Background. The proteasome inhibitor bortezomib induces apoptosis, reverses drug resistance of multiple myeloma (MM) cells, and affects their microenvironment by blocking cytokine circuits, cell adhesion and angiogenesis. The aim of the study was  to evaluate the efficacy and safety of bortezomib in the treatment and retreatment of relapsed MM and its aggressive  variant - plasma cell leukemia (PCL).

Material and methods. We enrolled 4 patients with PCL and 17 patients with relapsed MM who have failed at least two prior lines of treatment, including 4 patients treated with high dose therapy and autologous stem cell transplantation. The time from MM diagnosis to onset of bortezomib therapy varied between 3 and 149 months. Patients received bortezomib 1.3 mg/m² as  i.v. bolus twice weekly for 2 weeks, on days 1,4, 8 and 11, followed by 1 week without treatment, for up to six cycles. In 6 patients doxorubicin and dexamethasone  were added to the regimen (=PAD regimen) and in 2 patients with disease sensitive to the bortezomib therapy, bortezomib was re-administered in the consecutive relapses.

 Results: Partial response was achieved in 2 of 6 patients treated with PAD regimen and in 3 of 12 evaluated patients treated with bortezomib alone. In one case of recurrent MM who was three times treated with bortezomib, with preserving a 18-month break between first and second and 8 months between second and third therapy courses, all three treatments resulted in achieving a near complete remission which lasted each 6 months. The patient 120 months since MM diagnosis, further on bortezomib therapy, feels good. In one patient with primary PCL, a near  - complete remission was achieved subsequent to induction PAD treatment. Following cyclophosphamide, peripheral blood stem cell were successfully harvested and autologous peripheral blood stem cell trasnsplantation (PBSCT) was performed. Time to neutrophil > 0.5 x 10⁶ engraftment was 20 days and time to platelet > 20 x 10⁶ engraftment was 17 days.  PBSCT led to complete remission which lasted 7 months. Partial remission was achieved subsequently to relapse retreatment with PAD. At present, the patient is further on bortezomib therapy, in partial second remission, 22 months after diagnosis of PCL.

Adverse events: treatment with bortezomib was withheld in 5 patients (after 1, 2, 3, 4 and 5 cycles, respectively) because of skin lesions (erythema multiforme), subileus and aggravation of peripheral neuropathy. Side effects seen in the study included also herpes zoster in 3 patients, pyrexia, infections, nausea, vomiting, abdominal pain, pain in limbs, hypotension, thrombocytopenia.

Conclusions: In relapsed myeloma the rate of response to bortezomib alone is 25 percent, with a duration of response of 6 months. A presented here cases demonstrate the efficacy of repeat bortezomib treatments in the patients with recurrence of myeloma who were previously sensitive to such a treatment. We suggest, bortezomib in combination with other agents may be considered as an initial treatment of primary PCL. PAD regimen is effective and does not prejudice peripheral blood stem cell collection or subsequent engraftment.

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