Biology of Blood and Marrow Transplantation
Volume 13, Issue 4 , Pages 497-499, April 2007

Bortezomib after Allografting in Multiple Myeloma: Association between Neurotoxicity and Cyclosporine Treatment

Divisione Universitaria di Ematologia, Azienda, Ospedaliera San Giovanni Battista, Torino, Italy

Article Outline

 

Relapse following allografting in patients with multiple myeloma (MM) remains relatively high [1, 2]. The observations of a possible pivotal role of NF-κB in graft-versus-host disease and the efficacy of bortezomib in refractory/relapsed MM through the inhibition of NF-κB have provided the rationale for using this new agent in relapsed MM following allografting [3, 4, 5, 6, 7, 8, 9]. We focused on bortezomib-induced neurotoxicity in 24 relapsed patients following nonmyeloablative/reduced intensity allografting. Nineteen were partly described in an earlier report in the Haematologica/Hematology Journal [8]. Conditioning regimens were 2 Gy total body irradiation (TBI) based (n = 19) or a combination of thiotepa, cyclophosphamide, and melphalan (n = 5) [1, 8]. Donors were human leukocyte antigen (HLA) identical siblings (n = 22) or unrelated (n = 2). Postgrafting immunosuppression consisted of cyclosporine with mycophenolate mofetil or methotrexate. Bortezomib was administered after a median of 20 months from allografting (range 5-54), at first (n = 6) or second relapse (n = 10), or beyond second relapse (n = 8). Patients received bortezomib 1.0 (n = 8) or 1.3 mg/m2 (n = 16) on days 1, 4, 8, and 11 every 3 weeks for a median of 3 courses (1-8), alone (n = 5) or in combination with steroids (n = 19). Informed consent was obtained on enrollment according to the institutional review boards of the participating centers. Overall, bortezomib toxicity was observed in 17 of 24 patients (71%) including thrombocytopenia (8 of 24; 33%), neutropenia (2 of 24; 8%), and rash (1 of 24; 4%) [3]. However, incidence and severity of peripheral neuropathy were far higher than that currently reported in nontransplant patients: 14 of 24 (58%) including 7 of 24 (29%) with grade III-IV [3]. Importantly, 6 required bortezomib discontinuation because of severe neuropathy unresponsive to dose reduction. Another patient suspended treatment because of severe thrombocytopenia. Interestingly, the only factor significantly associated with the development of severe neurotoxicity was prolonged treatment, median 15 months, with cyclosporine (Table 1). Moreover, although statistical significance was not reached, severe neurologic side effects occurred more frequently in patients (6 of 7) on the higher bortezomib dose.

Table 1. Post-allografting Bortezomib and Neurotoxicity: Analysis of Risk Factors
Peripheral neuropathyGrade 0-2Grade 3-4P
Concomitant steroid therapy15/175/7.9⁎
>1 treatment line from postgrafting relapse to bortezomib7/171/7.3⁎
Previous treatment with thalidomide9/175/7.3⁎
Months from diagnosis to bortezomib, median (range)34 (19-164)31 (21-74).6†
Months of cyclosporine treatment, median (range)6 (328)15 (6-37).02†

⁎Fisher exact test;

†two-sample t-test.

The mechanisms of drug-induced neural damage remains unclear for many drugs and may result from several factors. Cyclosporine, a calcineurin inhibitor, is characterized by neurotoxic effect on both sensorial and motoric functions as well as on the central nervous system. Its toxicity has been associated with metabolic changes, microvascular, and assonal damage [10]. Prolonged cyclosporine treatment may have resulted in a subclinical damage that became clinically relevant with the administration of bortezomib. Conversely, we did not observe any correlation between neurotoxicity and previous thalidomide treatment. This may suggest different causal mechanisms of thalidomide neurotoxicity from those of bortezomib.

Overall disease response, evaluated in 18 patients after at least 2 bortezomib courses, was 72%, including 5 complete (CR) and 8 partial remissions (PR). After a median follow-up of 13 months (4-27) from the start of treatment, 7 patients had died from disease progression and 3 patients were alive in continuous response.

In summary, clinicians should be aware of the risk of severe neurotoxicity associated with bortezomib after prolonged cyclosporine treatment. Up-front dose reduction in the treatment schedule may be considered in these patients.

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Acknowledgements 

This work was supported in part by Progetti di Ricerca ex-60%; Regione Piemonte: Ricerca Finalizzata 2005 (Progetto Clinico-scientifico c di Coordinamento Regionale); Compagnia di San Paolo; Fondazione Cassa di Risparmio di Torino (C.R.T.) and Comitato Regionale Piemontese Gigi Ghirotti (Progetto Vita Vitae); Fondazione Neoplasie Sangue Onlus.

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References 

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PII: S1083-8791(07)00106-1

doi:10.1016/j.bbmt.2007.01.069

Biology of Blood and Marrow Transplantation
Volume 13, Issue 4 , Pages 497-499, April 2007

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