Reduced Dose PAD Combination Therapy (PS-341/Bortezomib, Adriamycin and Dexamethasone) for Previously Untreated Patients with Multiple Myeloma.
Rakesh Popat, MBBS1,*,
Heather E. Oakervee, MRCPath1,*,
Nicola Curry, MBBS1,*,
Nicola Foot, BSc1,*,
Curly Morris, FRCP2,*,
Mary Drake, MRCPath2,*,
Samir Agrawal, PhD1,*,
Patricia Smith, RGN1,*,
David Schenkein, MD3,*,
Dixie-Lee Esseltine, MD3,* and
Jamie D. Cavenagh, MD1
1 Haematology, St. Bartholomews Hospital, London, United Kingdom; 2 Haematology, Belfast City Hospital, Belfast, United Kingdom and 3 Millennium Pharmaceuticals, Cambridge, MA, USA.
Background: Bortezomib (formerly PS-341) has demonstrated significantactivity in patients with relapsed multiple myeloma. NumerousPhase I/II studies have also shown that it has activity in untreatedpatients, and we have previously reported results of the combinationof 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 occurat a reduced dose of bortezomib, and so here a dose of 1.0mg/m2was used in order to minimise toxicity.
Aims: The primary objective of this Phase II study was to assessthe feasibility of harvesting peripheral blood stem cells (PBSCs)after PAD, with secondary objectives being response rate, progressionfree survival, overall survival and safety, toxicity.
Methods: Patients with previously untreated multiple myelomawere elligible. The received 4x21 day cycles of PAD comprisingof bortezomib 1.0mg/m2 on days 1,4,8,and 11; 9mg/m2 of adriamycingiven by iv infusion on days 14 and dexamethasone 40mgon days 14, 811 and 1518 on cycle 1 anddays 14 during cycles 24. Following PBSC harvesting,they received high dose melphalan (MEL200) with PBSC rescue.
Results: At present 19 patients have been enrolled with a medianage of 61 (range 3465), 8 were male and 11 female and16 were of Durie-Salmon Stage III disease. Out of the 18 evaluablethe PR/CR rate was 89% (2 CR. 1 nCR, 4 VGPR, 9 PR). 15 patientscompleted all 4 cycles and all successfully mobilised PBSC (median5 x 106 CD34+ cells/kg, range 2.416). Of those not completingtherapy, one was withdrawn because of primary progressive disease;one died of pneumonia and severe bone disease having achieveda PR after 1 cycle, and the other developed line sepsis requiringcessation of intravenous therapy prior to completion of cycle1 (response thus unevaluable).
11 patients have received MEL200 so far with adequate haematologicalrecovery - median neutrophil (>0.5 x 109/L) and platelet(>20 x 109/L) engraftment of 14 (range 628) and 16(range 1140) days respectively. Of those who are assessableat 3 months following MEL200, 7 out of 7 have achieved at leasta PR (3CR, 1nCR, 1VGPR, 2PR). One patient was refractory toPAD, but has now successfully received MEL200 following re-inductionwith cyclophosphamide, thalidomide and dexamethasone combination.
Toxicities have been modest, with 1 serious adverse event (hospitalisationwith pneumonia) and 6 Grade 3 events (abnormal liver functiontest; thrombocytopaenia, neutropaenia, hyperglycaemia, sepsisand anxiety). Grade 34 neuropathy was not seen and theincidence of Grade 12 neuropathy was 16%.
Summary: This preliminary data suggests that reduced dose PADis well tolerated, efficacious (89% PR) and does not prejudicesubsequent PBSC collection. Due to the small numbers in thestudy, a meaningful comparison with PAD (bortezomib 1.3mg/m2)is not possible, however toxicities appear improved especiallywith regards to neuropathy. This data therefore supports thecontinued use of dose adjusted bortezomib in PAD if patientsdevelop toxicity. This reduced dose regime may also be of usein patients with pre-existing neuropathy or those with a poorerperformance status.