standards of care for this patient population.
Addition of thalidomide to MP produced around a six-month increase in progression-free survival (PFS) (20.4 months vs 15 months; hazard ratio (HR) 0.67, 95% CI 0.61–0.76, p<0.0001) and overall survival (OS) (39.3 months vs 32.7 months; HR 0.83, 95% CI 0.73–0.94, p=0.004).9
This combination has been
widely used but its use will decrease in the future owing to the superiority of lenalidomide plus low-dose dexamethasone.
Addition of lenalidomide to MP (MPR) followed by lenalidomide maintenance therapy (MPR-R) in patients older than 65 years of age, resulted in median progression-free survival of 31 months with MPR-R, significantly superior compared with MPR and MP alone. However, though positive efficacy results, safety can represent an issue due to an increase in the rate of adverse events especially in the over 75 years age group together with the emergence of second primary malignancies, especially haematological malignant diseases.10,11 Bortezomib added to MP (VMP) resulted in a median OS benefit of 13.3 months compared with MP (56 months vs 43 months; p=0.0008), in the VISTA trial maintained after a median follow-up of five years.12
This VISTA scheme has been subsequently optimised through the weekly and subcutaneous administration of bortezomib (instead of twice a week and intravenous administration). A novel less intensive bortezomib- based regimen, followed by maintenance, proved more effective.4
induction with six cycles of VMP or bortezomib-thalidomide-prednisone (VTP) patients then received maintenance therapy with bortezomib-prednisone or bortezomib-thalidomide. Overall response rate (ORR) was similar in both arms: 80% and 81% for VMP and VTP. CR rate was slightly superior for VTP (27%) compared with VMP (20%). However, the toxicity profile was better for VMP than VTP, which was associated higher frequency of peripheral neuropathy and serious cardiac adverse events. VT or VP as maintenance did not influence the outcome of either induction group. VMP was found to induce more profound responses: after median follow up of 72 months the CR rate was 20% (of which 70% were flow-CR) with VMP compared with 27% (45% flow-CR) with VTP.13
Non-alkylator-based induction regimens Comparing thalidomide–dexamethasone (TD) with MP, Ludwig et al found that in patients aged over 75 years, OS was longer with MP than TD (41.3 months vs 19.8 months, p=0.071) and mortality was higher during the first year with TD compared with MP (40 (28%) vs 22 (16%), p=0.014).14
dexamethasone combination may not be optimal for elderly patients, especially at high doses of thalidomide and dexamethasone.
Rajkumar et al compared lenalidomide plus high-dose dexamethasone with lenalidomide with low-dose dexamethasone in 445 patients with untreated symptomatic myeloma in an open label study.15
In an interim analysis
at one year, OS was 96% (95% CI 94–99) in the low-dose dexamethasone group compared with 87% (82–92) in the high dose group (p=0·0002). The trial was stopped and patients receiving high-dose therapy were switched to low-dose treatment. The authors commented that inferior OS with high-dose
dexamethasone seemed to be related to increased deaths due to toxicity, particularly in the first four months, and in elderly patients.
However, toxicity was greater.
The FIRST trial compares a lenalidomide and low-dose dexamethasone combination in transplant-ineligible patients with myeloma (for up to 18 cycles (Rd18) or until disease progression (Rd)) with MPT.16
With regard to the primary endpoint, continuous Rd reduced the risk of disease progression by 28% compared with MPT (HR 0.72; p=0.0006). Continuous Rd also reduced the risk of disease progression by 30% compared with giving Rd for 72 weeks (HR 0.70; p=0.0001). Median PFS was 25.5 months with continuous Rd, compared with 20.7 months with Rd for 72 weeks and 21.2 months with MPT. The benefit was independent of age, gender, race, geographic region, ISS stage, renal function, beta-2-microglobulin level, albumin level, ECOG performance status, lactate dehydrogenase level and cytogenetic risk.
MPT and MPV are established alkylator-based standards of care in elderly newly diagnosed multiple myeloma patients. Emerging data resulted in the approval of lenalidomide- dexamethasone combination as a new treatment option for this patient
The Spanish Myeloma Group has recently planned a total therapy approach for elderly patients consisting on the administration of both VMP and Rd but in a sequential or alternating scheme up to 18 cycles. The complete response rate achieved is 40% with median PFS of approximately three years.17
Importance of CR
An analysis of three European randomised trials involving 1175 patients by Gay and colleagues reveals the correlation between CR, PFS and OS.18 The researchers compared PFS and OS of newly diagnosed patients who achieved CR after MP, melphalan–prednisone– thalidomide (MPT), melphalan– prednisone–bortezomib (VMP), or melphalan–prednisone thalidomide– bortezomib followed by bortezomib– thalidomide maintenance (VMPT-VT) with those whose best response was very good partial response (VGPR) or partial response (PR) only. They noted that multivariate analysis confirmed that the achievement of CR was an independent predictor of longer PFS and OS, regardless of age, International Staging System stage, and treatment.
Significant benefit was also seen when analysis was restricted to patients older than 75 years, the three-year PFS was 79% in patients who achieved CR and 24% in those who obtained VGPR (HR 0.26, 95% CI, 0.12–0.58, p=0.001) and 23% in those who attained PR (HR=0.20, 95% CI, 0.10–0.41, p<0.001). Comparing VMP with VTP in a randomised Phase III trial involving 260 patients found that achieving immunophenotypic CR was associated with a significantly longer OS, especially in the VMP arm (66% remained alive after eight years). The study confirms that reduced-intensity induction with VMP followed by maintenance with VT or VP produces significantly better OS than achieved with VTP. In addition, CR, and particularly flow CR, should be an important goal in the treatment of this patient population.13
Importance of performance status Given the heterogeneity of elderly patients with MM, treatment
optimisation requires a time-efficient tool to evaluate the status of individual patients taking account of age, comorbidities, cognitive status and physical condition.
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