Durable complete remission of primary plasma cell leukemia with the bortezomib plus melphalan and prednisone (VMP) regimen^†

Primary plasma cell leukemia (PPCL) is an aggressive and unusual form of multiple myeloma defined as the presence of at least 20% of circulating leukocytes representing plasma cells [1]. To date no treatment regimen has been found to be clearly efficacious, and survival is generally reported to be short [2]. In 2008 a combination of melphalan, bortezomib, and prednisone (VMP) was reported to be highly effective and tolerable in patients with multiple myeloma who were not candidates for high dose therapy [3]. We recently treated a patient with PPCL using the VMP regimen and achieved excellent results.

An 81-year-old female was admitted to hospital for fatigue, shortness of breath, and left lower extremity edema. The patient was highly functional and before becoming ill was working part-time and taking care of her husband who had chronic dementia. On presentation, WBC was 10.5 × 10E3/mm³, hemoglobin 4.9 gm/dL and hematocrit 14.2%, platelets 129 × 10³/mm³, creatinine 0.79 mg/dL. The patient was transfused with packed red blood cells and improved significantly. She was also noted to have edema and discomfort in the left leg, a Doppler ultrasound demonstrated a deep venous thrombosis for which the patient was admitted and anticoagulated. The only medications at the time of admission were calcium. Physical exam was unremarkable except for swelling of the lower extremity. Skeletal bone survey demonstrated innumerable lytic lesions in the skull but was otherwise negative. The peripheral smear showed a prominent population of atypical large plasma cells (56% of WBCs) with an increased N:C ratio. Beta 2 microglobulin was 8.2 mg/L. Bone marrow biopsy was performed during the hospitalization, which demonstrated plasmablastic-type multiple myeloma with circulating plasmablasts/plasma cell leukemia. The marrow was 94% cellular of which contained 94% plasmablasts. Flow cytometry of the bonemarrow revealed 62% monoclonal plasma cells with a CD38+,CD138+, CD56+, and cytoplasmic kappa light phenotype. Serum protein electrophoresis located a clonal 4.1gm/dL spike in the mid-gamma region. Cytogenetics demonstrated an abnormal karyotype: 51,x,−x,der(1)t(1;11)(p12;q13)x2+3,+5,+9,+15,+19,+19-22[7]/46,xx[3].

The patient was treated with bortezomib, melphalan, and prednisone (VMP) as previously described [3]. The VMP regimen consists of seven 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, in combination with bortezomib (at a dose of 1.3 mg per square meter), by intravenous bolus on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. Supportive care was administered as described by San Miguel et al. After the first cycle of VMP, the patient developed significant myelosuppression with an absolute neutrophil count of 0.0, hemoglobin of 7.6, and platelets of 19,000. Her bortezomib dose was reduced to 0.7 mg/m2 for the second cycle and then increased to 1.0 mg/m2 for all subsequent cycles. In addition, the melphalan dose was reduced by 25% for the second and all subsequent cycles of VMP. Her CBC improved, and she had no further episodes of significant myelosuppresion. She tolerated the remaining cycles of therapy extremely well and was able to continue living independently and caring for her husband. Her deep venous thrombosis was treated with enoxaparin 1 mg/kg subcutaneously once daily.

During the eighth cycle, the patient developed a maculopapular rash on her extremities and trunk. This was thought to possibly be related to bortezomib. Because the patient was already in a complete remission serologically further therapy with VMP was stopped. The rash resolved within 1 week.

Bone marrow biopsy and peripheral blood examination after eight cycles of VMP showed no morphologic or immunophenotypic evidence of involvement by plasma cell neoplasm. There was no measurable m-component in the blood. Eleven and one half months after her original diagnosis, the patient was placed on bortezomib 1.5 mg/m² every other week for maintenance therapy. She has no long-term side effects from the VMP. Seventeen months after her diagnosis, she continues to be in a complete remission on maintenance bortezomib.

The results of treatment for PPCL are generally dismal; most patients succumb rapidly to their disease. In a recent Surveillance, Epidemiology, and End Results (SEER) database analysis of 296 cases of PPCL, the median overall survival (OS) was 4 months, and the median disease-specific survival (DSS) was 6 months for patients with PPCL; the 1-year, 2-year, and 5-year OS rates were 27.8%, 14.1%, and 6.4%, respectively [4]. Many patients with plasma cell leukemia harbor genomic changes such as hypodiploidy, t(11;14),14q32 (IgH), del(13q),17p, 1q21 amplification and del(1p21) that help to explain its aggressive nature [5, 6].

Recently, the immunomodulatory agents (thalidomide and lenalidomide) and the proteosome inhibitor bortezomib been used in this rare disease with some success. Thalidomide appears to have activity in PPCL [7]. Lenalidomide has demonstrated some success in relapsed secondary plasma cell leukemia [8, 9].

There are a small number of reports on the utilization of bortezomib for PPCL [10-20]. Published response rates to bortezomib combination therapy in PPCL are promising. In the largest published series of PPCL patients treated with bortezomib, the median PFS and OS in patients with primary PCL had still not been reached at 21 months (the time of the report) [13].

The VMP regimen is appropriate for patients ineligible for high dose therapy. In the original report of San Miguel et.al., the proportion of patients with a partial response or better were 71% with complete response rates of 30%. The median duration of the response was 19.9 months with VMP. This results of this trial also suggested that responses to VMP are not diminished by cytogenetic abnormalities. To our knowledge, there is no other report whose focus is a discussion of VMP used for the treatment of PPCL, although an article reviewing salvage therapy with lenalidomide and dexamethasone in relapsed PPCL mentioned a 76-year-old male who achieved a very good partial remission (VGPR) with first line VMP [9]. In conclusion, adjusted dose VMP as described by San Miguel et al. [3] was very well tolerated in this elderly female with PCL. A prolonged complete remission was achieved. This patient's response suggests that VMP is worthy of further study in PPCL and should be considered in patients for whom high dose therapy is not planned.