A Pilot Study To Explore the Tolerability and Efficacy of Thalidomide Containing Regimens To Reduce Tumour Cell Load Prior to HSC in Multiple Myeloma and the Feasibility of Harvesting HSC Following Thalidomide Containing Regimens.

Aim: To explore the role of thalidomide in pre-transplant induction treatment in multiple myeloma.

Patients and methods: Between Sept 2002 and March 2005, 37 patients with advanced, de-novo multiple myeloma (mean age 56 years, mean Serum. albumin 33g/L, and median b -2-microglobulin 4.0mg/L) were entered into a multicentre, phase 2 study of pre transplant induction treatment. The regimen included TDx3 (thalidomide 400mg/d, pulse dexamethasone 32mg TDS x 5d every 3 weeks PO), followed by DT-PACEx2 (thalidomide 400mg/d, dexamethasone 40mg/d x 4 PO and cisplatin 10mg/m²/d, doxorubicin 10mg/m²/d, cyclophosphamide 400mg/m²/day, etoposide 40mg/m²/d as 4 day infusion administered 4 weeks apart, supported with G-CSF 10m g/Kg/d). Thromboprophylaxis was warfarin (target INR 1.5–2.0) during TD and enoxaparin 40mg/day (adjusted according to platelet count) during DT-PACE. Stem cells were harvested at recovery from the second cycle of DT-PACE in the first 27 patients, but after review of the harvest results the remaining patients were harvested after first cycle of DT-PACE with an option to re-harvest after the second if the initial harvest was insufficient.

Paraprotein and BJP responses and stem cell collections were compared to a historical cohort of 58 patients treated with VAD and mobilised with cyclophosphamide 5G/m² and G-CSF 5m g/Kg.

Results: 23/37 patients completed study treatment, 21 had successful stem cell harvests. There were 2 deaths (1 sepsis, 1 haemorrhage) and 2 failed stem cell harvests.

After TD x 3 and VAD x3 the mean levels of paraprotein (or BJP) were 21% and 34% of pre-treatment levels, respectively (p=0.02). After DT-PACE x 2 and HD cyclophosphamide the mean levels of paraprotein (or BJP) were 14% and 31 % respectively (p=0.014).

At the completion of TDx3 42% of patients had achieved VGPR and 50% PR, whereas after VAD x 3 there was 12% CR, 17% VGPR and 45% PR (p=0.231). Following DT-PACEx2 there was 22% CR, 39% VGPR and 26% PR and after HD cyclophosphamide there was 9% CR, 19% VGPR and 45% PR (p=0.039).

The median number of CD34+ cells/kgBW harvested was 4.7 x 10⁶ after DT-PACE and 11.6 x 10⁶ after HD cyclophosphamide (p=0.001). The median number of aphereses procedures required was 2 for both study patients and historical controls. 58 serious adverse events included 20 episodes of infection (9 during TD and 11 during DT-PACE), 3 episodes of haemorrhage, 1 pulmonary embolus and 2 deaths.

Conclusion:

1. Thalidomide dexamethasone combination appears to be as efficacious as VAD in reducing tumour burden in de-novo multiple myeloma.

2. The addition of DT-PACE improves the pre-transplant CR and VGPR rate.

3. In most patients adequate stem cell harvest can be obtained, but yields appear to be less than after VAD/HD cyclophosphamide.

4. Thalidomide dexamethasone followed by DT-PACE is associated with tolerable but not insignificant toxicity.