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Myeloma Lead Clinical
Senior Haematology Registrar
Department of Haematological Medicine
Kings College Hospital
Myeloma continues to be an incurable disease, but modulation of the bone marrow microenvironment and the development of targeted therapy have created a novel approach to management. Myeloma is characterised by an indolent, asymptomatic early stage progressing to end-organ damage characterised by cytopenias, renal dysfunction, hypercalcaemia, pathological fractures and death from disease progression. The mainstay of treatment for the last four decades has been combination chemotherapy (CC) and steroids as induction, followed by high-dose chemotherapy with autologous stem cell transplantation (HDT) as consolidation therapy for patients aged less than 70 years. Median survival rates with these treatments range between three and five years, with most patients becoming refractory to further chemotherapy at relapse and no consensus agreement on treatment at relapse.
Thalidomide was originally offered as a treatment for morning sickness but withdrawn after identification of its teratogenic effects. Its use was based on observations, by Vacca et al,(1) of increased marrow vascularity in myeloma; in addition, D’Amato(2) reported the antiangiogenic activity of thalidomide. Treatment is complicated by neuropathy, somnolescence, constipation and venous thromboembolism (VTE). Teratogenesis remains a serious side-effect of thalidomide and, in an attempt to prevent this occurring in the future, Celgene has introduced its System for Thalidomide Education and Prescribing Safety (STEPS), a programme to monitor and control access to thalidomide.(3) The Pharmion Risk Management Programme (PRMP) is based on STEPS, and enrolment in the programme is obligatory for all patients receiving thalidomide from this source in Europe.
Initial experience with thalidomide as monotherapy was gained in a phase II trial of 84 relapsed/refractory patients; 61% had stage III disease and 90% were previously treated with high-dose chemotherapy and haematopoietic stem cell transplantation (HDT). Thalidomide was given at 200mg/day, escalated fortnightly up to 800mg/day, and achieved an overall response rate (ORR) of 32%.(4) These findings were confirmed in a follow-up study of 169 poor-risk patients.(5) Superior responses were reported in patients with normal cytogenetics, and a thalidomide dose-related response was observed. Schey et al(6) performed a dose-escalation study of thalidomide and observed no dose-related clinical response. The median dose of thalidomide was 300mg, and median time on treatment was six months, compared with 800mg and six weeks, respectively, in the Barlogie study.(5) The median response rate was 49%, and thalidomide was well tolerated. Glasmacher et al(7) 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(8–10) 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.
Mode of action
Thalidomide analogues were developed to improve the antimyeloma activity and the side-effect profile of thalidomide. Two 4-amino thalidomide derivatives (lenalidomide and Actimid) have been used in myeloma. Both have been shown to promote secretion of IL-2 and interferon gamma (IFNγ)(11) by inducing a Th1 response and enhancing natural killer (NK) cell activity.(12) Lenalidomide activity and potency is 50–2,000 times more potent than thalidomide in stimulating this T-cell proliferation response following primary induction by T-cell receptor (TCR) activation in vitro. In addition, use of these drugs leads to dose-dependent inhibition of the peripheral blood mononuclear cells (PBMC) proinflammatory cytokines TNFα, IL-1β and IL-6, as well as increase in the production of the anti-inflammatory cytokine IL-10.(13–15) These changes in the cytokine milieu induce apoptosis in myeloma cells and inhibit bone marrow angiogenesis and adhesion of myeloma cells to stromal cells. More recently, direct inhibition of myeloma cells and/or bone marrow stromal cell growth and survival via free radical-mediated oxidative DNA damage(14,16) and cyclooxygenase-2 inhibition(15,17) has been described.
Bioavailability of thalidomide is between 65 and 93%, with T(max) (time to peak concentration) of four hours in fasting and six hours in the fed state. Median half-lives are between 5.5 and 7.3 hours with 50 and 800mg doses, respectively. Thalidomide undergoes nonenzymatic hydrolisation, and 0.7% is excreted unchanged in urine with minute amounts undergoing hepatic metabolism. Lenalidomide is absorbed rapidly with T(max) of 1–1.5 hours, unchanged at higher dose levels and during multiple dosing. Food reduces C(max) rate by 39% and delays median T(max) to three hours. Lenalidomide excretion half-life is 8.2 hours, with most excretion in the first four hours and two-thirds recovered unchanged in urine. Low to moderate interindividual variability has been observed with little accumulation of the drug (AUC ratio day 28/day 1: 0.8–1.2).
Actimid (CC04047) was tested on a phase I trial in patients with relapsed refractory myeloma. Twenty-four patients were treated with 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.(18) 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.
Richardson et al(19) were the first to test lenalidomide (Revlimid) in a phase I trial using a dose escalation from 5 to 50mg/day. From a total of 27 patients, 72% had relapsed refractory myeloma and 64% were treated with previous thalidomide therapy. Grade 3 myelosuppression (MS) was noted in all patients (n=13) treated with a dose of 50mg/day. Of the 24 evaluable patients, a significant response of 25% reduction in paraprotein was noted in 71% of patients. Zangari et al(20) confirmed the clinical activity of lenalidomide in another phase I trial recruiting 15 patients with refractory myeloma, but significant myelosuppression was noted. As myelosuppression was dose-related, Richardson et al(21) randomised refractory myeloma patients between lenalidomide 30mg once daily and 15mg twice daily. 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).(22) 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. 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).(4) 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%). Hussein et al(23) combined lenalidomide 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%.
Rajkumar et al(24) reported 34 newly diagnosed patients treated with a combination of lenalidomide and dexamethasone in a phase II trial de-novo study. 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 non‑haematological toxicity, most commonly fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (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 by 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. Despite this, and in the light of the success of the introduction of the STEPS programme in the USA, it is likely that there will be a modified programmed prescription access plan for lenalidomide ahead of it being granted a licence. Prophylactic anticoagulation to reduce VTE and growth factor support for myelosuppression need to be better defined pathophysiologically(25) but should be considered for patients receiving lenalidomide in combination with chemotherapy who are at high risk of thromboembolism. A number of clinical trials are ongoing using lenalidomide in de-novo disease and in combination with a variety of schedules using chemotherapy agents such as melphalan and cyclophosphamide, and another study is looking at its use with Velcade. The role of lenalidomide as post-HDT maintenance is currently being studied in a phase III trial conducted by the Cancer and Leukemia Group B. The results of these studies are awaited with interest.