ALBERT

Description: Introduction: The role of autologous stem cell transplantation (ASCT) as first line treatment for newly diagnosed patients with myeloma is currently under evaluation given the high response rates to novel induction treatment. The outcomes for patients that do not proceed to ASCT following induction remain unclear and are likely to be determined by genetic risk and response to therapy. In order to evaluate this further, this single arm phase 2 clinical trial conducted at 13 sites in the UK was designed to determine the 2 year progression free survival for patients that achieved ≥ very good partial response (VGPR) following induction therapy without ASCT. Those achieving partial response (PR) were consolidated with ASCT according to routine practice. In this first analysis we report secondary endpoints: disease response and regimen-related toxicity in patients completing induction, including minimal residual disease (MRD) negativity by multiparameter flow cytometry. Methods: Patients with newly diagnosed myeloma eligible for ASCT received PAD (bortezomib 1.3mg/m2 days 1, 4, 8, 11; doxorubicin 9mg/m2 days 1-4 and dexamethasone 40mg days 1-4 (and days 8-11 and 15-18 for the first cycle only)) for up to 6 cycles (minimum of 4). Bortezomib was initially given intravenously (IV), but once approved this was switched to sub-cutaneous (SC). Those failing to achieve PR were offered salvage therapy off protocol. All others had peripheral blood stem cell (PBSC) mobilisation using cyclophosphamide + GCSF, followed by MRD assessment on bone marrow aspirates using multi-parameter flow cytometry. Depending on disease response, patients were then stratified to ASCT (PR) or no further treatment (≥VGPR). Responses were assessed using International uniform response criteria (Durie 2006) by intent-to-treat and toxicity scored according to CTCAE version 4.0. High risk disease was defined by the presence of one or more adverse FISH lesions (t(4;14), t(14;16), t(14;20), del(17p13), +1q21) as described in the MRC Myeloma IX trial. Results: Between March 2011 and January 2014, 153 patients were enrolled (median age of 55, range 28-71 years). 139 (91%) received between 4-6 cycles of PAD. The majority (135, 88%) received SC only bortezomib and 18 (12%) received at least 1 cycle IV. The overall response rate to PAD was 81% with 46% achieving ≥VGPR (sCR: 6 (4%), CR: 13 (8%), VGPR: 51 (33%), PR: 54 (35%)). FISH data was available for 122 patients, 91 (75%) patients were standard risk and 31 (25%) were adverse. Responses were similar irrespective of ISS or genetic risk (standard, ≥VGPR 44%, PR 34%; adverse, ≥VGPR 55%, PR 29%). MRD results are currently available in 70 of the 124 patients achieving PR post PBSC harvest. Of this group 41 achieved ≥VGPR post-harvest (22 MRD+ and 19 MRD-) and hence did not proceed to ASCT, 13 patients achieved CR of which 8 were MRD negative. Toxicity was as expected for PAD and predominantly haematological. Notably the incidence of neuropathy was lower than that previously reported with IV bortezomib. Grade 3-4 events were: neutropenia: 18%; thrombocytopenia 7%. Grade 2-4 peripheral neuropathy was reported in 27% compared to 40% in the HOVON-65/ GMMG-HD4 Trial using IV bortezomib. Grade 1-2 neuropathy was similar for patients who received IV (55.6%) or SC (60%) bortezomib; however only 7% of patients receiving SC bortezomib developed grade 3 neuropathy compared to 28% with the IV route. Conclusions: SC PAD is a highly effective induction regimen for patients with newly diagnosed myeloma achieving a ≥VGPR of 46%. Of the 41 patients achieving ≥VGPR post-harvest with MRD result available, 46% were MRD negative. Response rates were similar across ISS and with adverse FISH. The use of SC bortezomib improved tolerability and substantially reduced neurotoxicity. ISRCTN no: 03381785. Disclosures Popat: Janssen: Honoraria. Cavenagh:Janssen: Honoraria. Schey:Janssen: Consultancy, Honoraria. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cook:Janssen: Honoraria, Research Funding. Yong:Janssen: Honoraria.

