ABSTRACT: 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(Drug information on melphalan) plus prednisone(Drug information on prednisone) (MP). Novel agents (thalidomide, lenalidomide, bortezomib(Drug information on bortezomib)) are dramatically changing frontline therapy of MM. Randomized studies have shown the superiority of adding one novel agent to MP, either thalidomide(Drug information on thalidomide) (MPT) or bortezomib (MPV). The combination of lenalidomide with low doses of dexamethasone(Drug information on 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
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.
Randomized Studies Comparing MP and MPT Regimens: Results
MP-Based Combinations
The first novel agent to be combined with MP was thalidomide. To date, five randomized studies have been published comparing MP with MP plus thalidomide (MPT) as primary treatment in elderly patients with MM.[7-12] The design of these studies, inclusion criteria, and doses of chemotherapy and thalidomide have varied (Table 1). However, the results are quite reproducible. These are shown in Table 2 and can be summarized as follows:
• Response rates—of either at least partial response or at least very good partial response (VGPR)—were significantly increased in the MPT arm in all five studies.
• PFS was significantly improved in the MPT arm in four out of five studies.
• OS was significantly improved in the MPT arm in three out of five studies; however, OS is partly dependent on the efficacy of salvage treatment after progression and on the availability of novel agents for relapse management.
As a consequence of these studies, the regimen MPT is now considered a new standard of care and it has been approved by the European Medicines Agency (EMEA) for the treatment of patients older than 65 years with newly diagnosed MM. However, safety may be a concern, especially in very old or frail patients. For example, in the Nordic trial, the median patient age was 78 years, and the proportion of patients with an Eastern Cooperative Oncology Group (ECOG) performance status higher than 2 was 30%.[12] This high incidence of more frail patients resulted in a high rate of toxic death (23 deaths in the first 6 months in patients over 75 years of age in the MPT arm versus a rate of 12 deaths during the first 6 months in the MP arm) and lower compliance with treatment (59 treatment discontinuations in the MPT arm versus 18 in the MP arm). As a consequence, PFS was not improved in the MPT arm. One might speculate that higher doses of melphalan (0.25 mg/kg/d for 4 days every 6 weeks) and thalidomide (200 mg/d for 1 week, and up to 400 mg/d) and inclusion of older and more frail patients were the reason that a better response rate did not translate into a longer PFS in the MPT arm.[12]
Conversely, in the French trial in patients over 75 years of age, doses of melphalan and thalidomide were lower (0.2 mg/kg/d and 100 mg/d, respectively) and both response rate and PFS were significantly superior in the MPT arm compared with the MP arm.[10]
MP and MPV Regimens Compared: Results of the VISTA Randomized Trial
The second agent to be combined with MP is bortezomib. Following encouraging data from a phase I/II trial of the combination MP plus bortezomib (MPV),[13] the large randomized Velcade as Initial Standard Therapy in Multiple Myeloma (VISTA) trial compared MP and MPV.[14] Results were recently updated[15] and are summarized in Table 3. MPV was significantly superior to MP for all parameters that measured response or outcome. An important finding from this trial was that the complete response (CR) rate was 30%; this is quite comparable to the rate achieved with HDT in younger patients. Thus, MPV is also now an EMEA-approved standard of care regimen for use in elderly patients.
However, while results were not significantly diminished in patients in this trial who were older than 75 years, safety was a concern. In the MPV arm, the incidence of grade 3/4 peripheral sensory neuropathy was 14%, and 30% of patients had to discontinue treatment or at least discontinue bortezomib because of treatment-related adverse events.[14]
Lenalidomide has also been used with MP (MPR regimen). While a phase I/II study has yielded encouraging results,[16] preliminary analysis of a randomized trial comparing MP, MPR, and MPR plus lenalidomide maintenance failed to show a better PFS in the MPR arm than in the MP arm, despite a higher response rate in the former.[17] Again, this might be explained by higher myelotoxicity and lower compliance in patients older than 75 years.
Dexamethasone-Based Combination Regimens: Results of Randomized Studies
Dexamethsasone-Based Combinations
The combination of thalidomide and dexamethasone (TD) has been widely used as primary therapy in MM. This combination was compared to MP in a randomized study in elderly patients.[18] While the response rate, including CR rate, was superior in the TD arm, there was no benefit in terms of PFS, and OS was significantly shorter in the TD arm, particularly in patients over 75 years of age (median, 19.8 months—versus 41.3 months in the MP arm) (Table 4). These results were explained by the higher toxicity and lower compliance in the TD arm. In this study, both the thalidomide dosage (50 to 400 mg/d) and the dexamethasone dosage (4-day blocks at 40 mg/d) were probably too high in patients who were older than 75 or who had poor performance status; the elevated dosages might also explain the high incidence of early deaths from infection or cardiac complications.
Determining the optimal dose of dexamethasone to be combined with IMiDs in frontline therapy of MM was the purpose of a randomized study recently published by the ECOG. This study compared lenalidomide plus high-dose dexamethasone (40 mg/d for 4 consecutive days, 3 times a month) with lenalidomide plus low-dose dexamethasone (40 mg weekly).[19] Here, too, while the response rate was superior with high-dose dexamethasone, median PFS and 1-year survival were significantly longer in the low-dose arm (Table 4) because of higher toxicity in the high-dose arm. The incidence of any grade 3/4 adverse events was 52% in the high-dose dexamethasone arm, compared with 35% in the low-dose dexamethasone arm (P=.0001). As a result, there were more early deaths (5% vs 1%; P=.003) and more treatment discontinuations due to adverse events (27% vs 19%) in the high-dose dexamethasone arm. This trend was particularly evident in patients over the age of 70. The fact that the median duration of treatment was 9.7 months in the low-dose dexamethasone arm, compared with only 3.8 months in the high-dose dexamethasone arm, may explain why median PFS and 3-year OS were superior in the low-dose arm.[20] In any event, lenalidomide plus low-dose dexamethasone might be another standard of care in elderly patients and is currently being compared to MPT in an ongoing randomized trial.
