ALBERT

Description: Introduction: Histone deacetylase inhibitors (HDACis) have demonstrated clinical efficacy in multiple myeloma, particularly in combination with proteasome inhibitors. CHR-3996 is a class 1 selective HDACi with potent anti-myeloma activity in vitro. Aminopeptidase inhibitors act downstream of the proteasome and prevent breakdown of proteasome generated peptides into amino acids. Synergistic cytotoxicity was observed in vitro when CHR-3996 was combined with the aminopeptidase inhibitor, tosedostat through rapid activation of NFkB followed by increased expression of the repressors IκBα, A20, CYLD, BIRC3. The MUK-three study was designed to translate these pre-clinical findings into a phase 1 clinical trial. This dose escalation study aimed to determine the maximum tolerated dose, safety and preliminary activity of CHR-3996 administered in combination with Tosedostat for patients with relapsed, refractory MM. Here we present the final study results. Methods: MUK-three was an open label multi-centre UK Phase I/IIa trial for patients with relapsed and relapsed/ refractory myeloma who had failed conventional treatments. Patients were permitted to meet the haematological entry criteria using growth factor and/or blood product support. During dose escalation subjects received CHR-3996 (20-40mg days1-28) and Tosedostat (0-60mg days 1-28) (Table 1) every 28 day cycle until disease progression or withdrawal. Dose limiting toxicities (DLTs) were evaluated during cycle 1 and dose escalation followed the 3+3 design. Responses were assessed using modified IMWG uniform response criteria, with the primary endpoint for the expansion phase of stable disease (SD) rate after 4 cycles of therapy. Toxicity was graded by CTCAE V4.0. Results: The trial was open to recruitment from July 2012 to December 2015. 20 patients were treated during dose escalation, including 8 at the recommended dose (RD) and 12 at dose levels (DL) 1-3. Only 1 DLT was observed at DL3 (grade 4 thrombocytopenia); however, this DL was deemed not tolerable due to the high incidence of low grade gastrointestinal toxicities. Hence the RD was determined as DL3b, CHR-3996 20mg and Tosedostat 60mg. A further 2 patients were treated at RD during dose expansion to make the required 10 patients for the protocol defined initial analysis at which point the trial closed. At the RD (n=10) median age was 63 years (range 47-73). 80% of patients had received at least 4 prior lines of therapy (median 4, range 2-9); 50% were ISS II, 30% ISS III; 4/6 patients with evaluable FISH data had 1q gain. The median time from diagnosis to treatment for the overall population was 85.3 months (27.5-198.8). The median number of cycles received was 2.5 (range 2-8) and 2 patients remain on treatment with 8 stopped due to disease progression. The 2 patients ongoing (received 5 & 9 prior lines) had their schedule adjusted to a 5 day a week dosing to further improve tolerability. Both had a clinical response (1MR, 1PR) and remained progression free at 6 months. 3/10 patients had SD after 4 cycles, the overall response rate (≥PR) was 1/10(10%) and the clinical benefit rate (≥MR) 2/10 (20%). Overall outcomes were: PR 10%, MR 10%, and SD 30%. Median time to maximum response was 1.84 months (95% CI [1.09, 8.65]). Toxicities at the RD were manageable, 30% of patients required a dose reduction. 22 serious adverse events were reported in 16 patients across all doses, mainly infections (10/22, 45.5%). The commonest grade 3-4 toxicities reported for all 22 patients were: platelet count decrease (12, 54.5%), white blood cell decreased (6, 27.2%), diarrhoea (5, 22.7%). The most frequent grade 1-2 toxicities were fatigue (15, 68.2%), nausea (14, 63.3 %), anorexia (14, 63.6%), anaemia (13, 59.1%). 1 patient withdrew due to toxicity, and there were no treatment related deaths. Conclusions: This study demonstrated that the novel combination of CHR-3996 and tosedostat was safe and tolerable in multiply relapsed, refractory myeloma patients many of which had poor bone marrow function. The recommended dose of the combination was 20mg and 60mg, respectively. Following further adjustment to an intermittent 5 day/ week dosing schedule, treatment was well tolerated and clinical benefit observed. This suggests that further evaluation of this novel combination is warranted. Acknowledgments: This trial was part of the Myeloma UK Clinical Trial Network, ISRCTN: 24989786. Disclosures Williams: Novartis: Honoraria; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau; Takeda: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Yong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding. Cook:Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Glycomimetics: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Jenner:Amgen: Consultancy, Honoraria, Other: Travel support; Takeda: