Bortezomib as Front-Line Therapy in Primary Plasma Cell Leukemia
Authors: Pietrantuono Giuseppe , Guariglia Roberto , Villani Oreste , Martorelli Maria Carmen , D’Auria Fiorella , Zonno Antonia , Lerose Rosa , Fioritoni Giuseppe , Zamagni Elena , Rossini Fausto , Filardi Nunzio , Pagano Livio , Musuraca Gerardo , Pitini Vincenzo , Quintini Gerlando , Falcone Antonietta , Bringhen Sara , Palumbo Antonio , Musto Pellegrino 
Published: April 2020

Abstract
Plasma cell leukemia (PCL) is an aggressive, rare variant of multiple myeloma (MM), with peculiar clinical and biological characteristics, which represents about 2–4% of all MM. PCL exists in two forms:
primary PCL (about 60% of cases) presents “de novo”, without previous evidence of MM; secondary PCL, which accounts for the remaining 40%, consists of a leukemic transformation occurring in about 1% of patients with a previously diagnosed MM.
We have recently shown that bortezomib is an effective agent for the treatment of both primary and secondary PCL, mainly in the setting of pre-treated disease (Musto et al, Cancer 2007). In the present study we conducted a multicenter retrospective survey focused on unselected patients with a diagnosis of primary PCL who had received bortezomib exclusively as first line therapy for the treatment of their disease, outside of clinical trials. To-date, 15 patients, diagnosed according to International Myeloma Working Group criteria, have been collected, 12 of whom (seven male and five female, 49 to 77 year-old) have been so far evaluated for response. Circulating plasma cells ranged from 3 to 95 × 10e9/L. Seven patients had an IgG M-component, two had IgA, two light chains, while one patient was not secretory. Five patients had concomitant extramedullary disease. Unfavourable cytogenetic abnormalities were observed in 4 out of 7 patients with available karyotype. Bortezomib was generally given using the standard schedule of 1.3 mg/sqm days 1, 4, 8, 11, with an interval of 10 days between cycles. Minor modifications were performed, according to tolerance. Three patients received dexamethasone (VD), two dexamethasone and thalidomide (VTD), six doxorubicin and dexamethasone (PAD), and one oral melphalan and prednisone (MPV) in combination with bortezomib, for 2–6 cycles. Three patients underwent autologous, two allogeneic and one a sequence of autologous followed by non-myeloablative allogeneic stem cell transplantation after induction therapy. One out of five eligible patients failed to collect peripheral blood stem cells. Grade 3–4 hematological, neurological, infectious and renal toxicities occurred in 6, 2, 1 and 1 patient, respectively. Other toxicities (diarrhoea, nausea, skin rash) never reached grade 3. According to the International Uniform Response Criteria, 4 partial remissions (reduction of M-component &gt; 50%), 5 very good partial remissions (reduction of M-component &gt; 90%, with positive immunofixation), and 3 complete remissions (negative immunofixation) were achieved (100% overall response). In all patients circulating plasma cells disappeared. One patient with pre-existing renal damage died of progressive disease after 3 months, developing more severe renal failure. Another patient died in CR 6 months after diagnosis, while performing allogeneic stem cell transplantation. Three patients relapsed after 5–8 months and 2 of them died with progressive disease within 4 months from relapse. The remaining 8 patients are alive, and 6 of them maintain their remission phase after 9 to 19 months. One-year progression-free survival and overall survival were 50% and 66.6%, respectively. Primary PCL is usually characterized by poor prognosis. Global response rate to standard chemotherapy is less than 50% and median survival is only 7 months. Stem cell transplantation may be more effective in some, but not all cases. Our findings suggest that, in these patients, the front-line use of bortezomib induces a very high rate of good quality responses, whose duration, however, may be short. This suggests that, in primary PCL, bortezomib should be integrated within more intensive therapeutic programs, including other active drugs and, when possible, stem cell transplantation.