survival.

Description: Introduction Plasmablastic lymphoma (PBL) is a rare, aggressive subtype of non-Hodgkin lymphoma. Published data are predominantly in the form of case reports and small retrospective case series. Initial reports of PBL were described in HIV positive patients (pts) with disease in the oral cavity, and in pts after organ transplantation on immunosuppressive therapy. The natural history may have evolved recently, with case reports of PBL in immunocompetent patients. There is no established standard of care therapy, though HIV positive pts benefit from initiation of anti-retroviral therapy, tend to respond to chemotherapy, have historically been associated with CD20 expression, and have increased overall survival rates compared with HIV negative pts with PBL. We now describe our experience in pts with PBL who received treatment at the University of Texas MD Anderson Cancer Center (UTMDACC). Methods We conducted a retrospective analysis of pts diagnosed with PBL between August 2000 and August 2012. We evaluated the baseline demographics, stage, therapy, response rate, progression-free survival (PFS) and overall survival (OS). Results 28 pts (males n=23) with PBL were identified, with a median age of 51 (range 26-81). 10 patients had a diagnosis of HIV, and 15 were EBV positive. 7 pts had stage I disease, 2 had stage II, 1 had stage III and 18 had stage IV disease. The primary site of disease in the 7 pts with stage I disease was: 2 in the maxillary sinus, 2 in the nasal cavity, and 1 each in the colon, testicle, and lower jaw. 2 pts with stage II disease had primary sites in bowel and tonsils. 7/17 (41%) of HIV negative pts and 2/10 (20%) of HIV positive pts had stage I/II disease. The median LDH was 492 IU/L (313-618), median Ki-67 proliferation index was 85%, and all pathological samples were CD20 negative. Median follow up was 16 months (1-120). 27 pts received systemic therapy (1 pt elected hospice care). PBL was an initial cancer diagnosis for 25 pts who received the following as first line therapy: Hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone alternating with methotrexate and cytarabine) (n=10), CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) (n=7), modified CVAD, 2 with EPOCH (etoposide, vincristine, cyclophosphamide, Adriamycin, prednisone) (n=4), bortezomib/dexamethasone (n=1), and the DeAngelis protocol (methotrexate, vincristine, procarbazine, with intrathecal methotrexate) (n=1) for CNS involvement. 2 pts had prior therapy for diagnosis of diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) prior to diagnosis of PBL. The first pt with DLBCL was treated with Rituximab-hyper-CVAD 6 years earlier, and gemcitabine/oxaliplatin for the diagnosis of PBL. The second pt had CLL which underwent Richter's transformation to PBL, and was treated with hyper-CVXD (cyclophosphamide, vincristine, liposomal daunorubicin and dexamethasone). 1 pt underwent auto-stem cell transplant, while 8 pts received localized radiation (5 for consolidation and 3 for palliative therapy); 5/7 pts with stage I disease received consolidation with involved field radiation. After first line therapy, 20/27 patients (74%) achieved complete response, 5/27 (19%) partial response, and 2/27 (7%) stable disease. Median PFS and OS were 24.1 and 28.8 months, respectively. 5 year PFS and OS were 40% and 38%, respectively. Early stage disease (stage I or II) and younger age at diagnosis (less than 40 years old) were associated with improved survival. 5 year PFS for stage I/II pts was 90%. Conclusion 41% of HIV negative pts had stage I/II disease. Early stage PBL pts who received combined chemotherapy followed by radiotherapy achieved a good PFS of 90% at 5 years. PBL consistently lacked CD20 expression irrespective of HIV status. PBL can be seen in both HIV+ and HIV– patients with overall 40% long term survival. Disclosures: Qazilbash: Otsuka Pharmaceuticals: Research Funding. Fanale:Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Consultancy, Honoraria, Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees.