Consultancy, Honoraria, Other: Travel support; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Morgan:Univ of AR for Medical Sciences: Employment; Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Description: Introduction. The impact of therapy in the management of disease relapse in patients with myeloma (MM) needs to be balanced with the impact on quality of life (QoL). The benefit of a salvage autologous stem cell transplant (ASCT2) has been demonstrated in terms of durability of response over non-transplant consolidation (NTC) (G Cook, et al., Lancet Oncology, 2013 Vol. 15, No. 8, p874-885). However, the impact of ASCT2 on patient reported outcomes (PRO) has not been reported to date. Therefore, patients' experience of pain and global measures of QoL, as part of a systematic assessment of PRO were measured at key points before, during and after randomisation in this multi-centre national phase III trial. Methods. 174 patients were randomised and data are presented on 171 who completed self-rated QoL assessments using EORTC QLQ-C30 and the EORTC myeloma module (MY-20). Pain assessments using BPI-SF were also incorporated. Genomic DNA was prepared from PBMNC using standardised GLP methods. Results. Completion rates for EORTC QoL and BPI-SF assessments were 83.3% and 77.1% at registration, and 59.6% and 53.8% at randomisation, respectively. Over half of patients reaching 1 year post-randomisation completed both assessments. EORTC QoL and BPI-SF forms had average 6% and 10% missing data, respectively. These completion rates are commensurate with previous longitudinal studies. EORTC QLQ-C30 Global health status/QoL subscale scores were significantly higher (better) in the NTC arm at 100 days and 6 month post-randomisation (P=0.0496), but not at later time points. BPI-SF pain scores showed significantly higher pain severity in the NTC (4.3/10) than the ASCT2 (2.9/10) patients only at 2 years post-randomisation. However, for pain interference with aspects of daily living, NTC patients reported significantly lower scores at 6 months (P=0.0155), 1 year post-randomisation (P=0.0466) and 2 years post-randomisation (P=0.0348). The MY-20 assessment showed that at 100 days and 6 months post-randomisation, the subscale scores for Side-effects of treatment were significantly higher in the ASCT2 arm than in the NTC arm, but not at later time points up to 2 years. Kaplan-Meier estimate of time-to-progression (TTP) by randomised allocation suggested that patients with an EORTC global QoL score greater than median (ie better QoL) at randomisation and who received ASCT2 had a significant TTP advantage over those receiving NTC (HR 0.3 (95% CI 0.15-0.61), p=0.006). However, with multivariate Cox regression analysis accounting for stratification factors this difference was not significant. Patients who reported a lower (ie better) than median level of concern on the Side-effects of treatment subscale and who received ASCT2 had a significant TTP advantage over those receiving NTC (Kaplan-Meier HR 0.24 (95% CI (0.10-0.55), p=0.003). This survival difference was still observed after multivariate Cox regression analysis (HR 5.02 (95% CI 1.00-25.20), p= 0.0499). We tested for genomic associations of SNPs from key genes reported to be involved in pain perception and analgesic responsiveness, and subjective outcomes. There were no significant associations for the opioid mu-receptor (OPRM1) and pain or QoL. However, the rs2236861 SNP in the opioid delta-receptor (OPRD1) showed nominally significant associations with worst pain (p=0.022), average pain (p=0.03) and pain interference (p=0.02) at baseline. The rs1045642 SNP in the ABCB1 drug transporter gene was nominally associated with worst pain (p=0.047) and average pain (p=0.019) after bortezomib-based induction therapy. A SNP rs13361160 in the chaperonin CCT5 gene was associated with worst pain (p=0.033), least pain (p=0.006) and pain interference (p=0.03). It was also associated with self-reported global QoL (P=0.014). Conclusions. We report the first PROs using self-reported QoL and pain assessments in myeloma patients having salvage ASCT or NTC. Global QoL was worse and side-effects of treatment higher after ASCT2 for up to 6 months post-randomisation but then equalised. Pain caused less interference with daily living after NTC but became more severe at 2 years, possibly associated with relapse. Patients who reported lower concerns about side-effects of treatment after ASCT2 had a significant TTP advantage. The genomic analyses suggest a potential inherited predisposition that influences both pain and quality of life and warrants further exploration. Disclosures Ahmedzai: Mundipharma: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Grunenthal: Consultancy, Research Funding, Speakers Bureau. Snowden:Sanofi: Consultancy; MSD: