Bortezomib, Adriamycin Dexamethasone (PAD) Combination Therapies or Patients with Relapsed or Refractory Myeloma Previously Treated with VAD or VAD like Therapy.
Authors: Morris Treen C. , Drake Mary , Kettle Paul J. , Brunton Aishleen , Cavenagh James D. , Oakervee Heather E. , O’Dwyer Michael , Murray Margaret , O’Shea Tanya , Cook Gordon 
Published: April 2020

Background: Although active as a single agent Bortezomib has been shown to be highly effective in combination therapy and particularly high rates of response have been obtained in newly diagnosed patients with the PAD combination. This combination has not been studied before now in patients with relapsed or refractory disease. We have chosen to study this combination in patients who have received a VAD (Vincristine Adriamycin and Dexamethasone) or VAD like therapy (VAMP, Z-DEX, etc) as initial treatment for their myeloma as there is therefore an opportunity to compare the response of their initial disease to VAD or VAD like therapy with the response obtained upon relapse with PAD, each patient acting as their own “control”.

Aims and primary objectives: This phase II study was to assess the feasibility and potential efficacy of PAD therapy patients who had previously received VAD or VAD like therapy. Three cohorts were identified:

patients who had received VAD and a subsequent autologous transplant patients who had received VAD but had not been transplanted patients who were refractory to VAD (less than partial response)

In Cohorts 1 and 2, one additional treatment could be given after their initial line of therapy; patients in group 3 would proceed directly to PAD therapy. In view of patients previous exposure to Anthracycline additional echocadiograms were reviewed after each two cycles of PAD Chemotherapy. Twenty three patients will be entered in each cohort.

Methods: Eligible patients received up to six twenty one day cycles of PAD comprising Bortezomib 1.3mgm2, days 1,4,8 and 11, Adriamycin 9mgm2 by IV infusion days 1 – 4 and Dexamethasone 40mg orally given on days 1 – 4, 8 – 11 and 15 – 18 in cycle one and days 1 – 4 during subsequent cycles. Patients were permitted to proceed to autologous transplant (or second autologous transplant) at the end of therapy if blood stem cells were harvested or available from previously harvest patients. Patients on PAD were given antiviral and pneumocystitis prophylaxis and vitamin supplementation as per unit protocol; early Bortezomib reduction for neuropathy was encouraged.

Results: To date fifteen patients have been enrolled, seven in cohort 1, two in cohort 2 and six in cohort 3; ten male and five female age, 35–65 years, of the six relapsed patients (cohorts 1 & 2) evaluable for response all six have achieved at least a very good partial response (VGPR) and all six have had a better response to PAD than their original VAD like therapy. Of the three refractory patients, all three have had some reduction in paraprotein level and one patient has achieved a partial response and has proceeded to successful stem cell harvest.

Conclusions: PAD therapy appears to be a very promising line of therapy for relapsed and refractory myeloma, obtaining better responses than their previous VAD or VAD like therapy.