The case
A 59-year-old woman presented to the emergency department with a left rib fracture. She was a known hepatitis B carrier with otherwise unremarkable past medical history. A bone scan 4 months later showed bony metastasis at multiple ribs and thoracic spines. Two months after the bone scan, CT-guided biopsy of the thoracic spine lesion confirmed plasmacytoma, which was negative for CD20 but positive for CD79a with lambda light chain restriction. The patient received thalidomide and dexamethasone treatment for 2 months before referral to hospital. Serum protein and urine protein electrophoresis performed at hospital did not reveal any monoclonal gammopathy. Thalidomide (100 mg daily) and dexamethasone (20 mg daily on days 1–4, days 8–11, days 15–18, every 28-day cycle) were continued for 7 cycles, and she underwent high-dose melphalan (200 mg/m2) with autologous stem-cell rescue 8 months after referral to hospital. Her IgA levels upon bone-marrow transplantation were 89 mg/dl (normal levels 70–386 mg/dl) (Figure 1). The patient received thalidomide 100 mg daily as maintenance therapy for 14 months after bone-marrow transplantation. Serial serum protein and urine protein electrophoresis showed continual absence of monoclonal gammopathy.
Figure 1 | Diagram showing IgA levels in relation to events during the patient's treatment.
Abbreviations: ABMT, autologous bone-marrow transplantation; CEOP, cyclophosphamide, epirubicin, vincristine and prednisolone for 3 cycles; PAD, bortezomib, doxorubicin and dexamethasone; RT/MPT, radiotherapy and combined melphalan, prednisolone and thalidomide therapy; Thal/Dex, thalidomide and dexamethasone; VEL-CMP, bortezomib, cyclophosphamide, melphalan and prednisolone; Vel/Dex, bortezomib and dexamethasone for 2 cycles.
Fourteen months after stem-cell rescue, the patient presented with obstructive jaundice with serum bilirubin level 47 
mol/l (normal levels <19 mol/l), alkaline phosphatase 526 U/l (normal levels <140 U/l), alanine transferase 303 U/l (normal levels <30 U/l) and gamma glutamyltransferase 385 U/l (normal levels <42 U/l). A CT scan showed an enhancing tumor of 3.1 
3.3 3.4 cm at pancreatic head, and a solitary pleural deposit of 1.7 cm in length in addition to the old lytic bone lesions (Figure 2a). Endoscopic biopsy of this mass 1 month after the CT scan showed a homogeneous plasma cell infiltrate. A stent was inserted in subsequent endoscopic retrograde cholangiopancreatography to relieve the obstructive jaundice. Biopsy of that pleural mass also showed features of plasmacytoma. In view of the tumorous presentation, three cycles of CEOP (cyclophosphamide 650 mg/m2, epirubicin 50 mg/m2, and vincristine 1.4 mg/m2 on day 1, prednisolone 100 mg/d on days 1–5) were administered, but a follow-up CT scan showed an interval increase in size of the pancreatic head tumor (Figure 2b). Two cycles of bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11) and dexamethasone were given but repeated CT showed further interval progression of the pancreatic head tumor, and new pleural deposits. The patient received melphalan 4 mg/m2 and prednisolone 40 mg/m2 on days 1–5 for two cycles and local irradiation (40 Gy delivered in 20 fractions) to pancreatic head without any interval regression of pancreatic head tumor (Figure 2c). Moreover, monoclonal gammopathy of IgA appeared, with serum IgA levels at 1,840 mg/dl and paraprotein levels at 2.4 g/l (Figure 1). The patient received salvage therapy with bortezomib (1.3 mg/m2 on day 1, 4, 8 and 11 in a 28-day cycle) plus adriamycin (9 mg/m2 on days 1–4) and dexamethasone (40 mg daily on days 1–4) for three cycles, but a persistent rise in serum IgA levels occurred (Figure 1). Bortezomib plus cyclophosphamide (100 mg/m2 daily on days 1–4), melphalan (4 mg/m2 daily on days 1–4) and prednisolone (40 mg/m2 daily on days 1–4) (VEL-CMP) was started. Three weeks after VEL-CMP, absence of monoclonal gammopathy was confirmed by both serum immunoglobulin levels and serum immunofixation. Moreover, CT showed complete resolution of pancreatic mass and pleural deposits (Figure 2d). The patient remained in complete remission for 3 months. At this time, there was recurrence of a weak monoclonal band on serum protein. Her paraprotein and IgA levels gradually increased (Figure 1), and she did not respond to lenalidomide, which was given at 15 mg daily on days 1–14, every 21 days for 2 months. The patient finally succumbed to refractory disease 4 years after her initial presentation.
Figure 2 | CT images of the patient showing the extramedullary relapses.
a | The peripancreatic mass (white arrow) was detected at the time of obstructive jaundice. b | The mass (white arrow) showed interval enlargement despite CEOP and bortezomib–dexamethasone therapy. c | After MPT therapy, the pancreatic mass (white arrow) remained static in size. d | After one cycle of VEL-CMP therapy, the mass had disappeared and the pancreas appeared normal (white arrow). Abbreviations: CEOP, cyclophosphamide, epirubicin, vincristine and prednisolone; MPT, melphalan, prednisolone and thalidomide; VEL-CMP, bortezomib, cyclophosphamide, melphalan and prednisolone.
