Use of intrapleural bortezomib in myelomatous pleural effusion

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Myelomatous pleural effusion (MPE) is a manifestation of an aggressive course of multiple myeloma (MM) (Iannitto et al, 1988; Alexandrakis et al, 2004) and approximately 80 cases have been reported to date. MM associated with MPE has been related with a poor prognosis and it is often associated with high-risk disease. There is no standard treatment for MPE and the survival is generally <4 months (Kamble et al, 2005).

Bortezomib has been shown to have impressive activity in patients with relapsed-refractory MM (Richardson et al, 2005). We describe a case of MPE that was successfully treated with intrapleural plus i.v. bortezomib administration.

A 66-year-old, immunoglobulin (Ig) G-λ MM male patient, who had progressive disease despite a tandem autologous bone marrow transplantation (doubling of the serum M-component level, 30 g/l), was admitted to our hospital because of severe respiratory distress. A thorax computed tomography (CT) scan revealed a left pleural effusion and a 5-cm paravertebral nodular lesion involving the upper lobe of the right lung.

Morphological, flow-cytometric and immunocytochemical analysis of the pleural fluid (Palmer et al, 2000) and an echo-guided lung biopsy showed the presence of atypical CD38+ IgG-plasma cells (Fig 1A). Pleural fluid electrophoresis (Fig 1B) showed an M-component that was identical to that identified in the serum. The patient received two courses of bortezomib (1·3 mg/m2) plus dexamethasone (20 mg), i.v., in a 3-week cycle on days 1, 4, 8, and 11; pegylated liposomal doxorubicin (Caelix®, Shering-Plough, Milan, Italy) at a dose of 40 mg/m2 was also administered on day 1 of each cycle. Evacuative thoracenteses were needed twice a week. We observed a 75% reduction of the serum M-component (10 g/l) without any improvement of the pleural effusion formation rate.

Figure 1.

 (A) Immunocytochemical evaluation of pleural fluid: CD138+ neoplastic plasma cells (anti-CD138 immunostaining, original magnification 400×); (B) M-component on pleural fluid electrophoresis; (C) massive left pleural effusion and nodular paravertebral lesion involving upper lobe of the right lung on CT performed on admission; (D) computed tomography scan showing the reduction of the left pleural effusion and 50% reduction of the paravertebral lesion after four courses of intrapleural bortezomib.

Pharmacodynamic modelling of bortezomib has shown a dose-dependent proteasome inhibition that is related both to the single dose in mg/m2, and to the total dose delivered (Orlowski et al, 2002). We therefore decided to overcome the poor response of pleural MM effusion by increasing the local bortezomib concentration using combined i.v. and intrapleural infusion. The patient gave his informed written consent to the intrapleural administration of bortezomib.

Thus, on days 1, 4, 8, and 11 of the next two cycles, after performing an evacuative thoracentesis, we infused half the planned dose of bortezomib inside the pleural cavity, the remaining dose being administered i.v. with dexamethasone. No acute side effects were registered after intrapleural bortezomib infusion. Pleural fluid progressively cleared and after the second intrapleural dose of bortezomib the pleural fluid turned from haemorrhagic to serous. Its formation rate slowed down and it became cell-free after the third dose. After completion of the first course (four intrapleural doses), pleural effusion no longer formed. A CT scan documented an almost complete recovery of the pleural effusion and a 50% reduction of the nodular lung lesion (Fig 1C,D).

Twelve months after MPE onset, the patient is still asymptomatic with stable serum M-component and pleural effusion level.

We cannot rule out that the dramatic clinical response of the MPE we witnessed could be the effect, at least in part, of the previous i.v. therapies. However, these results were obtained in a patient who was unresponsive after two courses of pegylated liposomal doxorubicin, dexamethasone and bortezomib. The sudden drop of the pleural effusion formation rate and the change of the pleural fluid chemicophysical characteristics within a week of intrapleural treatment (two bortezomib doses) suggest that this therapy might have played a role in the rapid recovery.

Myelomatous pleural effusion has a poor prognosis, especially when it occurs late in the course of the disease and neither systemic nor local therapies have been effective in terms of survival and management. This experience suggests that intrapleural bortezomib administration can be effective and devoid of side effects. Therefore, we believe that it could be considered as a therapeutic option in the management of MPE.

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