The utility of CTD as induction therapy in newly diagnosed plasma cell myeloma was the subject of the MRC Myeloma IX (MRCIX) trial, a multicenter phase III randomised study involving 1970 patients, comparing CTD induction with CVAD (cyclophosphamide, Vincristine, doxorubicin, doxorubicin, dexamethasone) prior to ASCT. Six 21 day cycles of cyclophosphamide 500 mg, dexamethasone 40 mg D1 to 4, 12 to 15, and thalidomide 100 mg (aiming for 200 mg if tolerated) were administered (unless maximal response was achieved earlier). Eligible patients received ASCT where possible.r
It is the consensus of the eviQ Haematology reference committee that dexamethasone 40 mg PO is given on days 1, 8, 15 of each cycle due to tolerability.rr
This study also compared CTDa (attenuated) versus MP (Melphalan and prednisolone) in older patients ineligible for ASCT with high dose melphalan conditioning. A further randomisation step allocating to maintenance thalidomide and no-maintenance was also included.
Newly diagnosed patients with myeloma age greater than 18 years were eligible. Patients with extramedullary disease or renal failure (dialysis, Creatinine >500 micromol/L, unresponsive to 72 hours hydration, urine output less than 400 mL/day) were excluded.r
Overall, the findings of the Myeloma IX study suggest that CTD and CTDa are well-tolerated non-inferior alternatives to CVAD (or MP) as induction therapy for newly diagnosed Multiple Myeloma.
CTD has been examined in several phase II studies in the relapsed refractory setting.
Dimopoulos et al in a phase II study studied 53 patients with relapsed/refractory disease receiving cyclophosphamide 150 mg/m2 PO twice daily 1 to 5, thalidomide 400 mg PO daily days 1 to 5 and days 14 to 18 and dexamethasone 20 mg/m2 PO days 1 to 5 and days 14 to 18 on a 28 day cycle for 3 courses followed by maintenance. They reported an ORR (CR+PR) of 60% with median OS 17.5 months and median TTP of 8 months.r
Garcia-Sanz et al reported a phase II study examining 71 patients with relapsed/refractory disease receiving cyclophosphamide 50 mg PO daily, thalidomide was commenced at 200 mg and up to maximum tolerated dose (800 mg daily) and reduced to 200 mg after achieving best response, dexamethasone 40 mg PO daily days 1 to 4 every 21 days or substituted by prednisolone 25 mg PO second daily. The authors reported 60% ORR (CR + PR) at 6 months.r
Kyriakou et al examined 52 patients with relapsed/refractory myeloma receiving up to 6 monthly cycles of cyclophosphamide 300 mg/m2 PO weekly, dexamethasone 40 mg PO daily day 1 to 4 monthly, thalidomide escalating dose to a maximum of 300 mg daily. The authors reported an ORR of 78% with median time to maximum response 4 months and 2 year OS 73% and 2 year EFS 34%.r
Sidra et al reported 62 patients, including 15 newly diagnosed cases receiving cyclophosphamide 500 mg PO on days 1, 8, 15, thalidomide 100 mg daily increasing to 200 mg, dexamethasone 40 mg daily days 1 to 4, 15 to 18 on a 28 day schedule. 83% achieved a PR or better (86% in untreated group).r
In the context of AL amyloidosis, Wechalekar et al used almost an identical protocol to MRC Myeloma IX and 76% achieved a CR + PR with treatment related mortality of 4%.r Venner et al then performed a matched comparison between this protocol and CVD in patients with AL amyloidosis at the National Amyloidosis Centre in London between 2008-2012, and showed that CTD had similar ORR to CVD (79.1% CTD vs 71.0% CVD, p=0.32) and 1-year overall survival (66.7% CTD vs 65.2% CVD, p=0.87), but CVD had higher CR rates (40.5% vs 24.6%, p=0.046) and longer median PFS (28.0 months vs 14 months, p=0.039).r
On an intention to treat basis the ORR for CTD vs CVAD was 82.5% vs 71.2% p<0.0001. CR rates were 13% for CTD vs 8.1% CVAD. Response rates at 100 days in those who did receive ASCT were similar. The median PFS was 27 months in the CTD arm vs 25 months in CVAD group (no significant difference) and OS was comparable in both groups.r
Response rates did not differ for adverse FISH groups ([gain 1q, del17p, t(4;14), t(14:16), t(14:20)]) vs favourable but there were clear differences in their median PFS (33months favourable vs 19 months adverse).