Description: Abstract 1860 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent induction of apoptosis due to degradation of survival signals during mitotic arrest. Cancers, such as multiple myeloma (MM), that depend on the short-lived survival protein Myeloid cell leukemia (MCL)-1 are highly sensitive to treatment with ARRY-520 in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy and biological activity of ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks without/with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients (pts) had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both bortezomib [BTZ] and an immunomodulatory [IMiD] agent), unless refusing or ineligible for this therapy. Cohorts were enrolled in a classical 3+3 dose escalation design. Results: Enrollment in this Phase 1 study is complete. Thirty-one pts have been treated, with a median age of 60 years (range 43–79) and a median of 6 prior regimens (range 2–16). All pts received a prior proteasome inhibitor (30 pts BTZ, 4 pts carfilzomib) and an IMiD-based agent (28 pts lenalidomide, 23 pts thalidomide). Twenty-four pts had an autologous stem cell transplant. The maximum tolerated dose (MTD) was determined to be 1.25 mg/m2/day without G-CSF. As neutropenia was the dose-limiting toxicity (DLT), dose escalation with G-CSF support was conducted and the MTD for ARRY-520 with G-CSF was determined to be 1.5 mg/m2/day. At the MTD, 1 of 7 pts had a DLT of febrile neutropenia. At doses above the MTD, additional DLTs of Grade 3 mucositis and Grade 3 corneal disorder were observed. ARRY-520 demonstrated an acceptable safety profile. The most commonly reported treatment-related adverse events (AEs) included hematologic events (anemia, leukopenia, neutropenia, thrombocytopenia), as well as anorexia, blurred vision, diarrhea, dizziness, fatigue, febrile neutropenia, mucositis, nausea and rash. No treatment-related AEs of neuropathy or alopecia were reported at the MTD. ARRY-520 has been dosed over extended periods of time (to date, median 7 cycles [range 1–44]), with no evidence of cumulative toxicity. The plasma concentrations of ARRY-520 were determined over a 7-day period during Cycle 1 following the Day 1 and 2 infusions of ARRY-520. The preliminary noncompartmental PK parameter estimates in this population were similar to those observed in prior oncology studies. The PK was characterized by low clearance (CL = 2.2 L/hr/m2) and a large volume of distribution (Vss = 232 L/m2). The t1/2 of elimination was very long (67 hrs). Concentrations were typically maintained above the in vitro IC50 for KSP inhibition for ≥ 7 days suggesting therapeutically active concentrations of drug were maintained in pts for sustained periods. Further analyses of PK relative to safety and activity are on-going. ARRY-520 showed activity as a single agent across a range of doses in this heavily pretreated population (31 evaluable pts) with 3 confirmed partial responses (PR) and 1 confirmed minimal response (MR) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 7 prior therapies (range 2–8). Responses were durable; to date, the durations of responses for PRs were 3.4+ months (mos), 11.9+ mos and 12.0 mos, respectively. Of interest, the time to response with ARRY-520 was prolonged, with a median time to PR of 3.7 mos (range 3.7–8.1). Notably, responses were observed in pts refractory to multiple standard-of-care agents. In addition, 4 pts experienced a best response of stable disease (SD) lasting ≥ 10 mos. To date, 5 pts remain on study, including 2 of 3 PRs. Conclusions: In this Phase 1 study, ARRY-520 shows promising evidence of clinical activity, with a long duration of response and an acceptable safety profile in heavily pretreated MM Patients. A Phase 2 portion of the study is ongoing to obtain additional information on the efficacy, safety and biological effects of ARRY-520 at 1.5 mg/m2/day with G-CSF support. Disclosures: Shah: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding. Off Label Use: ARRY-520. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Celgene: Research Funding; Merck: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Litwiler:Array BioPharma: Employment. Karan:Array BioPharma: Employment. Hilder:a: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

Description: Introduction: Lenalidomide (Len), an analog of thalidomide (Thal) is a novel, oral, immunomodulatory agent that is effective against multiple myeloma (MM). In 2 prospective, randomized, double-blind, placebo-controlled phase III trials, Len with dexamethasone (Dex) induced a significantly higher overall response (OR) rate and complete remission (CR) rate, as well as longer time-to-progression (TTP) in comparison with Dex alone. Here, we investigate the long-term overall survival (OS) with Len/Dex. Methods: We evaluated the pooled results from both randomized trials (MM-009, MM-010) of 704 patients who had relapsed or refractory MM, without prior resistance to Dex, who received either Len (25 mg daily for 3 weeks every 4 weeks), or placebo. Dex was given at 40 mg on days 1–4, 9–12, 17–20 every 4 weeks for 4 cycles. From cycle 5 onwards, Dex was given at 40 mg on days 1–4 only. Response rate and TTP are based on data obtained before unblinding (June 2005 [MM-009] and August 2005 [MM-010]). Follow-up data on OS were obtained up to January 2007. Forty-seven percent of patients who received placebo/Dex crossed over to receive Len +/− Dex. Results: Of 704 patients, 353 were treated with Len/Dex and 351 with Dex alone. Baseline characteristics were well balanced between patients receiving Len/Dex and those receiving Dex alone. Median TTP, OR, and CR were significantly improved in patients treated with Len/Dex compared with Dex alone (Table). Of patients who progressed on Dex alone prior to unblinding, or were found to be receiving Dex alone after unblinding, 47% crossed over to Len +/− Dex. Despite these patients crossing over to Len +/− Dex at progression or at the time of unblinding, the OS was significantly improved in patients treated with Len/Dex compared with Dex alone (hazard ratio 1.295; 95% confidence interval 1.040–1.614; p=0.02). Median OS in the Len/Dex group was 35 months and 31 in the Dex alone group (p