Consultancy, Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; Celgene: Other: Educational support, Speakers Bureau. Williams:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Cavenagh:Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Parrish:Janssen: Speakers Bureau; Celgene: Speakers Bureau. Yong:Amgen: Honoraria; Novartis: Consultancy; Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Autolous: Consultancy. Cavet:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Bird:Celgene: Speakers Bureau; Janssen: Other: Educational support; Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Ashcroft:Janssen: Consultancy, Other: Educational support. Brown:Bayer: Research Funding; Roche: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Morris:Celgene: Other: Meeting support; Janssen: Other: Meeting support. Cook:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Description: Background Bendamustine has efficacy as first-line treatment in multiple myeloma (MM) (in combination with prednisone), and in refractory patients who have been heavily pre-treated. Dose finding studies have not been performed for bendamustine in heavily pre-treated relapsed/refractory patients. MUK one is a randomised phase II selection trial assessing the activity & tolerability of two doses of bendamustine (B), 60mg/m2 vs 100mg/m2, in combination with thalidomide (T) & dexamethasone (D) in patients with relapsed/refractory MM. Methods Patients were randomised to receive B(60)TD or B(100)TD (B days 1 & 8 ; T 100mg od; D 20mg d1, 8, 15 & 22; 28 day cycle). Eligibility was based on confirmed MM with measurable disease, ECOG 0-3, platelets 〉75x109/L & neutrophils 〉1.5x109/L at 1st or later relapse. In the initial protocol, patients with lower platelets/neutrophils attributable to myeloma were eligible. Activity and tolerability were joint primary endpoints. The primary activity endpoint was ≥PR within 6 cycles. Tolerability was defined as the ability to receive at least 2 cycles of treatment at full dose with no delays of 〉2 weeks, without primary growth-factor support. Response rates 75x109/L, regardless of marrow infiltration. Consequently, two analysis populations are defined. (i) Primary analysis population: patients fulfilling amended eligibility criteria without PD after 1 cycle, having ≥1 dose of study drug, (B60TD evaluable n=45; B100TD evaluable n=14). (ii) Combined population: as for (i) but including patients with PD after cycle 1, (B60TD combined n=54; B100TD combined n=20). This group represents an intention to treat population with the amended criteria. 46% (80% CI [37-56]) of patients in the B60TD combined population achieved ≥PR, with a median PFS of 7.5 months (95% CI [5.3-8.7]). In the B100TD combined population 25% (80% CI [13-42]) of patients achieved ≥PR, with a median PFS of 2.6 months (95% CI [1.7-5.6]). In the assessment of tolerability, 70% (80% CI [59-79]) of B60TD primary patients assessable for tolerability received ≥2 cycles of full-dose treatment with no delay 〉2 weeks. Median number of B60TD cycles was 6 (range 1-9), with 64% patients receiving ≥6 cycles. 32% patients experienced ≥ grade 3 neutropenia, 25% ≥ grade 3 thrombocytopenia, & 14% ≥ grade 3 anaemia. There was 1 grade 3 neurotoxicity, & no grade 3 nausea or GI disturbance. Of the B100TD primary patients 71% (80% CI [51-87]) met tolerability criteria. Median number of cycles was 4 (range 1-9), 29% patients receiving ≥6 cycles. 64% patients experienced ≥ grade 3 neutropenia, 21% ≥ grade 3 thrombocytopenia, & 21% ≥ grade 3 anaemia. There were 3 grade 3 neurotoxicities, no grade 3 nausea & 1 grade 3 diarrhoea. Thromboembolism rates with prophylactic anticoagulation was 4% overall. 84% of patients had ≥3 prior therapies, PS 0/1 (85%) & relapsed MM (78%); 37% were ISS 3 at entry, mean b2M=5.6. Most had prior T (90%), Lenalidomide (74%) & Bortezomib (84%); 74% had ≥1 prior autograft. Discussion The combination of BTD shows promising response rates at the 60mg/m2 dose, despite only 70% of evaluable patients receiving at least 2 full cycles of bendamustine with ≤2 week delay, in this challenging multi-treated group of patients. The B100TD arm closed to recruitment at interim analysis due to lack of tolerability on the basis of pre-defined stopping rules. Responses were also lower in this arm compared to B60TD arm, which may reflect the ability of patients to receive more cycles of treatment to schedule at 60mg/m2 than at 100mg/m2. Although not passing the strict pre-specified tolerability boundaries, B60TD appears deliverable beyond 2 cycles in multiply-pretreated MM, with PR in excess of 45%, comparing favourably other novel agent combinations in this heavily pre-treated population. Disclosures: Schey: Napp: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cook:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Cavet:Celgene: Consultancy, Research Funding.

