PAD Given at Relapse Is More Effective Than VAD Given as Induction Therapy - Results of a Phase II Study.
Authors: Morris Treen C. , Kettle Paul J. , Drake Mary B. , Brunton Aisleen , Cook Gordon , Leahy Maeve , O’Dwyer Michael , Enright Helen , O’Shea Tanya , Popat Rakesh , Oakervee Heather , Cavenagh James D. 
Published: October 2019

Abstract
Introduction: The combination of Vincristine, Adriamycin and Dexamethasone (VAD) followed by autologous transplantation has been a standard of care for patients with Myeloma for a number of years. Recently, it has been shown that a combination of Bortezomib with Adriamycin/Dexamethasone (PAD) is a highly effective induction agent with response rates of up to 95% (Oakervee et al, BJH2005; 129: 755–62). We postulated that the superior efficacy of PAD chemotherapy could be demonstrated by studying patients who have been previously treated with VAD or a VAD-like regimen (VAMP, C-VAMP, Z-DEX etc.) by comparing the response to PAD given following relapse to the response previously obtained with the VAD or VAD-like regimen, in terms of both relative and absolute changes in the paraprotein or light chains and the degree of remission obtained by the standard EBMT criteria.
Materials and Methods: A Phase II study was developed with three cohorts, each planned to recruit 23 patients. Cohort 1; patients treated with VAD or VAD-like regimen who previously had an autologous transplant; Cohort 2 - similar patients but without previous transplant and Cohort 3 - patients refractory to VAD. Patients in groups 1 and 2 were allowed to have received one further line of treatment following VAD but patients in group 3 would proceed directly to PAD. A total of 42 patients have been recruited and as recruitment to cohort 1 is now complete, this report will focus on these 23 patients.
Results: 23 patients in Cohort 1 (9 females, 14 males) had a median age of 60 years (range 41–73). 8 patients had received thalidomide-based regimens following relapse after transplantation and had relapsed again. 15 patients were in first relapse. The time from diagnosis to PAD chemotherapy was 46 months (18–179 months). Previous treatment given was VAD 13, C-VAMP 5, C-VAD 3, Z-DEX 2. Patients received a median of four cycles of PAD. 8 patients achieved CR following PAD compared to 3 post-VAD p=0.013 using McNemar’s Chi-squared test with continuity correction. Comparison of the fall in paraprotein showed a median fall of 89% post-PAD compared to 60% post-VAD. This difference was significant by the Wilcoxon Matched Pairs Rank Test (p<0.003). There were no reports of increased cardiotoxicity. A number of patients proceeded on to second transplant following their response to PAD therapy.
Conclusion: PAD is a highly active therapy for patients with myeloma in relapse, even if they have received a prior VAD or VAD-like regimen the differences are statistically significant despite the fact the patients have all experienced at least one relapse. PAD therapy will be incorporated into the NCRI (UK) Myeloma X regimen as an induction therapy in patients who have relapsed post autologous transplantation, with patients randomised to consolidation with a second autologous transplant or conventional dose cyclophosphamide.