ALBERT

Description: The role of maintenance therapy for the long term control of the plasma cell clone in patients induced into response with either intensive or conventional treatment is an important outstanding question. We addressed this in the MRC Myeloma IX study which incorporates intensive and non-intensive pathways selected according to PS and age. In the intensive pathway patients were randomised to either CTD or CVAD induction, followed by High Dose Melphalan (HDM) before being randomised to either thalidomide or no maintenance. In the non-intensive pathway patients were randomised to either MP or attenuated CTD prior to the maintenance randomisation. For patients randomised to thalidomide it was initiated at d100 following HDM or at the end of induction in the non-intensive arm with the aim of delivering 100mg daily until relapse. A dose reduction algorithm for side effects was used. Between the years of 2003–8, 820 patients were entered into the maintenance randomisation, median age 64 (intensive 59, non-intensive 73), median follow-up 32 months. Prognostic features were evenly distributed between the arms. FISH and cytogenetics were done using standard methods. Response was assessed by IWG criteria. For overall survival (OS) there was a non-significant trend in favour of the no maintenance arm, which enables us, by calculating confidence limits on the hazard ratio, to make the assertion that no maintenance could be up to 7% worse than thalidomide at 5 years (p=.005). Further analysis showed that there was no significant difference in OS in either the intensive or the non-intensive arm. The duration of time on thalidomide maintenance appeared to make no difference to OS. There was a non-significant improvement in progression free survival (PFS) across the maintenance randomisation as a whole and in the intensive pathway a significant benefit of maintenance was seen in the patients achieving less than a VGPR post initial induction therapy prior to HDM, (hazard ratio 1.9, p=.007). This PFS difference did not translate into a survival benefit because the survival after progression in the PR patients receiving maintenance thalidomide was poor (p=.002). In addition we looked at the time spent off thalidomide, the recovery time, (the time between stopping thalidomide and progression) as a possible predictor of survival after progression. Treated as a continuous variable in the Cox model this showed a trend for longer survival after relapse in those with longer recovery time (p=.056). In the non-intensive pathway a similar but less pronounced effect of thalidomide maintenance on PFS was seen. These results are consistent with a consolidation rather than a maintenance effect for thalidomide in this setting. The impact of maintenance in different cytogenetic subgroups was also determined [17p-, 13q-, 14q abnormalities including t(4;14), t(14;16), t(6;14), t(14;20) and t(11;14)]. For the 17p- group, the difference in OS between no thalidomide and thalidomide is large (HR = 4.55, p=.02) with the thalidomide patients faring worse, although this is based on only 30 patients. For the non 17p- group there is no difference in PFS (HR = 1.24, p=.37), in the 17p- group, however, the PFS is worse. In addition, of the 22, 17p- patients receiving CTD or CTDa as initial therapy, the 10 who received no thalidomide maintenance are all still alive, whereas 9/12 of those who went on to receive thalidomide maintenance have died. It seems that thalidomide given at induction and again in maintenance, may be particularly detrimental in 17p- patients. Although thalidomide maintenance may improve PFS, there is no demonstrable benefit on OS. It is important to identify 17p- in order to exclude these patients from receiving thalidomide maintenance.

Description: Standard treatment for younger patients with presenting myeloma is VAD followed by high-dose melphalan with stem cell support. However this regimen requires a central venous catheter with risks of recurrent line infections and central venous thrombus. A number of oral alternatives have been used including dexamethasone (Dex), thalidomide (Thal) or combinations (Thal/Dex), although to date no randomized control trial has compared an intravenous with oral induction therapy. In older patients melphalan/prednisolone (MP) remains the standard approach. Thal combinations (MPT, CTD, DVdT) improve response rates and providing side effects can be managed effectively may also be appropriate for an elderly population. Patients with myeloma have an increased risk of venous thrombotic events (VTEs), and presenting patients receiving Thal may be at increased risk due to bulk disease. Combination with anthracyclines may also exacerbate this risk. The MRC Myeloma IX trial has been designed to address some of these issues. Younger patients are randomized to receive intravenous CVAD or an oral Thal containing regimen, CTD prior to autologous transplantation; older patients are randomized to MP or the Thal containing regimen, CTDa. At trial initiation (May 2003) physicians were advised that patients should start low-dose Thal (100mg od in the intensive and 50mg od in the non-intensive arm) and slowly dose escalate to 200mg. Patients at high risk of VTE should be considered for full anticoagulation with either warfarin or LMWH. As of Aug 2004 420 patients (239 intensive, 181 non-intensive) have been randomized and a total of 30 VTEs in 28 patients have been reported (22 intensive, 6 non-intensive). In the intensive arm there were 8 DVT, 9 PE and 7 line-related thromboses. In the non-intensive arm there were 4 DVT and 2 PE. CVAD CTD CTDa MP DVT 4.2% 2.5% 4.4% 0% PE 1.7% 5.8% 2.2% 0% Line related 5.0% 0.8% NA NA Total 10.9% 9.1% 6.6% 0% The median time from randomization to DVT/PE was 54.5 days (range 15–113). 4 patients were identified who had additional risk factors (2 immobility, 1 recent operation, 1 renal failure). Only 1 patient was receiving prophylaxis having previously suffered a DVT. There was one PE-related death. Importantly 2 PE and 5 DVT occurred in patients not receiving Thal therapy. All central thrombosis occurred in relation to the central line. In the non-intensive arm the addition of Thal increased VTE risk compared to MP. In conclusion myeloma patients have an increased incidence of VTE (5.9%–8.3%) although in this study so far patients on MP appear to have no excess thrombotic risk. Patients receiving infusional regimes are also at increased risk of line-related events (additional 5.0%). Using the combination of a slowly increasing Thal dose and thromboprophylaxis based on identification of high risk patients the addition of Thal marginally increased DVT/PE risk over and above the risk seen in patients with infusional regimens, but even in a large study such as this the number of events are too small to make firm recommendations. Currently our advice remains unchanged and ALL high risk patients should receive thromboprophylaxis.