Description: Introduction Although ASCT in MM is standard consolidative therapy in first line treatment definitive evidence for its use in salvage therapy is lacking. The principal aim of this multi-centre phase III randomised controlled trial was to evaluate the durability of response (DuR) of a second ASCT compared with a less intensive alkylating agent consolidation, after a bortezomib-containing re-induction strategy. Patients and Methods Eligible patients with MM relapsing after a prior ASCT were enrolled. All patients were re-induced with PAD therapy (Bortezomib 1.3mg/m2 iv D1, 4, 8 & 11; Doxorubicin 9mg/m2/day iv D1-4; Dexamethasone 40mg/day PO D1-4: additionally D8-11 & D15-18 on cycle 1 only) delivered in 4-6 21-day cycles before 1:1 randomization to either a second ASCT (Melphalan 200mg/m2 iv; ASCT2 supported by either stored stem cells or remobilized stem cells) or low dose consolidation with weekly cyclophosphamide 400mg/m2 PO for 12 weeks (C-weekly). Response assessment (by IMWG criteria) was analyzed after re-induction and 100 days post-randomization and time-to-disease progression (TTP) determined. Patients were stratified by β2microglobulin (β2M) at trial entry and response to re-induction and analyzed according to cytogenetic abnormalities by iFISH (unfavorable: t(4,14), t(14,16) and del17p). The primary endpoint was Time-to-progression (TTP) with secondary endpoints of OS, overall response rate (to PAD and randomized intervention), feasibility of stem cell mobilization in salvage therapy, safety & quality of life. Results The Data and Safety Monitoring Board (DSMB) recommended randomization closure and early result release owing to the primary end-point having been met. 297 patients were entered into the study and 174 randomized from April 2008 to November 2012: ASCT2 n = 89, C-weekly n = 85. Median age was 61 (range 38 -75) with 73.6% of patients relapsing more than 24 months from first ASCT. ORR to re-induction therapy was 79.4%% with 16.0% sCR/CR rate. Post-randomization, sCR/CR was significantly higher in ASCT2 (39.3%, 95% CI 29.1, 50.3) than C-weekly (22.4%, 95% CI 14.0, 32.7) cohorts with more patients upgrading response to sCR/CR in the ASCT2 (n = 22) than C-weekly (n = 7) cohorts. At the time of analysis, 125 of 174 patients have progressed, 57 in the ASCT2 (64%) and 68 in the C-weekly (80%) cohorts. Median TTP was 19 months (95% CI 16, 25) for ASCT2 compared with 11 months (95% CI 9, 12) for C-weekly (HR 0.36 95% CI 0.25, 0.53; Cox regression analysis p

Description: Introduction Minimal residual disease (MRD) assessment by multicolour flow cytometry (MFC) following upfront therapy is a powerful prognostic tool in multiple myeloma (MM) and there is growing evidence supporting its role as an outcome measure in clinical trials. There is however no published data assessing its utility in the relapse setting. Our aim was to test the utility of MFC at first relapse following a second autologous transplant (ASCT2) or weekly cyclophosphamide (C-weekly) consolidation following re induction chemotherapy in patients entered into the BSBMT/UKMF Myeloma X trial. Patients and Methods Eligible MM patients relapsing after a prior ASCT were enrolled and received a bortezomib-containing re-induction regimen (PAD, Bortezomib, Doxorubicin and Dexamethasone) before being randomized to either ASCT2 or C-weekly. The primary endpoint was time-to-progression (TTP) with secondary endpoints of overall survival and overall response rate (to PAD and randomized intervention). Bone marrow aspirate samples were analyzed by MFC at trial entry to establish neoplastic phenotype and then at specified time-points following treatment. After red cell lysis and washing, samples were labelled with CD27-FITC, CD56-PE, CD19-PerpCPCy5.5, CD38-PE-Cy7, CD138-APC and CD45-APC-Cy7. A minimum of 500,000 events were acquired on a FacsCanto II cytometer and data was analyzed using a standardized gating strategy. Sensitivity of the assay is 0.01% of leucocytes. Response assessment (after re-induction, 100 days post-ASCT2 or 30 days post C-weekly) and disease progression were determined using IMWG criteria. Unfavourable genetic abnormalities were defined as FGFR3/IGH, IGH/MAF and TP53 deletion by interphase FISH. Results 297 patients with a median age of 61 (range 38 -75) were entered into the study and 174 randomized from April 2008 to November 2012: ASCT2 n=89, C-weekly n=85. Of the whole trial cohort, MFC analysis was available in 224 at presentation, 162 at completion of re-induction therapy, 46/89 at D100 post ASCT2 and 50/85 at D30 post C-weekly. In an intention to treat analysis of all available randomized patients, achieving MRD negativity was highly predictive for improved TTP: All patients (MRD+ 12mns 95%CI 10-13 vs. MRD- 24mns 95CI NR; logrank P=0.0003), ASCT arm (MRD+ 15mns 95%CI 11-19 vs. MRD- 24mns 95%CI 16-42; logrank P=0.0227) & C-weekly arm (MRD+ 11mns 95%CI 8-12 vs. MRD- 15mns 95%CI 9-NR) logrank P=0.0107). MRD status was also assessed in conjunction with IMWG conventional categorical response assessment. CR was demonstrable in 39% of patients post ASCT2 and 22% of patients following C-weekly. The presence of MRD predicted outcome in those patients achieving a CR and the most favourable outcome was seen in CR/MRD- patients (

