Phase I/II trial of Lenalidomide plus Bortezomib combined with Dexamethasone in elderly patients in 1st relapse or primary refractory after first line therapy for multiple myeloma.

The therapy results of multiple myeloma (MM) in elderly patients are less
favorable due to several factors, including the presence of concomitant
diseases and increased toxicity and poor tolerability of intensified treatment
regimens. Higher age has been identified as a risk factor in many clinical
trials. In addition, elderly patients with MM frequently fail to complete
rescue treatment at first or later relapse.
The standard treatment of elderly patients with MM has been Melphalan plus
Prednisone, Melphalan alone, Dexamathasone alone or Melphalan plus
Dexamethasone. None of these regimens has been shown to be clearly superior
while toxicity may differ. Recent improvement of the first-line treatment of MM
of the elderly patient include the addition of Thalidomide to
Melphalan/Prednisone or to Dexamethasone. These new combinations have resulted
in increased overall and complete response rates and a prolonged disease-free
survival. However, ultimately, patients continue to relapse and many patients
suffer from debilitating side-effects, such as irreversible polyneuropathy.
The present treatment options for elderly patients with first or later relapse
of MM include Thalidomide, Bortezomib and Lenalidomide as a single agent, or
combined with Dexamethasone. Recently, two randomized trials showed a superior
effect of Lenalidomide plus Dexamethasone over Dexamethasone alone.
Bortezomib en Lenalidomide are both effective anti-myeloma agents which have a
complementary mode of action and which do not have an overlapping toxicity
profile. The combination of these drugs appears to be a viable opportunity for
the treatment of elderly patients with MM

Phase I:
-To determine the maximum tolerated dose (MTD) and recommended phase II dose
level (RDL) of Bortezomib administered once weekly, and of Lenalidomide
administered for 3 weeks when combined with Dexamethasone in a 28-days schedule.

Phase II:
-To investigate the efficacy of a maximum of 8 cycles of Bortezomib plus
Lenalidomide with Dexamethasone at the RDL, as determined by the (s)CR+VGPR
rate

The study is designed as a prospective, multicenter phase I/II study.

Phase I:
During induction therapy a combination of Bortezomib, Lenalidomide and
Dexamethasone will be adminstered in 28-days cycles untill a maximum of 8
induction cycles. The planned doses for investiagtion are as follows:
-Bortezomib: 1.3 mg/m2 i.v. on days 1, 8 and 15. Bortezomib will be
escalated to a dose of 1.6 mg/m2
-Lenalidomide: 10 mg/day orally on day 1-21. lenalidomide will be escalated
to a dose of 20 mg/m2
-Dexamethasone: 20 mg orally on days 1, 2, 8, 9, 15, and 16.
During maintenance therapy Lenalidomide will be administered at a dose of 10 mg
on days 1-21. Maintenance cycles will be repeated at 28-days intervals untill
relapse, progression or a medical condition that requires stopping the treatment

Phase II:
During induction therapy a combination of Bortezomib, Lenalidomide and
Dexamethasone will be adminstered in 28-days cycles untill a maximum of 8
induction cycles. The planned doses for investiagtion are as follows:
-Bortezomib: recommanded dose level (RDL) or 1.6 mg/m2 (expected RDL) from
phase I) i.v. on days 1, 8 and 15.
-Lenalidomide: RDL or 20 mg/day (excpected RDL form phase I) orally on day
1-21.
-Dexamethasone: see phase I
During maintenance therapy Lenalidomide will be administered according to the
same schedule as in phase I.

Toxicity, especially myelosupression, polyneuropathy