Description: Background: Allogeneic hematopoietic stem cell transplantation (allo SCT) has two potential advantages over autologous SCT: a tumor-free graft and graft-versus-myeloma (GVM) effect. Allo SCT’s potential to induce long term remission has, however, been offset by high rates of transplant-related non-relapse mortality (TRM). Reduced-intensity conditioning (RIC) regimens for allo SCT are associated with lower TRM without compromising the GVM effect. Methods: We retrospectively analyzed our experience in 69 patients (30 females and 39 males) with heavily pretreated, relapsed myeloma, who received allo SCT at our institution between1985 and 2007. Eighteen patients received myeloablative regimens (MA), while 51 received RIC regimens. MA regimens were TBI-based in 5 patients, high-dose busulfan-containing in 6 patients and high-dose melphalan containing (180–200 mg/m2) in 7 patients. RIC regimens were a combination of fludarabine (90–120 mg/m2) and melphalan (100–140 mg/m2). Median age of patients at allo SCT in both groups was 51 years. Median interval from diagnosis to allo SCT was 35.4 months in MA group, and 34.2 months in RIC group. Eight (44%) patients in MA group and 36 (70%) patients in RIC group had prior autologous SCT. Six patients (33%) in the MA group and 11 (25%) in the RIC group received allo SCT from unrelated donors (p=0.3). Median number of prior treatment regimens were 5 (range 1–10) in both groups. Stem cell source was peripheral blood in 3 patients in MA group and 41 patients in the RIC group (p=0.0001). Results: Median follow-up in surviving patients was 27 months (3–98). All patients achieved engraftment. Cumulative TRM at 1 year was 56% in the MA group and 25% in the RIC group (p=0.03). Overall response rates in evaluable patients were 69% (CR=15%, PR= 54%) in MA group, and 79% (CR=23%, PR=56%) in the RIC group (p=0.47). Disease progression at 2 years was seen in 8 patients (44%) in the MA group and 25 patients (49%) in the RIC group (p=0.78). Median progression-free survival (PFS) in MA vs. RIC groups was 4.1 and 6.8 months, respectively (p=0.003) and median overall survival (OS) ) in MA vs. RIC group was 5.3 and 13.9 months, respectively (p=0.001). Cumulative Incidence of grade II–IV acute graft-vs.-host (GVHD) in MA vs. RIC groups disease was 33 vs. 27% (p=0.76); cumulative incidence of chronic GVHD in MA vs. RIC group was 54% vs. 47% (p=0.41) in evaluable patients. At the time of this analysis, 13 patients (25%) were still alive in RIC group, 7 of whom (14%) were in remission for up to 6 years post allo SCT. The most common causes of death were recurrent disease (30 patients; 43%), acute or chronic GVHD (16 patients; 23%) and opportunistic infections (5 patients: 7%). Conclusions: Allo SCT after RIC regimens is associated with longer PFS and OS and lower TRM. There was no increase in the risk of relapse, or acute or chronic GVHD. These regimens can safely replace MA regimens and may offer greater benefit if utilized earlier in the course of disease. Figure Figure

Description: Background: Allogeneic transplantation is a potentially curative approach in patients with myeloma. The potential benefit is offset by a higher risk of transplant-related mortality (TRM), graft-vs.host disease (GVHD) and opportunistic infections. The success of reduced intensity conditioning approaches has renewed interest in allogeneic transplantation. In this randomized phase II trial we evaluated whether lowering the dose of melphalan in a nonablative preparative regimen can lower the toxicity and TRM. Two reduced intensity regimens: fludarabine + melphalan 140 mg/m2 (FM 140) and fludarabine + melphalan 100 mg/m2 (FM 100) were compared in patients undergoing allogeneic stem cell transplantation. Methods: We enrolled 22 patients, 11 in each arm, who were 70 years of age or younger and had an HLA-identical sibling donor. Patients underwent allogeneic transplantation between April 2002 and January 2007. Median age was 52.5 years (Range: 32–63). GVHD prophylaxis consisted of tacrolimus and methotrexate 5mg/m2 on days 1, 3, 6 and 11. Median interval between diagnosis and transplant was 28 months (9–232). Only 6 patients (27%) received transplant for the consolidation of first remission, the rest had relapsed or refractory disease (73%). Twenty-one patients had a prior autotransplant; 3 of these had 2 prior autotransplants. Median number of prior treatment regimens was 5 (1–10). Cytogenetic abnormalities were observed in 8/22 patients (36%). Results: The 2 groups were comparable in terms of age, disease status, prior therapy and other prognostic factors. Median time to neutrophil engraftment in both arms was 12 days. TRM in the first 100 days was zero in both arms. Response rate (CR 18% + PR 64%) was 82%, with no significant difference between the 2 arms. After a median follow up of 25 months (26 months in FM 100, 21 months in FM 140), Kaplan-Meier estimates of 2-year PFS in FM 100 vs. FM 140 were 41% vs. 42%, respectively. Kaplan-Meier estimates of 2-year OS in FM 100 vs. FM 140 were 60 vs. 36%, (p=0.4), respectively. There was no significant difference in the incidence of grade II-IV acute GVHD (27 vs. 36%) or chronic GVHD (50 vs. 43%) between the 2 arms. There was a decrease in overall grade II-IV toxicity in the FM 100 arm (45% vs. 73%) that did not reach statistical significance (p=0.2) Patients transplanted in relapse had shorter PFS (0.09). Conclusions: The dose of melphalan in preparative regimen can be safely reduced without adversely impacting the engraftment in this heavily pretreated patient population. There was a trend towards lower grade II-IV toxicity and prolonged OS in the FM 100 arm. This approach may be more beneficial when used early in the course of treatment.