Description: Abstract 3040 The Polyomavirus hominis 1 BK virus (BKV) is a non-encapsulated DNA virus, which infects up to 90% of the world's population, and may reactivate at times of severe immunosuppression, including post haematopoietic stem cell transplantation (HSCT). The significance of BK virus reactivation post Haematopoietic Stem Cell Transplant (HSCT) remains unclear. We collected retrospective data on viruria, viraemia, haemorrhagic cystitis (HC) and acute/chronic graft versus host disease (a/cGVHD) in patients at our institution over the period 2006 to 2011. We compared with a multivariate matched control group of 38, who did not reactivate BK. The groups were matched for age, sex, donor source and conditioning regimen including use of Alemtuzumab. Global BK reactivation incidence was 32% (38/118) of allogeneic HSCT during this period. 73% (28/38) of those who reactivated received volunteer unrelated donor (VUD) grafts, and 50% (18/38) received Alemtuzumab. Patients were sub-divided into those with high grade viraemia (HGV, VL 〉104 copies/ml), 47% (18/38) or low grade viraemia (LGV, VL

Description: Abstract 4584 Haploidentical transplantation is an option for patients who do not have a timely identifiable sibling or volunteer unrelated donor (VUD). Benefits of this stem cell source include donor availability, highly motivated donors and the ability to select the best donor from several relatives taking: age/fitness, cytomegalovirus (CMV) status, ABO group and natural killer cell alloreactivity into account. Historically the high level of human leukocyte antigen (HLA) disparity led to increased graft failure and high rates of acute and chronic graft versus host disease (GVHD). Luznik et al (Blood 2001) demonstrated that the use of post stem cell return cyclophosphamide in RIC haploidentical transplantation (using bone marrow as a stem cell source) reduced acute and chronic GVHD to acceptable levels, but at the expense of higher relapse rates in their cohort. We postulated that the use of PBSC's with their inherently higher T cell complement would reduce relapse rates compared to bone marrow, whilst post cell return cyclophosphamide would reduce acute and chronic GVHD. We present 5 patients treated at our centre using a RIC T cell replete haploidentical transplant protocol utilising PBSC's and post cell return cyclophosphamide. The patients, (median age 51; range 44–58), were treated for: relapsed follicular non Hodgkin's lymphoma (NHL), secondary acute myeloid leukaemia, Mycosis Fungoides and Adult T-Cell Leukaemia/Lymphoma (ATLL). Four patients had received 1st line chemotherapy only and remained chemotherapy sensitive, 3 of whom were in complete remission, one in a partial response. None had undergone a previous transplant. The NHL patient was chemotherapy insensitive following 4 previous lines of chemotherapy, a splenectomy and 2 rejected sibling allografts. Three patients were a major ABO mismatch, the remaining 2 fully matched. Four patients were CMV +/+ and 1 mismatched. HLA disparity ranged from 2–5 alleles (2 and 3 patients respectively). Median CD34+ cell dose returned was 6.98×106 cells/kg (range 4.81–8.00), with a median CD3+ cell dose of 2.36×108 cells/kg (range 1.19–2.97). The conditioning regime used was that of Luznik et al's (Blood 2001) phase I trial: Fludarabine 30mg/m2 day -6 to -2, cyclophosphamide 14.5mg/kg day -6 to -5, total body irradiation 2 Gray day -1, post stem cell cyclophosphamide 50mg/kg day +3 to +4, tacrolimus 1mg IV day +5 onwards, mycophenolate mofetil 15mg/kg TDS day +5 to +35. Outcomes: Four of 5 (80%) patients were fully donor chimeric by day 28 however graft failure with autologous reconstitution due to previously undetected HLA antibodies occurred in 1 patient. This patient reconstituted autologous neutrophils and platelets at 15 and 26 days respectively. Median time to neutrophil and platelet engraftment was 16.5 days (range 14–17) and 12 days (range 11–14) respectively. All 5 patients reactivated CMV (the latest at day 112). With pre-emptive treatment however none developed CMV disease. The incidence of acute GVHD grade II – IV and grade III - IV by day 100 was 40% and 20% respectively. Limited chronic GVHD was seen in 3 patients. 2 were assessed as grade I-II and 1 patient grade III. All cases of acute and chronic GVHD were steroid responsive. In both ATLL patients a sustained suppression of human T-lymphotropic virus (HTLV) viral loads was observed post transplant. One patient subsequently died of sepsis at day 113, the patient who had rejected their graft went on to relapse. The remaining 3 patients continue in CR, performance status 0, currently at day 245, 280 and 438. This data shows that RIC T cell replete haploidentical transplantation using PBSC's is well tolerated and enables both early engraftment and full donor chimerism. The rates of acute and chronic GVHD (40 and 60%) are comparable to sibling and fully matched unrelated donors. All of which has resulted in 60% of patients remaining in CR, including both ATLL patients who have gone on to fully suppress their HTLV viral loads. Disclosures: No relevant conflicts of interest to declare.

