New hope for relapsed and refractory multiple myeloma.

Myeloma remains an incurable neoplasm despite the development of novel classes of drugs that have greatly prolonged survival of patients over the past 10 years. Patients with advanced refractory or relapsed and refractory myeloma who do not benefi t from these newly developed proteasome inhibitors or immuno modu latory drugs have a median overall survival of only 9 months; this period is an important historical reference to improve for future drug development for patients with refractory or relapsed and refractory myeloma. Thus, the need persists for the development of new antimyeloma drugs. Current preclinical and drug development research focuses on either developing more next-generation proteasome inhibitors and immunomodulatory drugs— known for their potent activity in myeloma—or seeks to discover new classes of agents such as monoclonal antibodies. Progress in myeloma research has been rapid; however, the period from the discovery of a drug until it becomes available for use in patients can be many years. Myeloma is a disease of elderly people, and so the wellbeing of patients is a key consideration in balancing between safety profi les and ability to control the disease. Furthermore, prolonged survival with myeloma implies the need to repeatedly control tumour cells because each time an individual relapses neoplastic cells develop increased drug resistance. Consequently, novel drugs are needed both to overcome resistance to previous treatment in relapsed patients, and to maintain a class eff ect. Moreover, patients with either refractory, advanced, or end-stage myeloma are more fragile and at risk of developing severe complications compared with those at earlier relapse and thus new agents need improved tolerability. Pomalidomide, an immunomodulatory thalidomide analogue, is a promising antimyeloma agent with encouraging responses in patients with refractory or relapsed and refractory myeloma. Pomalidomide has a potent antimyeloma activity in vitro and in vivo, acting both directly on myeloma cells and on the marrow microenvironment. In recent studies, pomalidomide has shown clinical effi cacy in lenalidomide and bortezomib refractory or relapsed and refractory myeloma, but has yet to show superiority over existing standards of care in patients with end-stage or relapsed and refractory myeloma. In The Lancet Oncology, Jesus San Miguel and colleagues have presented results from a multicentre, openlabel, randomised phase 3 trial of the combination of pomalidomide plus low-dose dexamethasone compared with high-dose dexamethasone alone, one of the standards of care in refractory or relapsed and refractory myeloma at the time the study was initiated. The trial enrolled 455 patients with at least two previous treatments who had failed both prior bortezomib and lenalidomide. Patients in the pomalidomide plus lowdose dexamethasone group had signifi cantly longer median overall survival times than did those treated with high-dose dexamethasone alone (12·7 months [95% CI 10·4–15·5] vs 8·1 months [6·9–10·8]; p=0·0285]). Moreover, 95 (31%) of 302 patients in the pomalidomide plus low-dose dexamethasone group achieved a partial response or better. These data are similar to those of previous phase 1 and 2 studies. Importantly, pomalidomide plus low-dose dexamethasone signifi cantly prolonged survival endpoints despite 50% of patients assigned to the control group also receiving pomalidomide after the recommended unmasking by the independent data monitoring committee. This study confi rms that use of pomalidomide in refractory or relapsed and refractory myeloma leads to myelosuppression adverse events, but also shows that they can be predictable and managed with use of haematopoietic growth factors or appropriate dose modifi cations. Consequently, few patients (9%) discontinued treatment with pomalidomide plus lowdose dexamethasone, further suggesting that the combination was generally well-tolerated. The eff ect of pomalidomide on the quality of life will be described in a subsequent report, but it seems logical to assume that the oral availability of pomalidomide, rapid onset of response, increased depth of response and prolonged survival will improve the quality of life of patients with refractory or relapsed and refractory myeloma. Moreover, although the dose modifi cation defi nition of pomalidomide according to the creatinine clearance is still ongoing, preliminary reports suggest it might not be necessary to modify the dose of pomalidomide in renal insuffi ciency. This is an important consideration because patients with advanced myeloma frequently have renal insuffi ciency that often requires a dose adaptation for many drugs. CN RI /S cie nc e Ph ot o Li br ar y