Description: In a retrospective pooled analysis of 11 clinical trials of lenalidomide-based therapy for relapsed/refractory multiple myeloma (MM; N = 3846), the overall incidence rate (IR, events per 100 patient-years) of second primary malignancies (SPMs) was 3.62. IR of invasive (hematologic and solid tumor) SPMs was 2.08, consistent with the background incidence of developing cancer. In a separate analysis of pooled data from pivotal phase 3 trials of relapsed or refractory MM (N = 703), the overall IR of SPMs was 3.98 (95% confidence interval [CI], 2.51-6.31) with lenalidomide/dexamethasone and 1.38 (95% CI, 0.44-4.27) with placebo/dexamethasone; IRs of nonmelanoma skin cancers were 2.40 (95% CI, 1.33-4.33) and 0.91 (95% CI, 0.23-3.66), respectively; IRs of invasive SPMs were 1.71 (95% CI, 0.86-3.43) and 0.91 (95% CI, 0.23-3.66), respectively. The risk of SPMs must be taken into account before initiating lenalidomide treatment. In the context of the observed survival benefit in relapsed or refractory MM patients, the benefit/risk profile of lenalidomide/dexamethasone remains positive.

Description: Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4,5] decane-2-propanamine) is an orally bioavailable cationic amphilic compound that inhibited STAT 3 activation in MM cells. It effectively blocked the signaling pathway of interleukin-6, resulting in activation of caspase 3 and apoptosis (Amit-Vazina et al, Br J Cancer, 2005). Atiprimod has also induced cytotoxicity in dexamethasone, doxorubicin, and melphalan resistant MM cell lines (Hamasaki et al, Blood, 2005). Based on these encouraging in vitro data, we initiated a multi-center, phase I trial of atiprimod for patients (pts) with refractory or relapsed MM who had 2 prior lines of therapy and serum creatinine less than 2 mg/dl. Primary objectives were to evaluate the safety of atiprimod in MM pts and to identify the maximum tolerated dose (MTD). Each cycle of treatment consisted of 14 consecutive days of oral atiprimod followed by 14 consecutive days without treatment. A standard phase I dose escalation was used to determine MTD with atiprimod dose levels at 30 mg, 60 mg, 90 mg, 120 mg, and 180 mg. To date, 14 pts from 4 centers have been enrolled with evaluable data in 12 patients. Median age was 60 (range 44–64); median prior lines of therapy were 4 (range 3–7); median duration from initial treatment to registration to this trial was 36 months (range 19–76). Cohorts of 3 patients have been treated at 30, 60, 90,120 mg/day and 2 patients have been enrolled at the 180 mg/day level; no cohorts have been expanded because of dose-limiting toxicity. Median number of cycles received by MM pts was 2 (range 1–5). Common Grade 1 toxicity events included diarrhea, liver enzyme elevation and dyspepsia. There were two Grade 2 toxicity events with 1 neutropenia at the 90 mg/day level and 1 diarrhea at the 120 mg/day level. One pt had Grade 3 transaminase elevation (peak AST 402, ALT 469 units/L, bilirubin 0.5 mg/dl) during the second cycle that resolved on its own during the 14 day period off treatment. Two patients with rapidly rising serum M proteins prior to enrollment had a transient but clear reduction of their M proteins (30% and 80%) after the first 14 days of atiprimod. Two pts at higher dose levels noted subjective improvement in their bone pain. Atiprimod was generally well tolerated in this heavily treated group of MM pts. The MTD has not been reached. Although there has been no response to date, clinical activity is not expected until higher dose levels are evaluated (240 mg/day, 300 mg/day, and 360 mg/day). After the MTD has been established, the study of atiprimod combinations should be considered based on the in vitro assessment of synergy with other active agents.