Description: Abstract 2980 Introduction: Deletion of chromosome 13, detected by conventional chromosome analysis (CC), has been suggested to be an independent indicator of poor prognosis in myeloma (MM). With the exception of a single study using conventional therapy this has not been confirmed in multicenter randomized controlled trials which have mostly used FISH analysis. We set out to assess the prognostic value of del(13) and compare its detection by FISH and CC. Methods: We have examined the effect of del(13) in a large multicenter randomized controlled phase III trial, MRC Myeloma IX (ISRCTN68454111), which tested the effect of induction therapy with a thalidomide combination in both an intensive (CTD vs CVAD prior to single HDM plus ASCT) and a non-intensive (CTDa vs MP) setting. From June 2003 to November 2007 samples from newly presenting MM patients were sent from hospitals throughout the UK to a central laboratory where CD138 purification for FISH was performed, with conventional cytogenetic culture(s), using unpurified cells, being set up wherever possible. Results: 1960 evaluable patients were entered into the trial (1111 intensive, 849 non-intensive) of which 1036 were evaluable for del(13) by FISH (613 intensive, and 423 non-intensive); del(13) was seen in 45% (470/1036) with a similar incidence in both pathways. With a median follow up of 3.7 years del(13) detected by FISH was associated with impaired OS (median, 42 vs 52 mo, p=0.004). The effect was stronger in the non-intensive pathway (median OS 25 vs 37 mo, p=0.001) than in the intensive one (median 58 mo vs not reached, p=0.095). However, this adverse prognostic impact was negated when the strong association of del(13) with the bad prognosis IGH translocations t(4;14), t(14;16) and t(14;20) (bad IGH) was taken into account. In comparison, 639 patients were evaluable for CC results (378 intensive, 261 non-intensive) with an overall abnormality rate of 35% (224/639). We note that the impact of detecting any abnormal karyotype was not significantly different from a normal/failed karyotype irrespective of intensive or non-intensive treatment being used (whole trial p=0.213, intensive p=0.249, non-intensive p=0.252) suggesting that the capacity to generate abnormal metaphases alone is not an adverse prognostic factor. Del(13) was seen in 45% of abnormal karyotype cases (102/224) and 16% of all cases tested for CC. Overall the detection of del(13) by CC was associated with an adverse prognostic effect on OS (median 34 vs 47 mo, p=0.039). However, the entire effect was in the non-intensive pathway (median 20 vs 34 mo, p=0.018) (Fig1A), with no detectable effect in the intensive pathway (median 69 vs not reached, p=0.679) (Fig1B). We addressed the impact of the treatment used, and in a comparison of the thalidomide and non-thalidomide regimes for all del(13) CC patients there was no significant impact on OS (p=0.538). However, in the non-intensive pathway there was a significant improvement in favour of thalidomide (median 33 vs 18 mo p=0.03). Multivariate analysis of the prognostic impact of genetic factors within abnormal metaphases showed that bad IGH (p=0.001), gain of 1q (p=0.001) and deletion of 17p (p=0.001) were the only independent prognostic factors. In further analyses including all FISH-detected abnormalities, the markers bad IGH (p

