High versus attenuated dose dexamethasone has little effect on the speed or depth of response to induction therapy for myeloma Giles H 1 2 , Ferretti L 1, Cook M 2, Aung YS 1 2, Yadav P 1 3, Cockwell P 1 3, Pinney J 3, Davies FE 4, Gregory WM 5, Owen RG 6, Jackson GH 7, Child JA 5 , Morgan GJ 4, Drayson M 1 1 School of Immunity and Infection, University of Birmingham, Birmingham, UK; 2 Department of Haematology, University Hospital Birmingham, Birmingham, UK; 3 Department of Renal Medicine, University Hospital Birmingham, Birmingham, UK; 4 Myeloma Research Centre, Division of Molecular Pathology, The Institute of Cancer Research, London, UK; 5 Clinical Trials Research Unit, University of Leeds, Leeds, UK; 6 St James's University Hospital, Leeds, UK; 7 Department of Haematology, University of Newcastle, Newcastle-upon-Tyne, UK Background High-dose corticosteroids in combination with novel anti-myeloma drugs produce high response rates 1 2 but they are associated with increased adverse effects compared to regimens containing attenuated doses 3 4 . In this retrospective study we compared the response rates of patients treated with high-dose dexamethasone (320mg/cycle) versus attenuated-dose dexamethasone (160mg/cycle) in combination with cyclophosphamide and immunomodulatory therapy. p=0.11 p=0.30 p=0.38 p=0.40 p=0.24 Methods This study included all patients from the MRC Myeloma IX trial (ISRCTN68454111) and the MRC Myeloma XI trial (ISRCTN49407852), who received induction chemotherapy with cyclophosphamide, lenalidomide/thalidomide and dexamethasone and had complete serum free light chain (sFLC) and paraprotein results at presentation and the end of induction chemotherapy. In both trials patients were divided between an intensive arm for younger fitter patients who were suitable to undergo high-dose melphalan and autologous stem cell transplantation (ASCT) and a non-intensive arm. Paraprotein responses at the end of cycle one of induction chemotherapy was calculated in all patients with significant paraprotein levels (≥10g/L) and the end of cycle one sFLC response was calculated for all patients with significant sFLC levels (sFLC ≥100mg/l and a difference between the involved and uninvolved sFLC ≥100mg/L). Figure 2: Percentage reduction in paraprotein and sFLC light chain levels for patients treated in the MRC Myeloma XI trial at the end of the first cycle of induction chemotherapy. Whisker boxplots showing the median, 25th and 75th centiles. Tails represent the 5th and 95th centiles. The diamonds represent the means. Mann Whitney U tests were performed to assess the statistical significance of the differences between the groups. RCD=lenalidomide, cyclophosphamide and dexamethasone (320mg/cycle); CTD=cyclophosphamide, thalidomide and dexamethasone (320mg/cycle); RCDa=lenalidomide, cyclophosphamide and dexamethasone (160mg/cycle) and CTDa=cyclophosphamide, thalidomide and dexamethasone (160mg/cycle). High-dose melphalan and ASCT significantly improved the percentage reductions in sFLC and paraprotein levels across all paraprotein classes in both Myeloma XI and Myeloma IX (Figure 3). Because this treatment was only given to patients treated with high-dose dexamethasone containing induction chemotherapy, it was not possible to directly compare the survival outcomes of the patients treated with high-dose dexamethasone versus those treated with attenuated dexamethasone based induction chemotherapy. p<0.01 p<0.01 p<0.01 p<0.01 p<0.01 Results There was no significant difference in the percentage reduction in paraprotein level or sFLC level at the end of induction chemotherapy between patients treated with CTD compared to CTDa in the MRC Myeloma IX trials and between patients who received RCD/CTD compared to those who were given RCDa/CTDa in the MRC Myeloma XI trial (Figure 1). A p=0.07 p=0.77 p=0.13 p=0.70 p<0.01 p<0.01 p<0.01 p<0.01 p<0.01 B Figure 1: Percentage reduction in paraprotein and sFLC light chain levels for patients treated with CTD or CTDa in the MRC Myeloma IX trial and RCD/CTD or RCDa/CTDA in the MRC Myeloma XI trial at the end of induction chemotherapy. Whisker boxplots showing the median, 25th and 75th centiles. Tails represent the 10th and 95th centiles. The diamonds represent the means. Mann Whitney U tests were performed to assess the statistical significance of the differences between the groups. RCD=lenalidomide, cyclophosphamide and dexamethasone (320mg/cycle); CTD=cyclophosphamide, thalidomide and dexamethasone (320mg/cycle); RCDa=lenalidomide, cyclophosphamide and dexamethasone (160mg/cycle) and CTDa=cyclophosphamide, thalidomide and dexamethasone (160mg/cycle). Figure 3: Percentage reduction in sFLC and paraprotein levels at the end of induction chemotherapy (PI) compared to at 100 days post high dose melphalan (pHDM) for a) patients treated in the MRC Myeloma IX trial and b) for patients treated in the MRC Myeloma XI trial. Whisker boxplots showing the median, 25th and 75th centiles. Tails represent the 10th and 95th centiles. Diamonds represent the means. Mann Whitney U tests were performed to assess the statistical significance of the differences between the groups. RCD=lenalidomide, cyclophosphamide and dexamethasone (320mg/cycle) and CTD=cyclophosphamide, thalidomide and dexamethasone (320mg/cycle). Conclusions Most studies have reported that improved quality of response is associated with longer survival, however a lack of correlation between overall response rate and overall survival has been observed in some trials 5. It is therefore important that randomised controlled trials are conducted to establish whether the lack of difference in response rates seen in this study translates into equivalent or superior survival rates for patients treated with regimens containing novel agents in combination with lower doses of corticosteroids compared to those treated with regimens containing high-dose dexamethasone. The optimum steroid dosing schedule, which maximises response rates and overall survival whilst minimising adverse effects needs to be established. At the end of the first cycle of induction chemotherapy there was no significant difference in the percentage reduction in paraprotein or sFLC levels between patients treated with RCD/CTD compared to those who received RCDa/CTDa (Figure 2), indicating that there is no significant difference in the rapidity of the onset of action between high and attenuated dose dexamethasone containing regimens. References 1. Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ et al. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011; 118(5): 1231-1238. 2. Benbouker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. NEJM. 2014; 371(10):906-17. Hernandez JM, Garcia-Sanz R, Golvano E, Bladé J, Fernandez-Calvo J, Trujillo J et al. Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma. British Journal of Haematology. 2004; 127: 159-164. Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A et al. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2—6; 107(4):1292-1298. Rajkumar SV, Greipp PR, Jacobus S, Callander NS, Fonseca R, Vesole DH et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010; 11(1): 29-37. Baldini L, Radaelli F, Chiorboli O, Famagalli S, Cro Lsegala M et al. No correlation between response and survival in patients with multiple myeloma treated with vincristine, melphalan, cyclophosphamide, and prednisone. Cancer. 1991; 1;68(1):62-7. This project was funded by the National Institute for Health Research Academic Clinical Fellowship programme. Department of Health Disclaimer: The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.