Trial Information

A Phase II Trial of Bortezomib, Doxorubicin and Dexamethasone (PAD) Induction Therapy in Patients With Untreated Multiple Myeloma (MM), Stratified for Markers of Bortezomib Resistance

This is an open-label, single-arm, multicentre study which will enroll approximately 105
patients. Open-label means all people involved in the study know the identity of the
intervention. Single-arm means there is one group of patients, all receiving the same
treatment. Four 21-day cycles of a combination of bortezomib i.v. (intravenous) 1.3 mg/m2
(Days 1, 4, 8 and 11), doxorubicin i.v. 20 mg/m2 (days 1 and 4) and dexamethasone p.o. (by
mouth) (days 1, 2, 4, 5, 8, 9, 11 and 12) (PAD) will be given. Patients will be discontinued
if disease progresses, or unacceptable treatment-related toxicity occurs. Following PAD
treatment, patients will have peripheral blood stem cells (PBSC) collected, and an
autologous stem cell transplant (ASCT) will be performed. Patients will then make monthly
visits to the Study Doctor until 1 year after start of treatment, and attend a final
follow-up visit at 2 years. Efficacy assessment of response to PAD will be made using the
International Myeloma Working Group (IMWG) criteria. The primary outcome is to compare the
overall response rate following 4 cycles of PAD induction therapy between patients with and
without extra copies of the long arm of the first chromosome (1q21) measured by fluorescent
in situ hybridisation (FISH) in their marrow at baseline. Patient reported outcomes will be
assessed using the AQoL (Assessment of Quality of Life). Safety will be evaluated throughout
the study by assessment of adverse events including changes in physical examination,
concomitant medication, ECOG (Eastern Cooperative Oncology Group) scores, vital signs and
clinical laboratory findings. A sample size of 105 provides 80% power (a=0.05) to detect a
difference in overall response rate of 28% at the end of 4 cycles of PAD. This is based on
the assumptions that 44% of patients have amplification of 1q21 1, 2, the overall response
rate with PAD combination therapy is 80%; the overall response rate with PAD if PAD therapy
does not overcome 1q21 amplification is assumed to be 64%, while without 1q21 amplification
it is assumed to be 92%. That is: Overall Response Rate (ORR) = P1q21 amplified x
ORRamplified + P1q21 not amplified x ORRnot amplified i.e. 80% = 44% x 64% + 56% x 92%. The
sample size of 105 allows for a 20% drop-out rate. Four 21-day cycles of PAD: a combination
of bortezomib i.v. (intravenous) 1.3 mg/m2 (Days 1, 4, 8 and 11), doxorubicin i.v. 20 mg/m2
(days 1 and 4) and dexamethasone p.o. (by mouth) (days 1, 2, 4, 5, 8, 9, 11 and 12).