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Summary In the Medical Research Council (MRC) Myeloma IX trial (ISRCTN684564111) patients were randomised to sodium clodronate or zoledronic acid and induction treatment: cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or cyclophosphamide, thalidomide and dexamethasone (CTD) followed by autologous stem cell transplant (ASCT) in the intensive pathway; attenuated CTD or melphalan and prednisolone (MP) in the non‐intensive pathway. Subsequent randomisation allocated patients to either thalidomide or observation. The European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QoL) questionnaires, QLQ‐C30 and QLQ‐MY24, were administered at baseline, 3, 6 and 12 months and annually thereafter, enabling the effect of sequential treatment on patient‐reported health‐related QoL (HR‐QoL) to be investigated. The protocol specified four subscales of interest: Pain, Fatigue, Global Health Status/Quality of Life and Physical Functioning at 3, 6 and 12 months that were compared using linear models. The intensive pathway showed significant differences in favour of CTD for Fatigue at 3 months and Physical Functioning at 12 months. The non‐intensive pathway and maintenance phase reported significant differences at 3 months; Pain (improved with attenuated CTD) and Global Health status/Quality of Life (improved with observation). The improved outcomes in MRC Myeloma IX were accompanied by some beneficial and few detrimental effects on HR‐QoL.

This study aims to guide the integration of serum free light chain (sFLC) tests into clinical practice, including a new rapid test (Seralite(®) ). Blood and urine analysis from 5573 newly diagnosed myeloma patients identified 576 light chain only (LCO) and 60 non-secretory (NS) cases. Serum was tested by Freelite(®) and Seralite(®) at diagnosis, maximum response and relapse. 20% of LCO patients had urine FLC levels below that recommended for measuring response but >97% of these had adequate sFLC levels (oligosecretory). The recommended Freelite(®) sFLC ≥100 mg/l for measuring response was confirmed and the equivalent Seralite(®) FLC difference (dFLC) >20 mg/l identified. By both methods, ≥38% of NS patients had measurable disease (oligosecretory). Higher sFLC levels were observed on Freelite(®) at all time points. However, good clinical concordance was observed at diagnosis and in response to therapy. Achieving at least a very good partial response according to either sFLC method was associated with better patient survival. Relapse was identified using a Freelite(®) sFLC increase >200 mg/l and found 100% concordance with a corresponding Seralite(®) dFLC increase >30 mg/l. Both Freelite(®) and Seralite(®) sensitively diagnose and monitor LCO/oligosecretory myeloma. Rapid testing by Seralite(®) could fast-track FLC screening and monitoring. Response by sFLC assessment was prognostic for survival and demonstrates the clinical value of routine sFLC testing.

There is a significant unmet need in effective therapy for relapsed myeloma patients once they become refractory to bortezomib and lenalidomide. While data from the front line setting suggest bendamustine is superior to melphalan, there is no information defining optimal bendamustine dose in multiply-treated patients. We report a multi-centre randomized two-stage phase 2 trial simultaneously assessing deliverability and activity of two doses of bendamustine (60 mg/m2 vs. 100 mg/m2) days 1 and 8, thalidomide (100 mg) days 1-21 and low dose dexamethasone (20 mg) days 1, 8, 15 and 22 of a 28-d cycle. Ninety-four relapsing patients were treated on trial, with a median three prior treatment lines. A pre-planned interim deliverability and activity assessment led to closure of the 100 mg/m2 arm due to excess cytopenias, and led to amendment of entry criteria for cytopenias. Non-haematological toxicities including thromboembolism and neurotoxicity were infrequent. In the 60 mg/m2 arm, treatment was deliverable in 61.1% subjects and the partial response rate was 46.3% in the study eligible population, with 7.5 months progression-free survival. This study demonstrates bendamustine at 60 mg/m2 twice per month with thalidomide and dexamethasone is deliverable for repeated cycles in heavily pre-treated myeloma patients and has substantial clinical activity.