Description: Background Lenalidomide is an effective treatment for myeloma and has been studied in a range of combination regimens worldwide. The results of these studies have suggested that prolonged exposure to lenalidomide is important to improve outcomes both as a maintenance agent post-transplant (Attal M et al NEJM 2012, McCarthy et al NEJM 2012) and in the transplant ineligible population (Palumbo A et al NEJM 2012, Benboubker L et al NEJM 2014). In the Myeloma XI study, the largest of its kind, we explored the use of oral lenalidomide continued to disease progression compared to no therapy in both newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) populations. Here we present the results of this maintenance randomization, which demonstrate the efficacy and safety of maintenance lenalidomide. Methods The Myeloma XI study is a Phase III, UK-based, multicenter, open-label, parallel group, randomized controlled trial for newly diagnosed symptomatic myeloma patients of all ages and includes a maintenance comparison of lenalidomide versus no maintenance. Newly diagnosed symptomatic myeloma patients both TE and TNE were enrolled to the study. Induction treatment in both pathways was with thalidomide or lenalidomide plus cyclophosphamide and dexamethasone, with appropriate dose reductions for TNE patients. TE patients proceded to a standard melphalan 200mg/m2 transplant. Patients were randomized to either maintenance lenalidomide or observation after achieving maximum response (TNE) or at 100 days after transplant (TE). Lenalidomide was administered at a dose of 10mg daily in 21/28 day cycles until disease progression. Dose adjustments for renal impairment and following AEs were permitted. The primary endpoints for the maintenance randomization were progression-free (PFS) and overall survival. Secondary endpoints included response, toxicity and PFS2. Time-to-event endpoints were measured from maintenance randomization. This abstract summarizes a preliminary analysis, final data will be presented at the meeting. The median follow up in this analysis is 26 months [IQR 12-41]. Results A total of 1550 patients, 828 TE and 722 TNE, median age 61 and 74 years, respectively, were randomized between lenalidomide (n=857) and no maintenance (n=693). The arms were well-balanced for clinical features and response to induction therapy (e.g. ISS stage III: 27% vs 23%, VGPR/CR: 73% vs 73%). The maintenance randomization has met its primary endpoint demonstrating a 55% reduction in risk of progression or death for lenalidomide compared to no maintenance (HR 0.45 [95%CI 0.39-0.52], median PFS 37 vs 19 months, p

Description: Background The Myeloma XI study is the first randomized study to investigate a response-adapted approach to induction therapy for newly diagnosed myeloma (NDMM). The study addresses whether, for patients achieving less than optimum response to an initial immunomodulatory (IMiD) triplet combination, defined as at least VGPR, the use of a sequential proteasome inhibitor (PI) based triplet can improve outcomes. In total 581 patients were randomized into the study which confirms the clinically significant benefit of deepening responses by utilizing treatment with a different mode of action, and that this leads to better outcomes. Methods This phase III, UK-based, multicenter, open-label, parallel group, randomized controlled trial for NDMM patients of all ages, randomized patients initially between a thalidomide or lenalidomide triplet combination with cyclophosphamide and dexamethasone. This IMiD triplet was continued for a minimum of 4 cycles (transplant eligible, TE) or 6 cycles (transplant non-eligible, TNE) and to maximum response. At the end of this IMiD regimen response was assessed. Patients with a suboptimal response (MR/PR) were randomized between further induction therapy with bortezomib, cyclophosphamide and dexamethasone (CVD) or no further induction therapy. Patients with a good response (VGPR/CR) proceeded straight to ASCT (if TE), whilst refractory (SD/PD) patients all received the CVD regimen. For patients receiving CVD, treatment was planned to continue to maximum response, and eligible patients would proceed to ASCT. The primary endpoints of the adapted approach randomization were progression-free survival (PFS) and overall survival. Secondary endpoints included upgrading of response compared to baseline and the impact of the PI combination in a high-risk subgroup. This abstract contains a preliminary analysis, final data will be presented at the meeting. The median follow up in this analysis is 29 months [IQR 17-44]. Results 581 patients (366 TE, 215 TNE) with initial response to IMiD of MR/PR were entered into the CVD randomization. In total 292/581 patients were randomized to receive sequential treatment with CVD. The arms were well-balanced with respect to clinical features and response (e.g. ISS stage: III 21% vs 19%, PR: 88% vs 88%). This randomization has met its primary endpoint. Overall the sequential use of CVD significantly improved PFS from a median of 24 to 30 months (HR 0.67 [95%CI 0.53-0.85], p=0.0005). This was largely due to a significant improvement seen