Reduced Dose PAD Combination Therapy (PS-341/Bortezomib, Adriamycin and Dexamethasone) for Previously Untreated Patients with Multiple Myeloma.
Authors: Popat Rakesh , Oakervee Heather E. , Curry Nicola , Foot Nicola , Morris Curly , Drake Mary , Agrawal Samir , Smith Patricia , Schenkein David , Esseltine Dixie-Lee , Cavenagh Jamie D. 
Published: April 2020

Background: Bortezomib (formerly PS-341) has demonstrated significant activity in patients with relapsed multiple myeloma. Numerous Phase I/II studies have also shown that it has activity in untreated patients, and we have previously reported results of the combination of standard dose bortezomib (1.3mg/m2), adriamycin and dexamethasone (PAD) in this setting where a response rate of 95% was seen. The CREST study has demonstrated that responses still do occur at a reduced dose of bortezomib, and so here a dose of 1.0mg/m2 was used in order to minimise toxicity.

Aims: The primary objective of this Phase II study was to assess the feasibility of harvesting peripheral blood stem cells (PBSCs) after PAD, with secondary objectives being response rate, progression free survival, overall survival and safety, toxicity.

Methods: Patients with previously untreated multiple myeloma were elligible. The received 4x21 day cycles of PAD comprising of bortezomib 1.0mg/m2 on days 1,4,8,and 11; 9mg/m2 of adriamycin given by iv infusion on days 1–4 and dexamethasone 40mg on days 1–4, 8–11 and 15–18 on cycle 1 and days 1–4 during cycles 2–4. Following PBSC harvesting, they received high dose melphalan (MEL200) with PBSC rescue.

Results: At present 19 patients have been enrolled with a median age of 61 (range 34–65), 8 were male and 11 female and 16 were of Durie-Salmon Stage III disease. Out of the 18 evaluable the PR/CR rate was 89% (2 CR. 1 nCR, 4 VGPR, 9 PR). 15 patients completed all 4 cycles and all successfully mobilised PBSC (median 5 x 106 CD34+ cells/kg, range 2.4–16). Of those not completing therapy, one was withdrawn because of primary progressive disease; one died of pneumonia and severe bone disease having achieved a PR after 1 cycle, and the other developed line sepsis requiring cessation of intravenous therapy prior to completion of cycle 1 (response thus unevaluable).

11 patients have received MEL200 so far with adequate haematological recovery - median neutrophil (&gt;0.5 x 109/L) and platelet (&gt;20 x 109/L) engraftment of 14 (range 6–28) and 16 (range 11–40) days respectively. Of those who are assessable at 3 months following MEL200, 7 out of 7 have achieved at least a PR (3CR, 1nCR, 1VGPR, 2PR). One patient was refractory to PAD, but has now successfully received MEL200 following re-induction with cyclophosphamide, thalidomide and dexamethasone combination.

Toxicities have been modest, with 1 serious adverse event (hospitalisation with pneumonia) and 6 Grade 3 events (abnormal liver function test; thrombocytopaenia, neutropaenia, hyperglycaemia, sepsis and anxiety). Grade 3–4 neuropathy was not seen and the incidence of Grade 1–2 neuropathy was 16%.

Summary: This preliminary data suggests that reduced dose PAD is well tolerated, efficacious (89% ≥ PR) and does not prejudice subsequent PBSC collection. Due to the small numbers in the study, a meaningful comparison with PAD (bortezomib 1.3mg/m2) is not possible, however toxicities appear improved especially with regards to neuropathy. This data therefore supports the continued use of dose adjusted bortezomib in PAD if patients develop toxicity. This reduced dose regime may also be of use in patients with pre-existing neuropathy or those with a poorer performance status.