Bisphosphonates are recommended in patients with osteolytic lesions secondary to multiple myeloma. We report on the safety of bisphosphonate therapy with long-term follow-up in the Medical Research Council Myeloma IX study. Patients with newly diagnosed multiple myeloma were randomised to zoledronic acid (ZOL; 4 mg intravenously every 21-28 d) or clodronate (CLO; 1600 mg/d orally) plus chemotherapy. Among 1960 patients (5.9-year median follow-up), both bisphosphonates were well tolerated. Acute renal failure events were similar between groups (ZOL 5.2% vs. CLO 5.8% at 2 years; incidence plateaued thereafter). The overall incidence of confirmed osteonecrosis of the jaw (ONJ) was low, but higher with ZOL (ZOL 3.7% vs. CLO 0.5%; P < 0.0001). ONJ events were generally low grade and most occurred between 8 and 30 months (median time to ONJ, 23.7 months). Among 10 patients with ONJ recovery data, four patients in the ZOL group completely recovered, two patients improved, and three patients experienced no improvement; one CLO patient experienced no improvement. Dental surgery or trauma preceded ONJ in six ZOL patients. The incidence of renal adverse events was similar for ZOL and CLO. ONJ incidence remained low and was lower with CLO compared to ZOL. We have seen no further ONJ cases to date.

Multiple myeloma (MM) is a heterogeneous disease. International Staging System/fluorescence hybridization (ISS/FISH)-based model and gene expression profiles (GEP) are effective approaches to define clinical outcome, although yet to be improved. The discovery of a class of small non-coding RNAs (micro RNAs, miRNAs) has revealed a new level of biological complexity underlying the regulation of gene expression. In this work, 163 presenting samples from MM patients were analysed by global miRNA profiling, and distinct miRNA expression characteristics in molecular subgroups with prognostic relevance (4p16, MAF and 11q13 translocations) were identified. Furthermore we developed an "outcome classifier", based on the expression of two miRNAs (MIR17 and MIR886-5p), which is able to stratify patients into three risk groups (median OS 19.4, 40.6 and 65.3 months, P = 0.001). The miRNA-based classifier significantly improved the predictive power of the ISS/FISH approach (P = 0.0004), and was independent of GEP-derived prognostic signatures (P < 0.002). Through integrative genomics analysis, we outlined the potential biological relevance of the miRNAs included in the classifier and their putative roles in regulating a large number of genes involved in MM biology. This is the first report showing that miRNAs can be built into molecular diagnostic strategies for risk stratification in MM.

With immunochemotherapy, remission duration and survival in patients with chronic lymphocytic leukaemia is dependent on the level of minimal residual disease (MRD) after treatment. This phase II trial assessed alemtuzumab consolidation post-chemotherapy in patients who responded with persistent low levels of detectable disease. Blood was screened for MRD using multi-parameter flow cytometry, 6-24 months post-chemotherapy. MRD-positive participants received alemtuzumab 30 mg subcutaneously 3 times weekly for 6 weeks. Following a marrow assessment, MRD-negative participants or non-responders stopped therapy and MRD-positive participants with 1 + log reduction had 6 more weeks of alemtuzumab. Alemtuzumab consolidation was received by 47 participants. One death and 19 of 22 serious adverse events reported from 17 (36%) participants were alemtuzumab-related. MRD eradication from blood and bone marrow was achieved in 39 (83%) participants at the end of consolidation, with 18 (38%) remaining MRD-negative in the blood 6 months later. Of the 18 participants who were MRD-negative at 6 months, the median time to MRD relapse was 46 months, which was similar to patients who were MRD-negative at baseline and were followed up. The 5-year progression-free survival (PFS) and overall survival (OS) of participants who were MRD-negative at 6 months was significantly better than MRD-positive participants [PFS: 78% vs. 39% (P = 0·010), OS: 89% vs. 64% (P = 0·029)].