in the TE pathway, HR 0.56 [95%CI 0.40-0.77], median PFS no therapy 31 months vs CVD 55 months, p=0.0003. In the TNE pathway there was an early benefit with improved median PFS 14 months vs 20 months, but similar hazard after 2 years (HR 0.83 [95%CI 0.60-1.17], p=0.297). Importantly upgrading of response was seen with 118/289 (41% [95%CI 35-47]) of evaluable patients who received CVD moving from MR/PR to VGPR/CR. 115/289 remained in the same response category MR/PR, but these patients still had a mean reduction in paraprotein during CVD of 24% [95%CI 11-17]. The upgrade in response was seen in both pathways and was not affected by the IMiD received in the initial induction randomization. The impact of CVD in cases with molecularly defined high-risk disease compared to standard and multiparameter flow cytometry assessment of minimal residual disease status will be presented at the meeting. In the transplant eligible pathway an improved depth of response persisted in the 253 patients completing ASCT with VGPR/CR responses post ASCT of 65% for those who were randomized to CVD (VGPR n=133, CR n=86) compared to 38% for those who went straight to transplant (VGPR n=120, CR n=46). Sequential CVD was well tolerated with patients receiving a median of 4 cycles of therapy (range 1-8). Relevant grade 3/4 toxicities were: neutropenia 7.1%, thrombocytopenia 7.5%, anaemia 3.1%, peripheral neuropathy 5.1%. Conclusion For the first time we have shown that the use of a response-adapted therapy based on the use of chemotherapeutic agents with a different mode of action in myeloma can improve response rates, both pre- and post-transplant and that these translate into improved PFS. On behalf of the NCRI Haem-Onc CSG Disclosures Jackson: Roche: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau. Davies:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Pawlyn:Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy. Jones:Celgene: Honoraria, Research Funding. Kishore:celgene: Other: travel grant. Garg:Janssen: Other: Travel support, Research Funding, Speakers Bureau; Takeda: Other: Travel support; Novartis: Other: Travel support, Research Funding. Williams:Takeda: Honoraria, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria. Karunanithi:Celgene: Other: Travel support, Research Funding; Janssen: Other: Travel support, Research Funding. Lindsay:Novartis: Other: Travel support; Janssen: Consultancy; Takeda: Other: Travel support; BMS: Consultancy, Other: Travel support; Celgene: Honoraria, Other: Travel support. Jenner:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel support. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kaiser:BMS: Consultancy, Other: Travel Support; Takeda: Consultancy, Other: Travel Support; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Owen:Takeda: Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Other: Travel support. Morgan:Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding.

Description: Abstract 4067 Background: Existing evidence has shown that continuing treatment with LEN plus dexamethasone (LEN-DEX) until disease progression in responding patients (pts) with relapsed/refractory multiple myeloma (RRMM) is associated with improved survival. In accordance with National Institute of Clinical Excellence (NICE) guidelines, LEN-DEX is reimbursed for treatment of RRMM pts after ≥2 therapies in England and Wales (current license after ≥1 prior therapy). The TCS database was designed as part of the NICE agreed pt access scheme, to track the duration of treatment for RRMM pts prescribed LEN-DEX. This scheme was not designed to record reasons for dose adjustments or treatment discontinuation. We studied LEN starting dose, dose modifications, and duration of treatment (in an anonymized dataset generated for statistical analysis). Methods: This prospective cohort analysis focused on pts enrolled in the TCS program between 1 July 2009 and 1 May 2010, to allow pts to be followed up for at least 2 years, unless they discontinued treatment earlier. The cut-off date was 30 June 2012. Associations between ordered categorical variables were measured by Spearman's rank correlation or Pearson's correlation for continuous variables. Baseline covariates (age and starting dose) were modeled using multivariable logistic regression with possible interactions considered. Statistical significance was considered at the 5% significance level. Results: A total of 1,286 pts with RRMM from 185 UK treatment centers were evaluable. The median age was 69 yrs (range, 34–91); 427 pts were aged 75 yrs (26%). Majority of pts (n = 835; 65%) initiated LEN treatment according to the recommended starting dose of 25 mg/d; 180 (14%) pts started at 15 mg, 212 (16%) at 10 mg, and 59 (5%) at 5 mg. Dose modifications were reported in 50% of pts, and the median number of changes in dose per subject was 1 (range, 0–15). The greatest percentage of dose modifications per cycle occurred in pts with the lowest starting dose (5 mg). A total of 340 (45%) pts who started on 25 mg/d and received 〉1 cycle required no dose adjustments. There was a relationship between dose adjustment and duration of treatment; pts without an adjustment received an average of 9.1 cycles while