Maintenance Therapy
The goal of maintenance therapy is to increase the duration of remission by controlling the malignant clone. In the past, interferon produced a moderate increase in PFS,[21] but because of toxicity, long-term treatment could not be justified. The concept of maintenance therapy is currently being revisited in elderly patients using novel agents.
With MPT primary therapy, there is no current evidence that thalidomide(Drug information on thalidomide) maintenance further increases PFS, since in none of the randomized trials evaluating MPT has this question been specifically addressed. However, it should be noted that in the two Intergroupe Francophone du Myélome (IFM) studies, the better PFS translated to an OS benefit despite the absence of maintenance therapy,[9,10] while in the Italian study, MPT induction was followed by thalidomide maintenance therapy but there was no OS benefit in the MPT arm due to a shorter survival after relapse.[8]
Three recent studies favor maintenance therapy in elderly patients. The most convincing is the MM015 randomized trial, which compared 9 cycles of MP, 9 cycles of MP plus lenalidomide (MPR), and 9 cycles of MPR followed by low-dose lenalidomide maintenance (MPR-R).[17] PFS in the MPR-R arm was dramatically superior to PFS in the other two arms. However, up to now there has been no OS benefit in the lenalidomide maintenance arm.
Preliminary analysis of an Italian randomized trial showed that, compared with the new standard MPV regimen, four-drug induction therapy (MPT plus bortezomib(Drug information on bortezomib)) followed by maintenance therapy with bortezomib plus thalidomide significantly increased both the response rate (38% CR vs 24%; P=.0008) and the 3-year PFS (60% vs 42%; P=.007).[22]
A randomized Spanish study also used maintenance therapy with bortezomib plus thalidomide or bortezomib plus dexamethasone(Drug information on dexamethasone) and showed a further increase in the CR rate during maintenance (from 25% before maintenance to 42% with maintenance).[23] Although these two studies did not directly assess the role of maintenance, they both show that maintenance therapy may improve results achieved by induction treatment.
When to Treat Elderly Patients
Diagnostic Criteria for Plasma Cell Disorders
Which Plasma Cell Disorders Should Be Treated?
MM is a late stage in the evolution of monoclonal gammopathies and is always preceded by a phase of monoclonal gammopathy of unknown significance (MGUS)—although this phase is not always recognized. An intermediate stage is smoldering (or asymptomatic) myeloma (SMM). The difference between SMM and MM is that patients with SMM must have no evidence of related organ or tissue impairment (end-organ damage). The criteria for end organ damage are CRAB symptoms (hypercalcemia, renal insufficiency, anemia, lytic bone lesions) or recurrent infection. The diagnostic criteria for MGUS, SMM, and MM are listed in Table 5.[24]
Risk Factors Associated With a Shorter Time to Progression in SMM
The risk of progression to overt symptomatic MM is 25% at 20 years for MGUS[25] and 73% at 15 years for SMM.[26] Therefore, considering the age-adjusted life expectancy of the general population and the potential toxicity of myeloma treatment, currently MGUS should not be treated and SMM is usually not treated before there is evidence of progression. However, although in MGUS the risk of progression is uniform (about 1% per year), in SMM the risk is 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and only 1% per year for the last 10 years.[26] Prognostic factors that are associated with a shorter time to progression are listed in Table 6.[26-33] For example, in a group of patients with a high percentage of plasma cells (10% or more) and a high serum M-component level (3g/dL or greater), the probability of progression at 15 years was 87%, compared with a probability of only 39% in patients with less than 10% plasma cells.[26]
Thalidomide has been tested in SMM, but toxicity was a serious concern.[34] Clinical studies of novel agents with a good efficacy/toxicity ratio seem justified in patients with SMM at high risk of transformation. Preliminary results of a Spanish randomized trial have showed that induction treatment with lenalidomide-dexamethasone followed by lenalidomide maintenance therapy significantly delays the risk of progression compared with no treatment.[35] However, the real proof of the benefit of this approach will be demonstration of an improved OS. Until there is evidence of such a benefit, outside of a clinical trial, careful observation remains the recommended management strategy in these patients.