Introduction FCR improves PFS and OS in CLL. Previous non-randomised Phase II trials suggest adding mitoxantrone to FCR (FCM-R) improves outcomes. The rituximab dose in CLL was inferred from lymphoma but in CLL even low doses of rituximab lead to the loss of CD20 expression (“shaving”) suggesting that low dose rituximab with chemotherapy may be effective. Aims The primary objective was to assess whether the CR rate to FCM-miniR was not inferior to FCR. Secondary objectives were MRD eradication, overall response rates and safety. Late endpoints (not reported) were PFS, OS and MRD relapse. Methods ARCTIC was a phase IIB, randomised, controlled, parallel group trial in previously untreated CLL performed in 34 UK centres. 206 patients were to be randomised to FCR or FCM-miniR with an 80% power to show that FCM-miniR did not lead to 10% worse CR rates compared to FCR. A formal interim analysis on the primary endpoint was planned after 103 patients. The schedule for oral FCR was equivalent to iv FCR with iv rituximab given on Day 1 (375mg/m2 Cycle 1; 500mg/m2 Cycles 2-6), oral fludarabine (24mg/m2/day for 5 days; Days 1-5) and oral cyclophosphamide (150mg/m2/day for 5 days; Days 1-5). FCM-miniR included intravenous mitoxantrone (6mg/m2/day) and 100mg rituximab on Day 1 of 6 cycles given 28 days apart. Patients with neutropenia delaying therapy received G-CSF (lenograstim 263mcg/day; Days 7-13) on all remaining cycles. Prophylaxis with co-trimoxazole and acyclovir was used. Results 200 patients were recruited, 100 to each arm. The interim analysis after 103 patients indicated that although the CR rate to FCM-miniR was similar to predicted it was inferior to FCR. The independent DMC advised that the trial would not show non-inferiority for FCM-miniR and recruitment was stopped. A further 97 patients were recruited up to the interim analysis. 21 patients still receiving FCM-miniR were advised to cross-over to FCR. 100 patients received FCR, 79 FCM-miniR and 21 patients randomised to FCM-miniR crossed over to FCR. The treatment arms were well balanced for the following: median age 63 (36-80) and 20% (n=40) over 70; 67.5% male; 17% prog. stage A, 47% stage B and 35.5% stage C. 33.5% had a creatinine clearance under 70ml/min. 60% (87/146) had unmutated Ig genes; 4% (6/164) 17p deletion; and 15% (26/168) 11q deletion. More 11q del patients were randomised to FCM-miniR (15 vs 7). 29.5% (59/200) discontinued therapy early including 30% (n=30) FCR and 35.4% (n=28) FCM-miniR. 141 (70.5%) completed 6 cycles. 93 (49%) of 189 received G-CSF - more with FCM-miniR compared with FCR (54% vs 44%). 117 (58.5%) patients experienced a dose modification; 57% for FCR and 62% for FCM-miniR; the most common being dose delay in 47% of patients. 181 SAE's were reported from 104 patients; 79 events from 49% (49/100) receiving FCR, 80 from 58% (46/79) receiving FCM-miniR and 47% (9/22) cross-over patients. 62.5% of related SAE's were infectious. 3 patients died due to an SAE, 1 FCR and 2 FCM-miniR. We report only the 179 intention-to-treat patients who did not cross-over. To date 146 of 179 patients (82%) have undergone independent central review. 70% (102/146) achieved a CR or CRi; 78% (62/79) FCR and 60% (40/67) FCM-miniR. 13/22 (59%) patients with a baseline creatinine clearance of Conclusion ARCTIC was stopped prematurely as it was clear that the arm containing mitoxantrone and low dose rituximab would not be non-inferior to FCR. However both FCR and FCM-miniR performed well with CR rates of 78% and 60% respectively. This compares favourably to CR rates of 38% for FC in LRF CLL4 Trial and 44% for FCR in the GCLLSG CLL8 Trial. MRD was undetectable in 55% of patients receiving FCR and 46% for FCM-miniR. Oral FCR in front-line CLL results in extremely high CR rates and the eradication of detectable MRD in the majority. Low dose rituximab (100mg per cycle; 600mg total dose compared to 2875mg/m2 for standard FCR) in combination with FCM appears to be effective although FCM-miniR is inferior to full dose FCR. However there is more toxicity associated with the addition of mitoxantrone confounding the comparison of rituximab doses. Disclosures: Hillmen: Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Celgene: Honoraria. Off Label Use: The use of ofatumumab in combination with chlorambucil in previously untreated CLL. The reported trial will support the extension of the ofatumumab licence. Schuh:GSK: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria.

