Plasma cell leukaemia (PCL) is characterized by circulating plasma cells >2 × 109/l in peripheral blood and/or a peripheral blood plasmacytosis >20%. Primary PCL (pPCL) is defined as a de novo appearance of disease, while secondary PCL (sPCL) corresponds to the leukaemic transformation of a previously diagnosed multiple myeloma (MM) (Albarracin & Fonseca, 2011). sPCL still remains an exceedingly resistant disease with median survivals of 2 months (Tiedemann et al, 2008; Musto et al, 2011a; Pagano et al, 2011). Lenalidomide has been reported to have some activity' in sPCL although it is short-lived (Benson & Smith, 2007; Musto et al, 2008), while better results have been described when this drug is used as first line therapy in pPCL (Musto et al,2011b). Bortezomib has been investigated with promising results as single agent or in combination both in pPCL and sPCL. However, although very effective in MM patients at relapse or at diagnosis (Richardson et al, 2010), the use of combined therapy with bortezomib, lenalidomide and dexamethasone (VRD) in PCL has not been reported. We report here, for the first time, the efficacy of VRD treatment in two patients with sPCL.
Case 1 was a 64-year-old male diagnosed with IgG/k stage IIIA [International Staging System (ISS) II] MM. He was treated with autologous stem cell transplant (ASCT) and achieved an immunofixation-negative complete remission (CR). Fourteen months later (21 months after diagnosis) he presented to the outpatient clinic complaining of fatigue. A month earlier, at usual follow up, he was still in CR. Blood cell counts revealed: white blood cells (WBC) 3·8 × 109/l (neutrophils 20%, lymphocytes 20%, plasma cells 45%, monocytes 15%), Hb 65 g/l, platelets 18 × 109/l. Lactate dehydrogenase (LDH) was 1345 u/l (normal range 150–300), creatinine 140 μmol/l, serum electrophoresis did not show an evident monoclonal spike (gamma globulin 8·4%, IgG 0·45 g/l) but serum immunofixation was positive for IgG/k. Serum free light chains (FLC) ratio was abnormal (K 189 mg/l). Bence Jones was 4·9 g/24 h with K light chains. Bone marrow biopsy evidenced a full substitution by monoclonal plasma cells CD38/CD138+, K+, CD 20+, CD56+, CD27−, CD19−. Fluorescence in situ hybridization (FISH) analysis showed a t(11;14). The patient started treatment with bortezomib 1·3 mg/m2 i.v days 1, 4, 8, 11, cyclophosphamide i.v.1 g days 1,8, dexamethasone 40 mg days 1, 2–4, 5–8, 9–11, 12 (VCD). After one cycle the patient showed progressive disease (WBC 6·5 × 109/l with 59% plasma cells and Bence Jones protein 5·5 g/24 h). Therapy was then modified to lenalidomide 25 mg days 1–14, bortezomib 1·3 mg/m2 i.v. days 1, 4, 8, 11, dexamethasone 40 mg days 1, 7, 14, 21. The patient had a complete clearance of disease after two cycles of therapy, evidenced by bone marrow biopsy, negative serum and urine immunofixation, normal serum FLC ratio, confirmed after four cycles of therapy. Unfortunately, the patient developed grade III neutropenia and pneumonia after cycle 4; and therapy was suspended for 2 months thereafter. At 7 months from sPCL diagnosis he suffered disease recurrence and died.
Case 2, a 71-year-old male diagnosed with IgG/k stage IIIA (ISS II) MM in February 2002, was initially treated with double ASCT, conditioned each time with melphalan 200 mg/m2, and achieved an immunofixation negative CR. At 92 months from ASCT, he presented at the Emergency Department, with fatigue. Blood cell counts revealed: WBC 22 × 109/l (neutrophils 10%, lymphocytes 5%, plasma cells 85%), Hb 89 g/l, platelets 77 × 109/l. LDH was 790 u/l (normal range 150–300), creatinine 80 μmol/l, B2-microglobulin was 2·8 mg/l, serum electrophoresis showed an evident monoclonal IgG/k spike (gamma globulin 43%, IgG 5·7 g/l). Bence Jones protein was 500 mg/24 h. A bone marrow aspirate identified 95% of monoclonal plasma cells CD38/CD138+, CD20−, CD56+, CD117+. FISH analysis showed a del 13q14. The patient was treated with three cycles of bortezomib i.v. 1·3 mg/m2 days 1, 4, 8, 11 every 21 d and dexamethasone days 1, 2–4, 5–8, 9–11, 12 (VD) achieving a minimal response. We then added lenalidomide 25 mg days 1–21 every month to the VD therapy and he completed five cycles of VRD, achieving an immunofixation-negative CR with normal serum FLC ratio. The patient was still in CR at 12 months from sPCL diagnosis, continuing lenalidomide as maintenance therapy (10 mg/d, for 21 d every month).
Although responses and survivals are extremely disappointing in PCL, both bortezomib and lenalidomide, individually used, have been reported to be effective. In a retrospective survey of unselected cases of both sPCL and pPCL (Musto et al, 2007), 12 patients received bortezomib for 1–6 cycles, as single agent or variously combined with other drugs. Three patients were treated with bortezomib as frontline therapy, nine after 1–4 lines of chemotherapy, including ASCT and thalidomide, with overall responses in 92% of the patients [five partial response (PR), four very good partial response (VGPR) and 2 CR]. Median progression-free survival (PFS) and overall survival (OS) after bortezomib were 8 and 12 months, respectively. Eight patients remained alive 6–21 months after bortezomib-treatment, four of whom with >VGPR.
Some case reports have described the possible, though temporary, efficacy of lenalidomide in sPCL (Benson & Smith, 2007; Musto et al, 2008). In another study, lenalidomide was given as consolidation/maintenance therapy after PR was obtained in patients previously treated with bortezomib, thalidomide, cyclophosphamide, liposomal doxorubicin, resulting in continued disease control for 20 months in pPCL (Sher et al, 2010).
Finally, in a multicentre Phase II trial aiming to evaluate the safety and antitumour activity of lenalidomide in combination with dexamethasone (LD) in 23 previously untreated pPCL, 6 PR (26·1%), 4 VGPR (17·4%), 1 near-CR (4·3%) and 3 CR (13%) were achieved (overall response rate 60·8%, VGPR or better 34·7%) (Musto et al, 2011b). With a mean follow-up of 15 months, OS and PFS were 65·2% and 52·1%, respectively.
Both our patients, who were primary refractory to bortezomib, achieved a stringent CR with one patient continuing lenalidomide as maintenance therapy after 12 months from sPCL diagnosis. Responses were very fast, although short lived in Patient 1, probably due to therapy discontinuation because of a severe infection due to neutropenia and haematological toxicity could be an important issue to consider. Based on these results we believe that this regimen should be tested in collaborative clinical trials.