Since the original published study, survival outcomes for the Myeloma IX trial have been re-analysed to take into account mature data from longer-term follow-up (median 5.9 years). Median PFS in the CVAD and CTD groups was 24 and 26 months, respectively (HR 0.98; 95% CI: 0.85–1.12). Median OS was 63 months with CVAD and 71 months with CTD (HR 0.90; 95% CI: 0.76–1.07).
Median PFS was significantly longer in the CTDa group than the MP group in the low intensity (no ASCT) arm (13 vs. 12 months; HR, 0.81; 95% CI, 0.69–0.94). Median OS was similar between the two groups (34 vs. 32 months; HR, 0.91; 95% CI, 0.77–1.07).
Survival outcomes were also analysed with respect to administration of maintenance thalidomide. Median PFS was significantly longer in the 408 patients randomized to thalidomide maintenance compared with the 410 patients randomized to no maintenance therapy (22 vs. 15 months; HR, 1.44; 95% CI, 1.22–1.70). It is important to note that median OS was similar in both groups (60 months in both; HR, 0.96; 95% CI, 0.79–1.17).
Of note, the PFS benefit only appears to have accrued to those 255 patients with favourable FISH profiles (29 vs. 18 months, p = 0.01). However, no OS benefit was seen, and an apparent negative effect on OS was seen in the unfavourable iFISH group receiving maintenance thalidomide (35 vs 47 months p = 0.01).r
In 2016, three Thalidomide-containing regimens – up to nine 28-day cycles of CTD, MPT, and TD were compared in an open-label, randomized controlled study for newly diagnosed myeloma patients who were not transplant eligible. In the 82 patients studied, ORR were 67.9% for MPT, 89.7% for CTD and 68.7% for TD (p=0.056 between CTD and MPT). Median PFS were 24.1 months (MPT), 25.9 months (CTD) and 21.5 months (TD). The study concluded that both MPT and CTD are suitable frontline regimens for myeloma patients who are not transplant eligible.r
The complete (CR), partial (PR) and overall response rates (ORR) of the studies investigating various versions of the CTD protocol in the relapsed refractory setting are tabulated below:
||ORR (%) (PR + CR)
|Dimopoulos et al 2004r
|Garcia-Sanz et al 2004r
|Kyriakou et al 2005r
Sidra et al 2006r
26 (newly diagnosed)
60 (newly diagnosed)
86 (newly diagnosed)
|Wechalaker et al 2007r
The median number of cycles of CTD delivered in Myeloma IX was 5. 29% of patients required a dose reduction in thalidomide due to toxicity. Early mortality was no different between the CTD arm and the CVAD arms (7.4% vs 9.4%).r
Despite the commonly noted venous thromboembolism associated with thalidomide use, there was no significant difference in deaths due to VTE between arms (4 in the CTD arm vs 3 in CVAD arm).
In comparison to CVAD, the CTD regimen was associated with a lower rate of haematological toxicity with grade 3 or 4 cytopenias seen in 4.5% of cases vs 11.5%. Rates of infection were also lower, in particular grade 3-4 infectious complications (11.7% vs 20.6%).
Despite expectations to the contrary, rates of grade 3 or 4 sensory or motor neuropathy were low in the CTD arm (3.8%) and did not statistically differ from CVAD (3.3%). Toxicities which were observed at statistically significant higher rates in the CTD arm were constipation (grade 3 or 4, 3.6% vs 1.5%) and skin rash (3% vs 0.7%).r
© Haematologica 2012
Toxicitiy of CTD in Relapsed/Refractory Myeloma
© The Hematology Journal 2004
Toxicities from Garcia-Sanz et al 2004r
Adverse effects related to treatment included: death 7% (infection 4% and arrhythmia 3%); neutropenia (Grade 3 to 4) 10%; infection 13%; DVT 7%; peripheral neuropathy 6%; constipation 24%; somnolence 18%; fatigue 17%; dizziness 8%.
Toxicities from Kyriakou et al 2005r
© British Journal of Haematology 2005
Toxicities from Wechaleker et al 2007r
© Blood Journal 2007