The prognostic value of biological, clinical and laboratory features was analysed in a series of 265 patients with chronic lymphocytic leukaemia (CLL) and prolymphocytic leukaemia (PLL). On univariate analysis seven features were shown to influence significantly the survival of the whole group of patients: absolute prolymphocyte count (ABS PROL), percentage of prolymphocytes (%PROL), WBC, spleen size, age, intensity of surface-membrane immunoglobulin (SmIg) and mouse (M) rosettes. Multivariate regression analysis of these features showed that only ABS PROL and spleen size had independent prognostic significance. The survival in PLL (38 cases) was significantly shorter than in CLL (227 cases) (median survival = 3 and 8 years, respectively). Patients with CLL with an increased %PROL (11-55%), defined as CLL/PL, could be divided into two groups: those with ABS PROL less than or equal to 15 X 10(9)/l (26 cases) fell within the 'standard-prognostic risk' for typical CLL (i.e. less than or equal to 10% PROL), whereas the survival outlook for the cases with ABS PROL greater than 15 X 10(9)/l (40 cases) was as bad as for PLL. A scoring system was generated with the four features that showed high prognostic significance: ABS PROL, spleen size, SmIg and M-rosettes. The score proved to be superior to any single feature as a predictor of survival, being especially useful in the analysis of the CLL/PL group: cases with high scores (greater than 2) had a median survival of 2.5 years, while the median has not been reached for those with low scores (less than or equal to 2). We suggest that this scoring system may help to identify the cases of CLL/PL that behave as PLL, and as such may benefit from different treatment.

Between 1972 and 1982, 112 consecutive previously untreated adults (aged 15-69 years, median 26) commenced therapy for acute lymphoblastic leukaemia (ALL) at St Bartholomew's Hospital. The first 63 patients entered into the study received initial treatment which comprised four cycles of adriamycin and vincristine, prednisolone and L-asparaginase with the first cycle (OPAL). In 1978, six cycles were given, with escalating doses of adriamycin and cyclophosphamide from cycle 3 (HEAV'D). Central nervous system (CNS) prophylaxis incorporated intrathecal methotrexate and cytosine arabinoside with cranial irradiation. Maintenance chemotherapy consisted of 6-mercaptopurine, cyclophosphamide and methotrexate for 3 years. Results obtained with the OPAL and HEAV'D regimens were not significantly different. The overall complete remission (CR) rate was 66% (73/111), factors correlating unfavourably with achievement of CR being advanced age (P less than 0.001) and L3 morphology/B-ALL immunophenotype (P less than 0.01). Fifty-three patients have relapsed, the bone marrow being the primary site in 43. Extramedullary relapse alone occurred in 10 (seven CNS, two testicular and one skin). Only three of the 64 patients who had complete CNS prophylaxis subsequently relapsed in the CNS as an isolated site. One patient died in CR, 19 remain in continuous CR between 2.5 and 10.5 years. The median duration of remission of the 73 patients who achieved CR was 18.5 months, factors correlating favourably with duration of CR being low blast cell count at presentation (P less than 0.002) and common ALL immunophenotype (P less than 0.04). Twenty-four patients remain alive, with a median survival of all patients of 18 months. Long-term survival is possible for approximately 20% of adults with ALL treated relatively intensively.