those with at least one form of adjustment received 14.3 cycles (P 〈 0.001). The median number of cycles administered was 7 (range, 1–38), similar to that seen in LEN clinical trials (median 9.2 mos in pts with ≥2 prior therapies); 456 (35%) pts remained on therapy for ≥12 cycles and 201 (16%) pts remained on therapy for ≥24 cycles. Six percent of all pts receiving ≥24 cycles had dose modifications directly after cycle 1, with the percentage of dose modifications steadily decreasing from cycle 6 onwards. There was a positive association between a higher starting dose and longer treatment duration (P 〈 0.001). Of the pts who started on 25 mg/d and ≤10 mg/d, 18% and 9% received ≥24 cycles, respectively. There was a significant negative correlation between age and the number of cycles administered (P = 0.018): of the pts aged

Description: Background Primary refractory myeloma is an important therapeutic challenge; understanding its clinical course and biology is essential if we are to recognize it early and target it therapeutically. Immunomodulatory (IMiD) drugs are widely used as induction therapy with good response rates but a small proportion of patients are refractory. The mechanism underlying IMiD resistance is poorly defined. Mutations in the cereblon pathway are a clear candidate but have not been widely looked for or reported. An important question is whether the primary refractory clone carries class-specific intrinsic resistance biology, leaving it sensitive to other non-cross reactive drugs, or if it is a universal resistance mechanism. We have examined the clinical course of patients with primary IMiD resistance, and whether they respond adequately to subsequent proteasome inhibition (PI), using the results of the largest clinical study in myeloma to date. Methods Myeloma XI is a UK based, open-label, parallel group, randomized controlled trial for newly diagnosed symptomatic myeloma patients of all ages. Treatment was with a combination of cyclophosphamide and dexamethasone plus either lenalidomide or thalidomide (CRD or CTD) for a minimum of 4 cycles (transplant eligible, TE) or 6 cycles (transplant non-eligible, TNE) or to maximum response. Those patients who had not achieved at least a minimal response or who had progressed during induction (PD) subsequently received a PI triplet (cyclophosphamide, bortezomib and dexamethasone, CVD). This abstract summarizes a preliminary analysis of these primary refractory cases, final data will be presented at the meeting. Results The study randomized 3894 patients of all ages giving adequate numbers to identify clinical/biological features in subgroups. Overall 207/3894 (5.3%) of patients had stable disease (SD) or PD at the end of the IMiD triplet. There was no significant difference between those who received thalidomide compared to lenalidomide (CTD: 110/1945, 5.7% CRD: 97/1949, 5.0%). A higher proportion of patients were refractory in the TNE pathway than TE (TE: 79/2042, 3.9%, TNE: 128/1852, 6.9%) 139 patients in the ITT population went on to receive treatment with bortezomib as part of the CVD regimen. The remainder n=69 were treated off protocol or died prior to treatment. CVD was well-tolerated in these patients with a median of 4 (1-8) cycles delivered. Of these patients 22/139 (16%) were also refractory to PI therapy whilst 57% upgraded their response compared to baseline: 32% [95%CI 24-40] to PR/MR and 25% [95%CI 18-33] to CR/VGPR. Patients with IMiD refractory disease had a significantly shorter PFS than those who responded to initial treatment median 8 vs 27 months, HR 2.10 [95% CI 1.77-2.49], p20% plasma cells in their bone marrow biopsy. There was a higher proportion of patients with light chain only disease and the percentage of patients with ISS stage III was double-refractory 41%, IMiD refractory 45% and responsive 29%. The proportions of patients with adverse translocations and high-risk copy number abnormalities will be presented at the meeting. Conclusions We present the first detailed analysis of IMiD refractory myeloma patients at diagnosis. There was no difference in the percentage of patients refractory to the different IMiDs thalidomide and lenalidomide. Very few patients were primarily refractory to both IMiDs and proteasome inhibitors, suggesting the mechanisms of primary resistance to IMiDs and PIs do not significantly overlap. However, where this did occur outcomes were poor. The biological mechanisms behind resistance will be further informed by molecular studies of these patients' tumour samples. On behalf of the NCRI Haem Onc CSG Disclosures Pawlyn: Takeda Oncology: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support. Davies:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:Takeda: Consultancy, Other: Travel Support; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy. Jones:Celgene: Honoraria, Research Funding. Kishore:celgene: Other: travel grant. Garg:Janssen: Other: Travel support, Research Funding, Speakers Bureau; Takeda: Other: Travel support; Novartis: Other: Travel support, Research Funding. Williams:Novartis: Honoraria; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau; Takeda: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Karunanithi:Celgene: Other: Travel support, Research Funding; Janssen: Other: Travel support, Research Funding. Lindsay:BMS: Consultancy, Other: Travel support; Novartis: Other: Travel support; Takeda: Other: Travel support; Janssen: Consultancy; Celgene: Honoraria, Other: Travel support. Jenner:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel support; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel support. