Evaluation of Safety and Efficacy of VELCADE as Maintenance Treatment in Patients With Multiple Myeloma Following High-Dose Melphalan Treatment and Autologous PBSCT (Minimal Residual Disease, Partial Remission or Stable Disease)
Protocol DSMM VIII is a multi-center, open-label study evaluating the safety and
tolerability, as well as the efficacy, of maintenance treatment with VELCADE in patients
with multiple myeloma with detectable disease activity following tandem high-dose
chemotherapy and autologous SCT. The time from SCT to the initiation of VELCADE treatment
will be 3 to 6 months.
The initial 11 patients entered into this trial will be treated at a dose level of 1.0 mg/m2
once weekly on 4 consecutive weeks followed by 2 weeks of rest. A total of 4 treatment
cycles is planned.
An interim analysis for safety and tolerability will be performed after at least the first
cycle of study drug has been completed. If the study treatment is found to be safe and no
dose-limiting toxicity has occurred, the dose of VELCADE will be increased to 1.3 mg/m2 and
another 11 patients will be treated at this dose level according to the treatment schedule
as outlined above. The dose escalation to 1.3 mg/m2 will be performed without delay if no AE
or SAE are reported to the principal investigator.
If the safety of a specific dose level is acceptable the efficacy of the maintenance
treatment will be statistically evaluated. The treatment is considered to be efficacious if
a minimum of 25% of all treated patients experience a success, considered as remission of
their disease within 6 months after the end of VELCADE treatment. The therapy will be
acceptable for further clinical studies if a minium of 25% successfully treated patients
will be observed.
Under these assumptions in the first step of the optimal two step design (Simon 1989) 21
patients have to be treated. As patients included during phase I are included in the
efficacy analysis, this means an additional 10 patients to be treated. If less than three
patients were successfully treated defined as an improvement in the remission status, the
study will be stopped, because the success rate is unacceptably low. If three or more of the
21 patients are successfully treated, another 29 patients will be included. At the end of
the study the success rate will be evaluated. If 8 or more of the 50 patients were
successfully treated the therapy will be acceptable for further studies.
Patients will be evaluated at scheduled screening and baseline visits. After providing
written informed consent to participate in the study, patients will be screened for study
eligibility during a screening period of 28 days. Baseline assessment consists of a detailed
history of pre-existing diseases, blood tests including disease-specific markers such as
ß2-microglobulin, IgG, IgA, IgM, immunofixation from blood and urine, serum free light
chains, a bone marrow biopsy, a skeletal survey, an electrocardiogram and a chest X-ray.
The study drug will be administered in study centers only. Prior to each administration of
study drug, a short medical history focusing on VELCADE-associated side effects will be
performed as well as complete blood cell counts, kidney and liver function tests.
A visit on day 30 following the last administration of study drug for the final assessment
of safety and tolerability is mandatory in all patients included in this protocol.
Serological myeloma specific markers (monoclonal immunoglobulin, serum free light chains and
immunofixation from blood and urine) will be performed at weeks 6, 12, 18 and 24 and
thereafter in 3 months intervals. Bone marrow biopsies will be performed when serological
markers indicate complete remission or progression, a skeletal survey once a year during
follow-up. During the study, disease will be assessed according to the EBMT/IBMTR/ABMTR
Safety will be evaluated by the occurrence of clinical and laboratory toxicities and changes
from baseline in physical examination findings, vital signs, and, if applicable, chest X-ray
and electrocardiogram findings. All patients will receive an aminobisphosphonate at 4 weekly
intervals. Other disease-modifying treatment such as alpha interferon or pulsed
corticosteroids are strictly prohibited.
Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary endpoints are to study the safety of four cycles of VELCADE in patients with multiple myeloma following high-dose chemotherapy and autologous PBSCT.
Hermann Einsele, MD
Dept. of Internal Medicine II, University of Wuerzburg, Klinikstr. 6-8, 97070 Wuerzburg
Germany: Federal Institute for Drugs and Medical Devices