Tumour lysis syndrome in multiple myeloma after bortezomib (VELCADE) administration

Abstract

Bortezomib (VELCADE) is a proteasome inhibitor, which has been recently used for the treatment of relapsed/refractory multiple myeloma (MM) with encouraging results. Tumour lysis syndrome (TLS) has been described during chemotherapy for many haematological malignancies, such as acute lymphoblastic leukaemia and high-grade lymphomas. TLS is very rare in MM with ten reported cases, including ~1% of patients receiving high-dose chemotherapy with stem cell support (ASCT). We report here a patient with refractory MM and deletion 13q, who had received more than four lines of previous treatment, including two ASCT, and had relapsed. The patient received bortezomib, as a single agent, at a dose of 1.3 mg/m² twice per week for 2 weeks, in a 3-week cycle, and developed TLS after the second dose of cycle one. Bortezomib therapy, due to the rapidity of its action, may result in TLS in myeloma patients who have rapidly proliferative disease with a high tumour burden. Therefore, TLS should be looked for during the first cycle of bortezomib treatment and suitable precautions should be considered.

Introduction

Tumour lysis syndrome (TLS) is a complication observed in tumours with a high cell turnover. TLS is usually caused by response to chemotherapy; however, it may also occur spontaneously. It has been described in various haematological malignancies, such as acute lymphoblastic leukaemia, Burkitt’s lymphoma and other high-grade non-Hodgkin’s lymphomas, in small lymphocytic lymphoma after fludarabine administration, and in chronic lymphocytic leukaemia after CAMPATH-1H treatment (Cohen et al. 1980; Fleming and Doukas 1992; Killick et al. 1997). TLS is associated with a significant morbidity and mortality, and is characterized by the increased release of intracellular contents (uric acid, potassium, phosphorus) that follows cell destruction, leading to hyperuricaemia, hyperkalaemia, hyperphosphataemia, and acute renal failure (Jeha 2001).

Bortezomib (formerly PS-341; VELCADE) is a proteasome inhibitor that is currently being investigated as a treatment for patients with refractory/relapsed multiple myeloma (MM) or as first-line treatment for myeloma patients, and has been approved by the FDA as a third-line treatment for relapsed myeloma patients (Richardson et al. 2003; Jagannath et al. 2003; Kane et al. 2003). It has been recently reported that bortezomib induced TLS in seven myeloma patients who had rapidly proliferative disease with a high tumour burden (Mehta et al. 2003). We present here another patient with refractory/relapsed MM who developed tumour lysis syndrome during the first cycle of treatment with bortezomib.

Case report

A 34-year-old man was diagnosed with IgGκ MM, stage IIIA, in February 1998. His previous treatment included: (a) three cycles of vincristine, doxorubicin, and dexamethasone (VAD) chemotherapy followed by high-dose melphalan (140 mg/m²) treatment with stem cell support; (b) twelve cycles of pulsed dexamethasone; (c) thalidomide (up to 800 mg daily) for 13 months; (d) two cycles of dexamethasone, thalidomide, cis-platinum, doxorubicin, cyclophosphamide, and etoposide ( DT-PACE) chemotherapy followed by a second high-dose melphalan (140 mg/m²) treatment with stem cell support followed by INF-α maintenance; and finally, (e) pulsed dexamethasone. All previous treatment resulted in partial responses, but the patient relapsed after a period of time. He relapsed again in August 2002 after his second treatment with pulsed dexamethasone. He was entered into a phase 2 (Protocol M34101–040 Millenium Pharmaceuticals) clinical trial of bortezomib. The baseline work-up showed bone marrow infiltration by plasma cells of nearly 100%, serum paraprotein of 112 g/l, immunoparesis, undetectable Bence-Jones protein, β2-microglobulin of 1.5 mg/l, serum creatinine level of 85 μmol/l, uric acid of 0.44 mmol/l, and normal electrolyte levels (sodium, potassium, calcium, phosphate). Fluorescent in situ hybridisation (FISH) analysis revealed deletion of 13q chromosome. The skeletal survey revealed collapse of multiple vertebral bodies.

Bortezomib was administered at a dose of 1.3 mg/m² twice weekly for 2 weeks in a 3-week cycle. After the second dose of bortezomib the patient developed fever with a temperature of 39.2 °C and was admitted to the hospital with a diagnosis of TLS. The criteria used for TLS definition were a combination of at least three of the following: ≥ twofold increase in LDH, ≥ 50% increase in creatinine, phosphate or uric acid, ≥ 30% increase in potassium, and ≥ 20% decrease in calcium without bisphosphonate treatment. The laboratory data at baseline and at the time of TLS are summarized in Table 1. Progression of disease was excluded by measuring paraprotein levels, which already showed a decline in paraprotein (80 g/l) after the second dose of cycle 1. There were no signs of infection; blood and urine cultures were negative, and chest X-rays revealed no abnormalities. The following dose of bortezomib was delayed and symptomatic treatment started including alkalinisation of the urine, hydration, and monitoring of renal function. The patient recovered within 4 days without deterioration of his renal function.