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Owen:Takeda: Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Other: Travel support. Jackson:Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Morgan:Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Univ of AR for Medical Sciences: Employment; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Description: Introduction Heterogeneity of molecular abnormalities in myeloma plasma cells (PCs) & their impact on clinical outcomes has been clearly demonstrated in newly diagnosed patients & advanced disease stages. Limited analysis at first relapse stage & in particular the impact of molecular risk categories on intensive re-induction/consolidation therapy limits the use of such analysis to predict suitable patient selection. Patients and Methods MM patients relapsing 〉18 months after a prior ASCT were enrolled into a phase III RCT, receiving a Bortezomib-containing regimen (Bortezomib, Doxorubicin and Dexamethasone) before being randomised to either a second ASCT or Cyclophosphamide weekly. BM aspirate samples at trial entry and at further disease progression were CD138 positively selected (Miltenyi AutoMac) and PC suspensions were fixed in Carnoy’s then stored at -20°C. Interphase FISH analysis (iFISH), was performed with commercial probes, scored and image captured (Zeiss AxioPlan microscopy with MetaSystems software). Depth of response (IMWG criteria) was analysed post-induction and 100 days post-randomisation with durability of response determined as time-to-progression (TTP). Results 222 samples from 297 patients were received & satisfactory CD138+ cell purity and yield was obtained in 149 samples (68% recovery). Of these, only 35 (28%) demonstrated no genetic defects by iFISH at trial entry. A single genetic abnormality was detected in 28 patients (23%): del13q (n=8), IGH rearrangement (n=16), MYC rearrangements (n=2) and del17p (n=2). 2 and ≥3 molecular genetic abnormalities defects were detected in 42 patients (28%) and 32 patients (21%), respectively. The commonest abnormality detected was an IGH rearrangement (n=62, 41%) & there were insufficient CD138+ cells for additional translocation testing in 11/62; Of the 51 IGH rearranged samples, a partner translocation was identified in 32 (63%): CCND1/IGH in n=15 (29%), FGFR3/IGH in n=14 (27%) and IGH/MAF in n=3 (6%) with an additional single genetic defect detected in 31 samples (50%). Del13q was present in 58 patients (39%) of whom 29 patients (50%) demonstrated one additional genetic defect (IGH rearrangement n=22, del17p n=3 and MYC rearrangements n=4), 20 patients (35%) demonstrated 2 additional defects and 2 patients demonstrated 〉2 additional defects. A rearranged MYC was detected in PCs from 24 patients (16%) with 2 & ≥3 additional defects detected in 13 & 6 patients’ samples, respectively. Del17p was detected in PCs from 22 patients’ samples (15%) with additional copies of Ch17 present in PCs of 8 patients (6%). All Ch17+ patient samples exhibited additional genetic defects. Where del17p clones were detected, 9 and 10 samples had 1 & ≥2 genetic defects. When del17p was present, MYC arrangements were also detected in 16 patients (73%). 20 patients (13%) demonstrated hyperdiploidy with 8 patients demonstrating no other defect. The presence of IGH and MYC rearrangements or del17p did not correlate with the duration of response from ASCT1 nor did it impact the ORR or sCR to bortezomib-based induction. The presence of IGH and MYC rearrangements or del17p did not impact on the TTP in the C-weekly cohort, however both del17p (median TTP - absent: 19 mns, 95%CI, 16-25 mns, vs. present: 10 mns, 95%CI, 2-11 mns; logrank p=0.002) and MYC rearrangements (median TTP absent: 24 mns, 95%CI 12-42 mns vs. present: 11 mns, 95%CI 1-18 mns; logrank p=0.006) impacted on TTP in the ASCT2 cohort. Only the presence of MYC rearrangements were predictive of reduced TTP in the ASCT2 group (Cox regression model interaction test HR 0.08, 95%CI 0.02-0.44; p=0.003) when accounting for treatment response to previous ASCT & response to induction therapy. Conclusion: IGH rearrangements were identified at a similar frequently to analyses reported at presentation though with disproportionately more FGFR3/IGH and MAF/IGH abnormalities. Otherwise, the incidence of genetic abnormalities was similar to rates reported at diagnostic with a frequent association of MYC rearrangements with del17p. Whilst both del17p and MYC rearrangements were associated with inferior durability of response following an ASCT, only a MYC rearrangement was of independent predictive significance. As follow-up is limited, the impact on overall survival currently remains to be determined. Disclosures: Williams: Janssen: Honoraria, Speakers Bureau. Snowden:Janssen: Honoraria, Research Funding, Speakers Bureau.