Treatment of Symptomatic MM in Elderly Patients
As with younger patients, elderly patients with symptomatic MM should be treated. The introduction of novel agents in primary therapy has had two important consequences:
• While there had been no significant improvement in conventional chemotherapy for 4 decades, we now have several possibilities that are significantly superior to MP (MPT, MPV, and lenalidomide with low-dose dexamethasone [Rd]).
• While patients over 75 years of age had been treated with reduced-dose alkylating agents or only with palliative approaches, they can now be treated with effective combinations.
As in younger patients treated with HDT plus ASCT, the objective of primary therapy in elderly patients should be to achieve CR.[36] The prognostic impact of achieving CR has been shown in a sub-analysis of the VISTA trial and in a retrospective analysis of recent Italian protocols.[37,38] However, induction therapy should not be too toxic; otherwise, the benefit of more effective treatment may be negated by an excessive toxic death rate or by poor compliance with treatment.[12,18]
Until the results of ongoing randomized trials are available, it is not possible to determine which of the new standard regimens is best. A number of criteria must be considered when deciding on the initial therapy for an elderly patient with symptomatic MM.
Most of these criteria are patient-related. Bortezomib-based regimens are preferred in patients with renal failure or a previous episode of deep vein thrombosis. IMiD-based regimens are preferred when oral administration is more suitable. Lenalidomide-based regimens are preferred in patients with concomitant peripheral neuropathy, since both thalidomide and bortezomib are potentially neurotoxic.
Other criteria are myeloma-related. For instance, bortezomib might be preferred in a patient with translocation (4;14), since it has been shown that even a short treatment may at least partially overcome the poor prognosis associated with this cytogenetic abnormality.[14,39] Data involving lenalidomide are less clear.
The key to treating elderly patients is to actually evaluate the efficacy/toxicity ratio and to reduce the toxicity of the regimens. To this end, the issue of the dose is critical.
Dexamethasone. The IFM demonstrated that despite higher response rates, PFS was not better with dexamethasone-based regimens than with MP—and that toxicity was greater (more infections, diabetes, and gastro-intestinal and psychiatric complications).[40] The IFM thus concluded that high-dose dexamethasone should not be routinely recommended as first-line therapy in elderly patients. As suggested by the results of the ECOG randomized trial,[19] dexamethasone is best used weekly (low-dose regimen) in all elderly patients (at a dosage of 40 mg/wk up to the age of 70 years, and at a dosage of 20 mg/wk in patients older than 70 years).
MP Regimens. In patients older than 75 years, melphalan(Drug information on melphalan) should be used at a reduced dosage (0.2 mg/kg on 4 consecutive days every 6 weeks). The dose of thalidomide should not be more than 100 mg/d.[10]
Bortezomib. In an attempt to find a way to reduce the risk of peripheral neuropathy, which is the most frequent reason for stopping bortezomib treatment, two groups have evaluated a new MPV regimen that uses weekly instead of twice-weekly administration of bortezomib.[22,23] Both groups found that efficacy was not significantly different with weekly administration but that the incidence of severe peripheral neuropathy was dramatically reduced.
Other measures are also important. These include prophylaxis for herpes-zoster infections in patients treated with bortezomib and prevention of deep vein thrombosis with low-molecular weight heparin(Drug information on heparin) or aspirin(Drug information on aspirin) in patients treated with thalidomide or lenalidomide. Careful monitoring of blood cell counts is mandatory in patients receiving alkylating agents and/or lenalidomide.
Before deciding on treatment, a geriatric evaluation must be performed in all frail patients over the age of 75 and in patients with severe comorbidities. In patients for whom geriatric assessment does not show a positive benefit/risk ratio, attenuated-dose treatment (such as low-dose alkylating agents) should be considered.
