Hospital Pharmacy Europe
Multiple myeloma is a malignant process characterised by clonal B-cell tumours of slowly proliferating plasma cells within the bone marrow.(1) Although it continues to be an incurable disease, modulation of the bone marrow microenvironment and the development of targeted therapy have led to a new approach to the management of the disease. Until recently, therapy has focused on the use of combination chemotherapy and steroids as induction, followed by high-dose chemotherapy with autologous stem cell transplantation (ASCT) in an attempt to eliminate or reduce the tumour burden.(2) However, chemotherapy in its different forms only minimally impacted on overall survival rates, with median survival rates ranging between three and five years and most patients becoming refractory to further chemotherapy at relapse.(3,4)
New active drugs have been introduced over the last decade, including immunomodulatory agents, such as thalidomide and thalidomide analogues (lenalidomide [CC-5013, Revlimid(R)] and Actimid [CC-4047]), and the proteasome inhibitor bortezomib (Velcade(R)). These new drugs not only target myeloma cells directly but exert an indirect effect by suppressing growth and survival signals elaborated by the bone marrow microenvironment’s interaction with myeloma cells.
The efficacy of thalidomide in advanced and refractory multiple myeloma was first reported in 1999.(5) Long-term follow-up of 169 patients enrolled in a phase II clinical study using incremental dosing of thalidomide (200-800mg/day) showed a response rate of 31% at eight months (â‰¥50% myeloma protein reduction), with extended survival.(6) Several thousand patients worldwide have since benefited from thalidomide. However, peripheral neuropathy is the major treatment-limiting toxicity, affecting 50-80% of patients; the severity and reversibility of this condition are related to both dose and duration of drug administration. The optimal dosage is ï¿½probably 100 or 200mg/day. A marked synergy between thalidomide and dexamethasone has prompted evaluation of this combination as part of first-line therapy for newly diagnosed multiple myeloma. Rajkumar et al reported that the response rate to thalidomide/dexamethasone as part of induction treatment before ASCT was superior to 60%.(7)
Glasmacher et al(8) identified and reviewed 42 dose escalation trials of thalidomide (200-800mg) and four trials prescribing fixed-dose regimen (50-200mg), with an overall response rate of 29.4%. Grade 3-4 adverse effects included somnolescence (11%), neuropathy (6%), constipation (16%) and VTE (3%), with 13.5% discontinuing thalidomide due to adverse events. Adverse events were related to dose but clinical response was not. Three reports(9-11) have now investigated thalidomide in newly diagnosed myeloma patients as monotherapy and in combination with similar response rates. The phase III NCRI/UKMF Myeloma IX trial in the UK is randomising de-novo patients between an anthracycline containing intravenous therapy (VAD [vincristine and doxorubicin]) and a thalidomide-containing oral combination with cyclophosphamide and dexamethasone (CTD) as induction therapy. The results of this trial are awaited with interest.
Teratogenesis is a serious side-effect and, to try to prevent this occurring in the future, Celgene has introduced the System for Thalidomide Education and Prescribing Safety (STEPS), a programme aimed at monitoring and controlling access to thalidomide.(12) In Europe, the Pharmion Risk Management Programme (PRMP) is based on STEPS, and enrollment in the programme is compulsory for all patients receiving thalidomide from this source.
Lenalidomide is a potent immunomodulatory derivative of thalidomide (ImiD) with marked activity against myeloma cells in vitro.
In a phase I trial, this new compound showed a strong activity in relapsed or refractory multiple myeloma, even in patients previously treated with thalidomide, with a maximum tolerated dose of 25mg/day orally.(13) Interestingly, no sedative or neurotoxic side-effects were reported.
The clinical activity of lenalidomide was confirmed in another phase I trial recruiting 15 patients with refractory myeloma, but significant myelosuppression was noted.(14) As myelosuppression was dose-related, refractory myeloma patients were randomised between lenalidomide 30mg once daily and 15mg twice daily.(15) Significant myelosuppression was noted at 15mg twice daily, and a 25% paraprotein reduction was seen in 38% of patients. Two phase III trials of relapsed refractory myeloma randomised between lenalidomide 25mg/day per oral and dexamethasone 40mg on days 1-4, 9-12, 17-20 every four weeks for four months then 40mg on days 1-4 every cycle thereafter versus placebo and dexamethasone given as the same regimen were performed simultaneously in the USA (MM-009) and Europe and Australia (MM-010).(16) Median time to progression (TTP) for patients in the placebo/dexamethasone group was 19.9 weeks in MM-009 and 20.4 weeks in MM-010 but was not reached in the lenalidomide/dexamethasone arm. Overall response rate (ORR) was significantly higher in patients treated with lenalidomide/dexamethasone compared with placebo/dexamethasone in both MM-009 (51.3% vs 22.9%; p<0.0001) and MM-0101 (47.6% vs 18.4%; p<0.001).(5) Grade 3-4 neutropenia was reported more frequently in patients given combination therapy than in patients treated with dexamethasone alone (MM-009, 24.1% vs 3.5%; MM-010, 16.5% vs 1.2%). Lenalidomide has been combined with dexamethasone, vincristine and pegylated doxorubicin in a phase II trial of relapsed refractory patients with an ORR of 70% and complete response (CR) + near-CR of 35%.(17)
In a phase II trial de-novo study, a combination of lenalidomide and dexamethasone was given to 34 newly diagnosed patients.(18) Lenalidomide was given orally 25mg daily on days 1-21 of a 28-day cycle. Dexamethasone was given orally 40mg daily on days 1-4, 9-12 and 17-20 of each cycle. An objective response was defined as a decrease in serum monoclonal protein level by 50% or greater and a decrease in urine M protein level by at least 90% or to a level less than 200mg/24 hours, confirmed by two consecutive determinations at least four weeks apart. Thirty-one out of 34 patients achieved an objective response, with two (6%) achieving CR and 11 (32%) meeting criteria for both very good partial response and near-CR, resulting in an overall ORR of 91%. Forty-seven percent of patients experienced grade III or higher nonâ€‘haematological toxicity, most commonly fatigue (15%), muscle weakness (6%), anxiety (6%), neumonitis (6%) and rash (6%). A further double-blind, phase III, placebo-controlled trial of dexamethasone versus the combination of lenalidomide plus dexamethasone in newly diagnosed patients is being undertaken by the Southwest Oncology Group.
