Professor of Haematology
Head of Department
Head of Stem Cell Transplantation Unit
Department of Haematology
Oncology and Clinical Immunology
Heinrich Heine University
Multiple myeloma is a B-cell malignancy characterised by a clonal expansion of plasma cells in the bone marrow, associated with a monoclonal immunoglobulin in the serum and/or urine. Patients with symptomatic disease require cytotoxic chemotherapy. In particular, high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation has improved response rates in comparison with conventional chemotherapy, with a rate of near-complete remissions of 50% vs 42%, respectively. This has translated into a prolonged seven-year survival of 42% versus 21%.(1,2) Despite further intensification of high-dose therapy by dose escalation of the conditioning regimen or by tandem high-dose therapy, sustained long-term remission has not been achieved in patients with multiple myeloma.(3,4) Novel agents such as thalidomide, bortezomib or lenalidomide have shown efficacy in patients with relapsed or refractory multiple myeloma and thus have been evaluated as components of first-line therapy.(5–7)
For patients not eligible for stem-cell transplantation, conventional therapy with melphalan and prednisolone has been the standard of care for some time. Several combination chemotherapies have been tested, but none has shown superiority over melphalan and prednisolone in terms of overall survival.(8) Recently, two randomised studies have shown that combination of thalidomide with melphalan and prednisolone improves rates of near-complete remissions from 48% to 76% when compared with melphalan and prednisolone alone. In consequence, three-year survival could be improved from 64% to 80%.(9,10) Therefore, this combination should be considered the new standard of care. Nevertheless, this combination therapy is more toxic than melphalan and prednisolone and due to increased incidence of thromboembolic events, anticoagulation is recommended during therapy. Therefore melphalan and prednisolone should be further recommended for patients with contraindications for anticoagulation and whose general condition has declined. Bortezomib and lenalidomide have prove effective even in the presence of poor prognostic parameters such as chromosome-13 deletion, whereas the efficacy of thalidomide in patients with chromosomal aberrations is limited.(11,12) Therefore, in these patients, bortezomib or lenalidomide should be considered as combination partners.
For patients younger than 65 years high-dose chemotherapy with 200 mg/m2 melphalan as conditioning regimen is the current gold standard of therapy. Incorporation of novel agents such as thalidomide, bortezomib or lenalidomide has been shown to improve response rates after induction therapy to 90%, but due to a short follow-up no improvement of duration of remission or overall survival could be demonstrated until now.(13–15) Most data in this setting are available for thalidomide.13 Thalidomide in combination with dexamethasone as induction therapy could increase the rate of partial and complete remission before high-dose therapy from 41% to 63% in comparison with VAD chemotherapy. On the other hand, the incidence of thrombo‑
embolic events and peripheral polyneuropathy has also increased in patients treated with thalidomide, from 3% to 17% and 4% to 7%, respectively. A first report on remission rates three months after transplant showed no differences between patients who had received thalidomide as part of the induction therapy.(16) Thus, at the moment it appears that novel agents as part of the induction therapy may improve response rates before transplant, while their long-term effect is not yet clear.
We therefore favour the use of novel agents as maintenance therapy after high-dose therapy following autologous stem-cell transplantation. The Intergroupe Francophone du Myélome (IFM) showed in a randomised study that patients with good risk prognostic parameters at the time of first diagnosis benefit from thalidomide maintenance therapy in comparison with patients without maintenance therapy.(17) The IFM researchers found that remission rates after tandem high-dose therapy could be improved from 56% to 67% in patients treated with thalidomide, resulting in significantly better three-year progression-free survival (36% vs 52%) and four-year overall survival (77% vs 88%). Similar results could be observed for thalidomide maintenance following single high-dose therapy.(18) Thus, for patients not included in a clinical study, maintenance therapy with thalidomide can be considered a current standard therapy. Still, 40–60% of patients have to discontinue thalidomide maintenance treatment due to intolerable side-effects, mainly severe peripheral polyneuropathy. Lenalidomide is a thalidomide derivative with a higher anti-myeloma efficacy in vitro. Apparently, it is also associated with a relatively low rate of toxicity, as shown in patients with advanced-stage multiple myeloma. Future studies will certainly include lenalidomide for maintenance therapy.
There is also an array of new drugs to improve supportive care. Over the last decade, treatment-related mortality with high-dose therapy could be significantly decreased, while the major toxicity is mucositis and haematological toxicity associated with febrile neutropenia. The majority of life-threatening infectious complications occur during the period of grade IV neutropenia. High concentrations of endogenous granulocyte colony-stimulating factor (G-CSF) have been observed in patients during the early phase of marrow aplasia.(19) During the later stages of marrow reconstitution following HDT the use of recombinant human G-CSF was found to accelerate neutrophil engraftment. Pegfilgrastim, a pegylated form of filgrastim, has a prolonged plasma half-life in vivo due to decreased renal clearance. Following administration of pegfilgrastim on day +1 after high-dose therapy, the G-CSF levels observed were more than 100 times higher in comparison to physiological concentrations during steady-state and more than tenfold higher in comparison to patients who had received a daily SC injection of G-CSF.(20) As a consequence, patients treated with pegfilgrastim had a significantly shorter duration of grade IV neutropenia in comparison with patients with no growth factor support (11 vs six days). Still, despite five-day faster neutrophil recovery, the duration of stay in hospital was not shorter because there was no difference with regard to degree of mucositis and need for parenteral nutrition. This problem might be solved by combined use of pegfilgrastim and human keratinocyte growth factor (palifermin). In fact, patients who had received this combined supportive care had less mucositis and fewer days requiring treatment with morphine or parenteral nutrition.(21) This resulted in a median reduction of five days in the stay in hospital after high-dose therapy. These improvements may allow the inclusion of more patients in high-dose therapies with advanced age and comorbidities. In the future, a better understanding of the pathophysiological mechanisms underlying multiple myeloma will provide the basis for the development of a molecular targeting therapy.
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