The VTD combination was well tolerated in all cohorts receiving bortezomib at the 1.0 mg/m2 dose and in those receiving 1.3 mg/m2 up to T 150 mg. Although 23% of trial participants had grade ≤2 peripheral neuropathy at trial onset, aggravation of this toxicity was infrequent with the VTD regimen. Myelosuppression in this heavily pretreated population (92% had one and 65% two transplants) became dose-limiting, but infectious complications were manageable. The VTD regimen had remarkable activity so that 63% achieved PR and 22% n-CR, despite the advanced, refractory and high-risk features of the trial participants: 76% had CA, LDH levels were elevated in 41% and GEP-defined high-risk status was present in 42%. OS and EFS both were shorter in the presence of CA and in case of prior T exposure. Although not designed to determine whether there was a dose effect of T or V on outcome, OS appeared superior when the higher dose of V (1.3 mg/m2) was employed. MR imparted superior EFS and OS, whereas the level of response did not appear to affect survival.
Recently, we have reported on the dramatically different outcomes of newly diagnosed patients when GEP-defined risk was considered.19
These observations have since been confirmed by the Mayo Clinic group in an up-front transplant regimen,27
in a multi-institutional salvage trial (APEX) comparing dexamethasone and bortezomib28,29
and, for EFS, in the present study. Based on GEP comparisons, especially of paired samples procured at diagnosis and relapse reported for our Total Therapy trials, a higher frequency of high-risk disease reported here (42%) was expected, compared to 13% in Total Therapy 2 and 15% in Total Therapy 3.19
Such high-risk designation applied to only 16% of patients accrued to the APEX study,28,29
a frequency similar to that observed in newly diagnosed cases. One can speculate that, in the case of accrual to the APEX trial from a more general practice population, those with high-risk had succumbed early, a reasoning supported also by a lower frequency of CA in the APEX compared to the current VTD trial (68 vs 76%, P
=0.072). In view of the superior outcomes with Total Therapies in the 85% of patients with low-risk MM, a higher proportion of those with high-risk was available at any given time for VTD trial participation at our institution.
Superior outcomes with Total Therapy 3 vs Total Therapy 2 were extended to patients with MMSET/FGFR3-type MM, which could be attributed to the incorporation of bortezomib in the more recent trial.26,30
Although the sample size with GEP information in the current study was small, patients with MMSET/FGFR3 MM seemed to benefit from VTD in our trial.
VTD has since been applied as up-front therapy in newly diagnosed patients with MM effecting high rates of CR and n-CR.31
Our Total Therapy 3 regimen has incorporated VTD (V at 1 mg/m2
, T at 200 mg, D at 40 mg) into PACE (cisplatin, doxorubicin, cyclophosphamide, etoposide), referred to as VTD-PACE regimen, for induction prior to and consolidation after melphalan-based tandem transplants.32,33
CR rates were similar to those observed on the T arm of Total Therapy 2; yet CR duration and EFS were significant and OS borderline superior in TT3. The adverse implications of the FGFR3-type MM in TT2 were no longer observed in TT3.
VTD or similar combinations, such as VRD (bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone)34
have since been employed together with melphalan and yielded remarkable activity in both previously treated and especially newly diagnosed patients with MM.35–37
Many trials are currently in progress or in planning stages to sort out the most effective and least toxic combinations of new agents in combination with melphalan toward maximizing CR rates and thereby further improving survival in MM.
Because of its rapid onset of response, we see a role for VTD as front-line therapy for both transplant and non-transplant candidates and in the setting of renal failure up to the level of hemodialysis-dependence.38
Due to its mild myelosuppression, VTD, but not VRD, can be given safely to patients with pancytopenia resulting from cumulative bone marrow damage inflicted by prior therapies. In this setting, we have also combined VTD with metronomically scheduled doxorubicin at a low daily of 5 mg/m2
administered by continuous daily infusions for 14 days.39,40
Results indicated excellent tolerance without aggravation of thrombocytopenia and astonishing anti-myeloma activity, which could be further enhanced by the addition of cisplatin at 1 mg/m2
likewise administered as continuous intravenous infusion for 14 days and of rapamycin (Barlogie, unpublished data). We and others are also exploring VTD and VRD in the treatment of primary AL amyloidosis. In a setting of intolerance of D, VT alone appears to be quite effective as well.
VTD-PACE is also highly effective in the setting of high-risk refractory myeloma with extramedullary disease presentations including central nervous system involvement (Barlogie, unpublished data). VTD could be safely added to dose-escalated and fractionated melphalan in the context of autotransplants to take advantage of the well-documented synergism between melphalan and the components of VTD,1
which results from inhibition of double-stranded DNA repair.41
Thus, we were able to administer melphalan at 100 mg/m2
after V at 1.0 or 1.3 mg/m2
on days 1, 4 and 7 (total dose, 300 mg/m2
) together with T at 200 mg/day for 7 days and D at 40 mg on the day of and after V plus melphalan (stem cell infusion on day 8) in the far-advanced disease setting with encouraging results.42
Finally, we were able to combine VTD-PACE with melphalan at 25 mg/m2
/day for 4 successive days and autologous stem cell support on day 6 (Barlogie unpublished). These combinations are all currently being explored in the refractory disease setting, especially for patients with high-risk GEP features.