Multiple Myeloma in the Elderly: When to Treat, When to Go to Transplant
Until recently, standard treatment of multiple myeloma (MM) in elderly patients who were not candidates for autologous stem cell transplantation was with the combination of melphalan plus prednisone (MP). Novel agents (thalidomide, lenalidomide, bortezomib) are dramatically changing frontline therapy of MM. Randomized studies have shown the superiority of adding one novel agent to MP, either thalidomide (MPT) or bortezomib (MPV). The combination of lenalidomide with low doses of dexamethasone is another attractive alternative. Recent results show that maintenance therapy with low-dose lenalidomide may prolong progression-free survival. The objective of these improved treatment regimens should be to achieve complete response, as in younger patients. However, toxicity is a significant concern, and doses of thalidomide and of myelotoxic agents should be reduced in patients who are older than 75 years or who have poor performance status. Weekly bortezomib appears to induce severe peripheral neuropathy less frequently than the same agent administered twice weekly. Autologous stem cell transplantation is feasible in selected fit patients over 65 years of age, and its results are improved by the addition of novel agents before and after high-dose therapy. However, considering the progress in non-intensive therapy, autologous transplantation should not currently be offered to elderly patients outside of a clinical trial.
Until recently, standard treatment of multiple myeloma (MM) in elderly patients who were not candidates for autologous stem cell transplantation was with the combination of melphalan plus prednisone (MP). Novel agents (thalidomide, lenalidomide, bortezomib) are dramatically changing frontline therapy of MM. Randomized studies have shown the superiority of adding one novel agent to MP, either thalidomide (MPT) or bortezomib (MPV). The combination of lenalidomide with low doses of dexamethasone is another attractive alternative. Recent results show that maintenance therapy with low-dose lenalidomide may prolong progression-free survival. The objective of these improved treatment regimens should be to achieve complete response, as in younger patients. However, toxicity is a significant concern, and doses of thalidomide and of myelotoxic agents should be reduced in patients who are older than 75 years or who have poor performance status. Weekly bortezomib appears to induce severe peripheral neuropathy less frequently than the same agent administered twice weekly. Autologous stem cell transplantation is feasible in selected fit patients over 65 years of age, and its results are improved by the addition of novel agents before and after high-dose therapy. However, considering the progress in non-intensive therapy, autologous transplantation should not currently be offered to elderly patients outside of a clinical trial.
Multiple Myeloma (MM) is a disease of the elderly: the median age at diagnosis is increasing along with the increase in life expectancy in the general population and is currently more than 70.[1] Age is an important prognostic factor in MM, and overall survival (OS) declines continuously by decade from age 50 to ages greater than 80.[1] This decline in OS may be explained in part by the higher incidence of more severe disease in older patients, but it is mainly explained by patient characteristics (eg, performance status, comorbities).[1,2] Elderly patients do not tolerate chemotherapy-related adverse events as well as younger patients, and they are rarely candidates for high-dose therapy (HDT) plus autologous stem cell transplantation (ASCT)-which, back in the 1990s, was the first improvement in the treatment of MM.[3] In the context of MM, the definition of “elderly” is generally based on the age limit for treatment with HDT plus ASCT. In most randomized studies that have compared ASCT and conventional-dose chemotherapy as primary treatments for MM, the upper age limit has been 65 years.[3] Thus, the usual definition of an elderly MM patient is one who is over 65 years of age
While the introduction of HDT supported by ASCT has markedly increased progression-free survival (PFS) and OS in younger patients, for four decades now there has been almost no improvement in the prognosis of elderly patients with MM.[4] Until recently, the standard of care has been the combination of melphalan and prednisone (MP).[5]
The introduction of immunomodulatory drugs (the “IMiDs”: thalidomide and lenalidomide) and of proteasome-inhibitors (bortezomib) has dramatically changed the management of MM in both younger and elderly patients. The use of these agents in patients who have relapsed and in patients with refractory disease has already improved outcomes,[6] and they are currently added to frontline treatment in patients with newly diagnosed disease.
Recent Improvements in the Treatment of Elderly Patients With Multiple Myeloma
TABLE 1
Randomized Studies Comparing MP and MPT Regimens: Patient Characteristics in MPT Regimens
Novel agents have been added to the treatment of elderly patients in three ways: the addition of one novel agent to the MP combination, the addition of one novel agent to dexamethasone, and the use of a novel agent as maintenance therapy after induction treatment.
TABLE 2
Randomized Studies Comparing MP and MPT Regimens: Results