Table 1.

Baseline values and values on admission (C1/D4 cycle 1/day 4)

Parameter	Baseline	C1/D4
Urea (mmol/l)	4.2	9.4
Creatinine (μmol/l)	85	122
ALT (U/l)	48	51
AST (U/l)	33	681
LDH (U/l)	330	11,308
Uric acid (mmol/l)	0.41	0.85
Sodium (mmol/l)	125	126
Potassium (mmol/l)	3.8	4
Calcium (mmol/l)	2.3	1.8
Phosphate (mmol/l)	1.13	1.66
Paraprotein (g/l)	112	80

Discussion

TLS is a life-threatening disorder which results of lysis from tumour cells, usually subsequent to chemotherapy. The laboratory characteristics of the syndrome are increased LDH, hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, disseminated intravascular coagulation (DIC), and renal impairment. TLS has been described in many haematological malignancies, including slowly proliferative B-cell diseases, such as CLL in response to effective therapies including Fludarabine and Campath-1H (Fleming and Doukas 1992; Killick et al. 1997; Jeha 2001). However, it is a rare complication in MM because plasma cells, which are terminally differentiated B-cells, have a low turn-over rate and the chemotherapy (usually melphalan, prednisolone, VAD or thalidomide) does not lead to rapid cytoreduction. TLS has been described in only two myeloma patients, who received thalidomide and dexamethasone monotherapy, respectively (van de Kerkhof et al. 2001; Cany et al. 2002). It has also been described in ~1% MM patients receiving high-dose chemotherapy with stem cell support. In that group of patients, TLS was associated with poor prognostic features such as high tumour mass, immature morphology, high proliferative activity of plasma cells and poor cytogenetics (Fassas et al. 1999).

Our patient had a high tumour burden with the bone marrow almost completely replaced by plasma cells and his disease was refractory to treatment. Moreover, he carried an unfavourable karyotype (deletion of 13q chromosome). He had no previous history of TLS although he had received intensive chemotherapy with a similar tumour burden on previous occasions.

Bortezomib is a proteasome inhibitor which has recently been introduced as third-line therapy for patients with relapsed MM. Bortezomib is effective through a number of mechanisms and causes apoptosis of plasma cells. It inhibits IκB degradation, prevents NF-κB activation, and induces apoptosis in MM cells. It is thought that the cytoreductive potential of bortezomib is exerted through down-regulation of growth/survival signalling pathways, up-regulation of molecules implicated in pro-apoptotic cascades, as well as up-regulation of heat-shock proteins and ubiquitin/proteasome pathway members (Mitsiades et al. 2002; Hideshima et al. 2003). In a recent phase 2 clinical trial, bortezomib has been shown to be effective in relapsed/refractory MM, reaching a response rate of up to 35%, irrespective of the cytogenetic status of the patient (Richardson et al. 2003). Our patient’s paraprotein level dropped after the second dose of bortezomib and he achieved a very good partial response after the third cycle of treatment. These promising results suggest that this agent is very effective in the treatment of MM and should be used more extensively in the future. It is, therefore, important to point out that as a cytoreductive agent, bortezomib may induce TLS in patients with a high tumour burden. It has been recently reported that seven out of 496 myeloma patients (1.4%) treated with bortezomib on three phase II, multi-centre trials, presented with TLS within 3 weeks of starting bortezomib therapy. Six of these patients had a very heavy tumour burden, five had been autografted previously, and three out of four patients with available karyotypes had del 13q. Six of these patients developed TLS on bortezomib as a single agent and one patient on bortezomib in combination with dexamethasone (Mehta et al. 2003). The patient described here also had a high tumour burden, had been autografted twice previously, and carried del 13q. He definitely developed TLS according to the criteria described previously: ≥ twofold increase in LDH, ≥ 50% increase in uric acid, and ≥ 20% decrease in calcium, while there was a 43.5% increase in creatinine levels. Our patient also had elevated AST values, which is very unusual for TLS. However, the reduction of AST to normal values (32 IU/l) only 10 days after the initiation of TLS indicates that, possibly, its elevation correlated with TLS. The reason for fever seems to be related to bortezomib administration, since fever is a rather frequently observed side-effect of bortezomib and there was no indication of infection.

TLS seems to occur more frequently in myeloma patients receiving bortezomib compared to myeloma patients receiving other chemotherapeutic agents, dexamethasone alone or thalidomide. Patients with rapidly proliferative disease and a high tumour burden are at higher risk of developing TLS post bortezomib treatment, mainly due to the rapidity of bortezomib action. Therefore, this complication should be looked for during the first cycle of treatment, and precautions such as hydration and allopurinol administration should be considered if there is evidence of TLS.