Description: Abstract 352 We present updated results from MRC Myeloma IX study evaluating the role of the addition of thalidomide to the induction and maintenance of patients with myeloma. The study ran from May 2003 – November 2007 and randomised 1,970 patients and now has a median follow up of more than 3.5 years giving it improved power to detect changes in outcome developing later after treatment. Projected median OS younger fitter patients 66 months, median OS older less fit patients 32 months. The trial comprised of 2 patient pathways, one for younger fitter patients comparing CTD (cyclophosphamide, thalidomide, dexamethasone) with CVAD (cyclophosphamide, vincristine, adriamycin, dexamethasone), all patients going on to receive an ASCT – median age 59 years. In older less fit patients, melphalan and prednisolone (MP) was compared to CTD attenuated – median age 73 years. In both pathways following initial treatment, eligible patients were randomised to low-dose thalidomide or no maintenance. Patient's response was monitored using electrophoresis, serum free light chain and multiparameter flow cytometry. Cytogenetics was availabel on up to 60% of cases and gene expression on a subset of these. CTD is a well tolerated regimen with a good safety profile giving excellent survivals in both groups of patients despite a small increase in risk of VTE. Using modified EBMT criteria, the addition of thalidomide to induction treatment increases both response rates and depth of response for all age groups. Preliminary results as follows: overall response: CTD vs CVAD: 91% v 82%; CR 21% v 14% and 100 days post-HDM, better responses were seen in CTD with CR rates 65% v 48%. Remission depth was also greater in CTD with more patients achieving minimal residual disease negativity by flow cytometry. The addition of thalidomide increases response rates overall, and particularly complete response (CR) rates (a 17% increase in CR rates post HDM, p=.006). In older/less fit patients CTDa vs MP: overall response 83% v 46%; CR 21% v 4%. Definitive results of these analyses will be presented as well as how they translate into PFS and OS and by cytogenetic subgroup. There is a substantial increase in response with the inclusion of thalidomide but at a median follow-up of three years we are not as yet seeing a substantial increase in survival in either of the two broad patient groups. We have collected data on treatment at relapse to explore how this confounds OS data. Importantly modelling analyses indicate when and to what extent, with further follow-up, the survival differences that should accrue from this increase in CR rate are likely to translate into a survival benefit. These results have a number of important implications. We show the benefit of the addition of thalidomide to myeloma treatment but also highlight the importance of later analysis of such trials because of the emergence of significant changes at these later time points. We will present full updated results from the study including the impact of thalidomide on cytogenetic subgroups and in the maintenance setting. Disclosures: No relevant conflicts of interest to declare.

Description: Minimal residual disease (MRD), as assessed by flow cytometry is a powerful predictor of outcome in multiple myeloma (MM). We and others have previously demonstrated that such analyses are informative in patients treated with autologous stem cell transplant (ASCT) and non-transplant regimens. It predicts outcome in patients in conventional CR and is applicable to patients with standard and adverse risk cytogenetics. As a consequence MRD assessment is under consideration as a surrogate endpoint for clinical trials. This is urgently needed in MM as 〉5yrs follow-up is typically required to demonstrate survival differences in trials of upfront therapy. If surrogate end points are to be used in clinical trials it is essential that a reproducible effect is demonstrable using multivariate models. Previous studies have confirmed the effect of MRD on PFS but a consistent effect on OS has been not been definitively shown. This may in part be due to the availability of effective salvage therapy but it is also possible that the traditional threshold of 10-4 for analysis and the categorization of patients as MRD-postive or negative is suboptimal. Flow cytometry does provide a quantitative assessment of residual tumour over a large range and the degree of tumour depletion may be more informative than a positive-negative analysis. 397 patients from the MRC Myeloma IX trial were included in this analysis. Patients were randomly assigned to CTD (cyclophosphamide, thalidomide, and dexamethasone) or CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) induction for 4-6 cycles followed by standard high-dose melphalan (HDM) ASCT. BM aspirates were obtained at day 100 for MRD analysis. 500,000 cells were evaluated with six-colour antibody combinations including CD138/CD38/CD45/CD19 with CD56/CD27 in all cases and CD81/CD117 in additional cases as required. PFS and OS data analysis was landmarked from the date of the MRD assesment. Of the 397 patients with MRD data available at day 100 after ASCT, 247/397 (62.2%) achieved

Description: The results of the MRC Myeloma VII trial and overview analysis of comparable trials have suggested that VAD-like induction chemotherapy followed by high dose therapy (HDT) with autologous transplantation may be regarded as a new standard treatment for multiple myeloma. However, there is a need for data from the extended follow up of patients in such trials to provide confirmatory evidence of the benefit of treatment incorporating HDT compared with conventional dose treatment, in particular to determine the long term difference in survival and the impact of attaining a complete response (CR) following intensive treatment. We present an updated analysis of Myeloma VII with median follow up of 5.5 years. Myeloma VII is the largest trial of its type in which patients with previously untreated multiple myeloma, age