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The treatment of multiple myeloma (MM) has changed markedly during the last decade. The number of therapeutic options available has increased, including high-dose therapy (HDT) with autologous stem cell transplantation (ASCT), and, as a consequence, patient outcome has improved. New active drugs include immunomodulatory agents, such as thalidomide and CC-5013 (Revimid), and the proteasome inhibitor bortezomib (Velcade), all of which 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 impact of dose intensity has been demonstrated in MM patients less than 65 years of age. Several prospective randomised trials, both in Europe and the USA, have shown that HDT, mainly with high-dose melphalan supported by ASCT, is superior to conventional chemotherapy (CC) and significantly increases complete remission rate and overall survival (OS; median 60 months).(1) In all studies, procedure-related death rate is low and not greater than that observed with CC. From these large studies, it can be concluded that HDT supported by ASCT is the standard of care in patients with newly diagnosed MM, at least up to the age of 65.(2)
At least one prospective randomised trial has shown the superiority of double versus single ASCT,(3) but we have to wait for the results of several ongoing trials of single versus tandem ASCT before drawing definite conclusions regarding this issue.
In patients older than 65 years, the standard of care in newly diagnosed MM is the oral melphalan–prednisone (MP) regimen. In this subgroup of patients, the impact of HDT is also under evaluation, and at least one randomised prospective trial has shown a higher OS using HDT compared with standard MP in patients up to 70 years of age.(4) This result has to be confirmed in future series.
In 1999, Singhal and colleagues first reported on the efficacy of thalidomide in advanced and refractory MM.(5) This agent was only the third compound independently active for the treatment of MM, after glucocorticoids and melphalan. Long-term follow-up of 169 patients enrolled in a phase II clinical study using incremental dosing of thalidomide from 200mg to 800mg per day showed a response rate of 31% at eight months (>-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 probably 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 MM. Rajkumar et al reported that the response rate to thalidomide/dexamethasone as part of induction treatment before ASCT was superior to 60%.(7)
Thalidomide can also be combined with chemotherapy because it does not lead to myelosuppression. Several ongoing randomised trials compare standard MP to MP + thalidomide as part of frontline therapy in newly diagnosed MM. Important thromboembolic complications have been described in combination with doxorubicin; they can be effectively eliminated by therapeutic anticoagulation with low-molecular-weight heparin. More studies are needed on thalidomide scheduling in different clinical scenarios: at the time of relapse as first reported, as part of first-line therapy in combination with chemotherapy or dexamethasone and as maintenance therapy in responding patients.
Bortezomib, a potent, reversible and specific inhibitor of the proteasome, is the first available compound of an entirely new class of agents. Physiologically, the proteasome plays a vital role in degrading regulatory proteins that govern many signalling pathways (including the cell cycle), transcription factor activation, apoptosis and pathways that regulate the expression of proteins directing angiogenesis, cell trafficking and metastasis. The antitumoural mechanisms associated with bortezomib involve many pathways. Proteasome inhibition may directly induce apoptosis, block the production of interleukin (IL)-6 (myeloma cells growth factor) and block the production of proangiogenic mediators, as the proteasome is frequently overexpressed in malignant cells (including myeloma cells).(8)
In a recent phase II study (SUMMIT trial), 202 heavily pretreated patients with advanced or refractory MM received bortezomib (1.3mg/m(2)) as an intravenous bolus twice weekly for two weeks, followed by one week without treatment, for up to eight cycles.(9) The response rate was 35%, with a median duration of response of 12 months. The most common adverse events were gastrointestinal symptoms, fatigue, thrombocytopenia and sensory neuropathy. Grade 3 adverse events included thrombocytopenia (28% of patients), fatigue (12%), peripheral neuropathy (1%) and neutropenia (11%). Grade 4 events occurred in 14% of patients. Drug-related adverse events led to discontinuation of bortezomib therapy in 18% of patients.
In a phase III trial (APEX study), 669 patients with relapsed or refractory MM were randomised to receive either bortezomib alone or high-dose dexamethasone alone.(10) A prespecified interim analysis found a statistically significant improvement in time-to-progression and a better survival in patients receiving bortezomib, compared with those receiving dexamethasone. Thus, the study was prematurely terminated, and all patients in the dexamethasone arm were given bortezomib.
Both phase II and III trials indicated that bortezomib was an important therapeutic option in patients with progressive disease after at least two prior treatments, and in 2004 the drug was approved with the trade name Velcade in both the USA and Europe.
Many research teams are now investigating the role of Velcade as part of first-line therapy in combination with dexamethasone or chemotherapy.
CC-5013 is a potent immunomodulatory derivative of thalidomide (ImiD) with a marked activity against myeloma cells in vitro. In a phase I trial, this new compound showed a strong activity in relapsed or refractory MM, even in patients previously treated with thalidomide, with a maximum tolerated dose of 25mg/day orally.(11) Interestingly, no sedative or neurotoxic side-effects were reported. Results are promising, and we are now awaiting the results of a large randomised prospective phase III trial evaluating the combination of CC-5013+dexamethasone vs placebo + dexamethasone. The trial was initiated in 2004 in patients with relapsed or refractory MM. Other studies have been initiated to evaluate CC-5013 alone and in combination with dexamethasone for response induction and maintenance in the context of autotransplantation. Other more recent thalidomide analogues are currently under evaluation in phase I/II trials.
Patients with newly diagnosed symptomatic MM have to be considered for HDT with ASCT, as it is the optimal combination to achieve marked tumour cytoreduction and prolonged survival. The discovery of new classes of agents exhibiting activity in myeloma that has become refractory to even HDT represents a new hope for patients. Further trials are needed to study the impact of the combination of conventional treatments or HDT with these new agents.