Trial Information

Efficacy and Safety of Velcade Plus Dexamethasone (VD), VD+Cyclophosphamide or VD Plus Lenalidomide in MMY Patients Who Are Refractory or Have Relapsed After Their Primary Therapy for MMY and Have Achieved Stable Disease After 4 Cycles of VD

It has been shown that quality of response corresponds with clinical benefit. Stable disease
is not regarded as a satisfactory result of therapy for relapsed and refractory multiple
myeloma. However, there is no consensus if, when and how treatment should be continued or
changed in the case of stable disease.

There are different strategies of achieving an optimal quality of response in relapsed and
refractory multiple myeloma. One is to treat for a longer duration with one regimen. The
alternative path can be a sequential approach adding another agent to the initial regimen
depending on the outcome of therapy after a defined treatment period. These two principles
will be evaluated in the present study.

Both Cyclophosphamide and Lenalidomide have proven to be efficacious in multiple myeloma and
combinations of both agents with bortezomib and Dexamethasone have been shown to be active
and tolerable.

In this study patients with relapsed/progressive or refractory multiple myeloma will start
treatment with bortezomiib and Dexamethasone. Response will be evaluated after four cycles.
Patients with complete, very good partial response or partial response will continue
treatment as initiated. Patients with stable disease will either continue treatment with the
bortezomib/Dexamethasone combination for another four cycles or will receive
Cyclophosphamide or Lenalidomide as an additional third agent for another four cycles.

Patients with multiple myeloma that are refractory to or have relapsed/progressed after
primary treatment for multiple myeloma will be enrolled in the study. All patients will
receive a combination of bortezomib plus dexamethasone for a total of four cycles. Based on
the response to this treatment, further study treatment is customized. Patients with a
complete, a very good partial or a partial response will continue to receive bortezomib and
Dexamethasone for a maximum additional four cycles, to an overall maximum of eight cycles.
Patients achieving stable disease, as defined by International Myeloma Working Group 2006
(IMWG 2006) response criteria, will undergo a central randomisation to continue treatment
with VD or VD plus cyclophosphamide or VD plus lenalidomide. Patients with progressive
disease will go off study treatment. After randomisation, patients will receive therapy for
up to four additional treatment cycles, to an overall maximum of eight cycles. Each cycle
will consist of three weeks treatment. There will be a long-term follow-up period with
monthly visits until relapse or progressive disease. Thereafter follow-up for survival will
be continued by at least a phone call every other month. This will be performed for all
patients until the last patient was treated and followed up for 1 year.

Safety will be assessed by the monitoring of adverse events, physical examination (including
neurological/peripheral neurological examinations), pulmonary examinations, vital signs
measurements, and clinical laboratory tests.

Patients will be treated in a 3-week cycle, up to a maximum of 8 cycles bortezomib 1.3
mg/m2 will be administered on day 1, 4, 8 and 11 as i.v. bolus infusion.

Dexamethasone 20 mg po will be administered on days 1, 2, 4, 5, 8, 9, 11, 12.
Dexamethasone will be administered as 2 tables of 8 mg plus 1 tablet of 4 mg
Cyclophosphamide 500 mg po will be administered as 10 tablets of 50 mg on day 1, 8, 15
Lenalidomide will be administered as once daily 10 mg tablet from day 1 to 14