Discussion of diagnosis
Plasmacytoma is a solitary, localized, tumorous collection of clonal neoplastic plasma cells, which might occur within or outside the bone (that is, extramedullary plasmacytoma [EMP]). EMP that occurs in the absence of systemic myeloma disease (primary EMP), often involves the upper aerodigestive tract and carries a low risk of evolution to multiple myeloma.1 On the other hand, EMP that develops secondary to multiple myeloma or during relapse after high-dose therapy has a poor prognosis.2, 3, 4 In the setting of autologous bone-marrow transplantation, EMP develops in about 10–14% of patients who relapse with a latency of 9–24 months after bone-marrow transplantation.2 Extramedullary sites involved include lung/pleura, pericardium/peritoneum, lymph nodes, soft tissues, breast, pancreas and central nervous system/leptomeninges.2, 3, 4, 5 Despite intensive treatment, outcome is uniformly poor, with a median survival of about 12 months after relapse.2, 3, 5 Neoplastic myeloma cells are dependent on the bone marrow microenvironment for survival and proliferation advantage.6, 7 The development of extramedullary disease in multiple myeloma, therefore, implies that myeloma cells are no longer dependent on bone marrow milieu for their survival, and hence signifies terminal disease.6, 7
Treatment and management
Alkylators and steroid agents, especially melphalan and prednisolone, have been the standard regimen for the treatment of myeloma for decades.8 Although addition of more drugs, such as VCMP (vincristine, cyclophosphamide, melphalan and prednisolone), has been expected to improve efficacy, a meta-analysis from 1998 showed that combined melphalan and prednisolone alone was just as effective.9
Clinical trials have confirmed the efficacy of thalidomide in multiple myeloma, which is partly because of its antiangiogenic effect.8 On the other hand, bortezomib is highly effective in refractory multiple myeloma.10, 11 In a phase II study, bortezomib resulted in a 35% response rate, with a 10% complete response rate in 202 patients with poor-risk myeloma, the majority of whom relapsed after autologous stem-cell transplantation.10 Moreover, studies that incorporated bortezomib as frontline myeloma therapy yielded high, complete response rates of 43–56% when bortezomib-based combination chemotherapy was followed by autologous bone-marrow transplantation.11, 12
Bortezomib acts by targeting NF-
B, which is constitutively activated in myeloma cells.13 Importantly, synergism of bortezomib with conventional chemotherapy has been demonstrated in myeloma cells.14 For instance, the lethal dose 50 (LD50) of myeloma cells to doxorubicin has been reduced 6-fold (from 150 nM to 26 nM) by the addition of subtoxic bortezomib to doxorubicin.14
Furthermore, bortezomib has been shown to restore chemosensitivity in myeloma cells that are resistant to melphalan and doxorubicin in vitro.14 In myeloma cell lines resistant to melphalan or doxorubicin, no inhibition of cellular proliferation was demonstrated with melphalan or doxorubicin alone, but marked inhibition of cellular proliferation was demonstrated when bortezomib was added, thereby demonstrating the restoration of chemosensitivity in chemoresistant myeloma cells.14
The patient in this case had multiple myeloma that was refractory to conventional and high-dose melphalan (M), cyclophosphamide (C), thalidomide and prednisolone (P) in addition to bortezomib (velcade; VEL), and would have been declared to have refractory terminal disease; however, she was treated with the VEL-CMP protocol, which comprised drugs that this patient had been refractory to. This decision was based on the following considerations: firstly, the rationale of combining bortezomib with melphalan is on the basis of data from Mitsiades et al., which showed synergistic cytotoxicity on myeloma cells, including melphalan-resistant myeloma cells.14 On the other hand, the combination of bortezomib with CMP was, in fact, a modification of the M2 protocol (combination of vincristine, carmustine, melphalan, cyclophosphamide and prednisone),15—vincristine was replaced by bortezomib as both are nonmyelotoxic and hence carry nonoverlapping toxicity to the other myelotoxic alkylators. This modification was well tolerated in the patient. Indeed, this VEL-CMP combination rendered a dramatic response in both the paraprotein and extramedullary tumors. This case is, therefore, an in vivo verification of the reversal of chemoresistance by bortezomib. The concept of chemosensitizing alkylator therapy by combining bortezomib was further illustrated by the use of VEL-CMP in newly diagnosed, elderly patients with myeloma, in whom VEL-CMP combination has shown superior response rate (89% versus 42%), event-free, and overall survival compared with historical controls using MP alone.16 Owing to this favorable result, VEL-CMP combination is being compared with MP in a randomized manner in newly diagnosed, elderly patients with multiple myeloma in the VISTA trial.17
The success of the concept has a major effect on the management of chemoresistant disease when various chemotherapy agents and regimens have been exhausted in these patients with myeloma. Restoration of chemosensitivity in chemoresistant myeloma cells allows rechallenge of previously unsuccessful therapeutic agents, which might allow further disease control in patients with refractory myeloma.
Conclusions
This case illustrates the restoration of chemosensitivity of myeloma cells when bortezomib is combined with alkylating agents. An obvious synergistic effect was demonstrated in this bortezomib–alkylator combination, given that the disease had been resistant to the individual alkylating agents, steroids and even bortezomib. This approach could be an important consideration in the management of heavily pretreated patients with chemorefractory multiple myeloma, even at the stage of terminal illness with extramedullary plasmacytoma.