Lenalidomide is likely to obtain a licence from the EMEA for use in relapsed myeloma in the first quarter of 2007. It is a well-tolerated oral agent with a convenient dosing regimen, and it is active in heavily pretreated patients either alone or in combination with dexamethasone or chemotherapy. It has a tolerable nonhaematological side-effect profile, although myelosuppression is seen and requires regular monitoring with full blood counts. In-vitro and animal data have not revealed any teratogenic effects of lenalidomide.
Actimid, another thalidomide analogue, is currently under evaluation in phase I/II trials.(19) In a phase I trial, 24 patients were treated with a dose-escalating regimen of oral Actimid for a median duration of 28 weeks (3-132). Actimid was well tolerated, with maximum tolerated dose (MTD) of 2mg/day with 12.5% incidence of VTE but no other significant nonhaematological adverse effects.20 The overall response rate was 71%, with 17% CR. Seventy-five percent of patients continued on the drug beyond the study period of 12 weeks.
Treatment strategies targeting nuclear factor ÎºB (NFÎºB, the protein that is central to the pathophysiology of multiple myeloma), the malignant cell/stroma interaction and the complex cytokine network could result in regulating the growth and development of the myeloma cell.(21-28)
Bortezomib is a specific inhibitor of the proteasome pathway.(29,30) Bortezomib inhibits the proteasome pathway, which is important for the activation of NFÎºB, in a rapid and reversible manner.(31,32)
Based on its preclinical and phase I activity in multiple myeloma,(33) a phase II study (SUMMIT) of bortezomib was initiated in patients with relapsed and refractory multiple myeloma.(29) The dose established for bortezomib in the treatment of relapsed, refractory myeloma is 1.3mg/m(2) given twice weekly on days 1, 4, 8, and 11 every 21 days.(29) Dexamethasone (20mg the day of and after each bortezomib dose) was permitted if progressive disease was observed after two cycles or with stable disease after four cycles. A total of 202 heavily pretreated patients were enrolled. Of the 202 patients entered, 193 were evaluable for response. ORR (CR + partial response [PR] + minimal response [MR]) was 35% (67 of 193 patients). Seven patients (4%) achieved CR, and 12 (6%) had a near-CR (myeloma protein undetectable by electrophoresis but immunofixation positive). An additional 34 patients (18%) had a PR, and 14 (7%) achieved MR.(29) The median time to disease progression for bortezomib as a single agent was seven months, compared with three months reported for the patients’ previous therapy (p=0.01). In a landmark analysis, patients who achieved CR or PR by the end of the second cycle survived significantly longer than those achieving other types of response. Drug-related adverse events of any grade, occurring in â‰¥25% of patients, included nausea (55%), diarrhoea (44%), fatigue (41%), ï¿½thrombocytopenia (40%), peripheral neuropathy (31%), vomiting (27%) and anorexia (25%). The most significant and common clinical adverse events were ï¿½neuropathy at 12% and gastrointestinal toxicity in the form of nausea and diarrhoea; experience shows that gastrointestinal toxicity is probably a reflection of autonomic neuropathy.(34) In a randomised phase III study of 669 relapsed/refractory multiple myeloma patients who had been treated with one to three prior therapies, patients were assigned to receive bortezomib (327 patients) as outlined above versus ï¿½dexamethasone (330 patients) 40mg per oral on days 1-4, 9-12, 17-20 once a week during five weeks for four cycles followed by 40mg per oral days 1-4 every 28 days for three cycles.(35) The primary endpoint was time to progression (TTP) using EBMT (European Group for Blood and Marrow Transplantation) criteria for progressive disease. The interim analysis, presented at ASCO 2004, showed that 254 progressive disease events had occurred. Patients receiving bortezomib demonstrated a highly significant benefit in TTP. Median TTP was 5.7 months (95% CI: 5.0, 7.9) on bortezomib and 3.6 months (95% CI: 3.2, 4.8) on dexamethasone (p<0.0001, log-rank test). Overall survival was longer on bortezomib (p=0.038, log-rank test), with 13 deaths on bortezomib and 24 on dexaï¿½methasone. However, at the time of the report, the median overall survival was not reached in either arm.
A recent phase II trial of bortezomib+dexamethasone as induction treatment prior to ASCT in patients with newly diagnosed myltiple myeloma showed this regimen to be effective and well tolerated in this patient population.(36) Bortezomib (1.3mg/m(2)) and dexamethasone (40mg) were administered for four 21-day cycles as induction therapy in chemotherapynaive patients. ORR was 66%, including 21% CR and 10% very good partial remission.
The exact position of bortezomib in the management of multiple myeloma and its future development await larger studies and longer follow-up in both newly diagnosed and relapsed refractory myeloma patients. Moreover, because of its toxicity profile, especially past the first few cycles of therapy and the need to have the agent for maintaining the response achieved (TTP in patients who have received one to three chemotherapeutic regimens is 5.7 months vs 3.6 months with dexamethasone(35)), its use in new tolerable dosages and schedules as well as in combination therapy needs to be urgently explored.
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