Description: Actimid™ (CC-4047[Celgene]) is a thalidomide derivative that induces apoptosis, disrupts myeloma-stromal cell adhesion, reduces cytokine secretion, is anti-angiogenic and stimulates anti-myeloma NK cell proliferation. In vivo T-cell and NK cell stimulatory cytokines are enhanced. We have reported a phase I study of daily Actimid with a MTD of 2 mg daily and have carried out a further phase I study using alternate day dosing. Methods: Patients (pts) with relapsed/refractory myeloma who had received at least one prior line of therapy were eligible.This was a dose escalation study designed to define the maximum tolerated alternate day (a/d) dose (1mg, 2mg, 5mg, 10mg). Pts discontinued therapy after 4 weeks if grade 3/4 non-haematological toxicity developed, grade 4 haematological toxicity had not resolved or there was progressive disease. Pts who relapsed following response were eligible to receive dexamethasone (20 mg od for 4 days alternate weeks). Results: 20 pts were treated with median age 58 years (range 34 – 75) and a median of 4 (range 1 – 7) prior lines of chemotherapy (including HDT(65%) and/or thalidomide (85%)). 3/20 pts developed grade 4 neutropaenia within 4 weeks of treatment. All were receiving 10mg a/d. This resolved in all pts within 5 weeks without recourse to growth factors and therapy was restarted at a lower dose. There were no dose limiting grade 3/4 non-haematological toxicities. The maximum tolerated dose was identified as 5 mg a/d. One patient was withdrawn from treatment following the development of relapsing /remitting fevers of unknown origin. He had previously had similar symptoms following treatment with bortezomib. One patient was withdrawn following the development of transverse myelitis and one patient withdrew consent within two weeks of commencing treatment. No pts withdrew due to recurrent neutropaenia. The median duration of exposure to single agent actimid is 5 months (1 – 14) and the overall median duration of therapy is 10 months (1 – 21). All 20 pts are evaluable for response. With a median follow-up of 12 months 12(60%) achieved at least a 25% paraprotein reduction. 19 achieved a best response of stable disease(SD) or better. 1/20 pts progressed within 4 weeks of starting therapy. 2/20 pts attained a complete response, 8/20 pts achieved at least 75% paraprotein reduction (VGPR+CR), 10/20 pts achieved a 〉 50% paraprotein reduction and a further 2/20 pts achieved a 25 – 50% paraprotein reduction. 6/20 pts had dexamethasone added. Two pts achieved a best response after the addition of dexamethasone (both had relapsed following PR and SD respectively and both achieved VGPR). Additionally 1/6 pts achieved MR and 3/6 pts achieved SD. In the group overall the median time to achieve maximum response was 4 months (1 – 17). 8/20 progressed on treatment with a median time to progression of 10 months (1 – 21). 5/20 pts have subsequently died due to progressive disease. There have been no treatment related deaths. Conclusions: Actimid is a well tolerated oral agent with activity in myeloma. The maximum tolerated dose was 5mg a/d. No grade 3/4 non-haematological toxicity was observed and the neutropaenia resolved rapidly. Responses were excellent with 50% patients achieving at least a 50% reduction in paraprotein. Dexamethasone improved response in 2/6 patients. This study indicates that Actimid has good anti-myeloma activity either as a single agent or in combination with dexamethasone and further clinical studies are justified.

Description: GCS-100 is a galectin-3 antagonist with an acceptable human safety profile that has been demonstrated to have an antimyeloma effect in the context of bortezomib resistance. In the present study, the mechanisms of action of GCS-100 are elucidated in myeloma cell lines and primary tumor cells. GCS-100 induced inhibition of proliferation, accumulation of cells in sub-G1 and G1 phases, and apoptosis with activation of both caspase-8 and -9 pathways. Dose- and time-dependent decreases in MCL-1 and BCL-XL levels also occurred, accompanied by a rapid induction of NOXA protein, whereas BCL-2, BAX, BAK, BIM, BAD, BID, and PUMA remained unchanged. The cell-cycle inhibitor p21Cip1 was up-regulated by GCS-100, whereas the procycling proteins CYCLIN E2, CYCLIN D2, and CDK6 were all reduced. Reduction in signal transduction was associated with lower levels of activated IκBα, IκB kinase, and AKT as well as lack of IκBα and AKT activation after appropriate cytokine stimulation (insulin-like growth factor-1, tumor necrosis factor-α). Primary myeloma cells showed a direct reduction in proliferation and viability. These data demonstrate that the novel therapeutic molecule, GCS-100, is a potent modifier of myeloma cell biology targeting apoptosis, cell cycle, and intracellular signaling and has potential for myeloma therapy.