Haematological Malignancies
up-front); differences in the conditioning regimens; and, particularly, differences in the intensity and duration of the chemotherapy arm (the dose of alkylating agents and steroids were higher in the SWOG and Spanish trials, which may explain why OS for conventionally treated patients was longer in these two studies compared with the IFM and MRC trials. Despite these discrepancies, HDT is currently considered the standard of care for younger patients with MM, mainly based on the benefit on response rate and EFS.
In the setting of novel agents, it is also important to define whether or not ASCT enhances the response rates obtained with these new induction regimens. Studies based on bortezomib combinations, including two randomised trials, have shown that the CR rate was improved following ASCT, suggesting that induction with novel agents and ASCT is a complementary rather than alternative treatment approach. Moreover, with TAD, Bz–Dex and Bz–TD, preliminary data already show a prolongation in PFS. Nevertheless, longer follow-up is needed. Some investigators argue that the ‘induction with novel agents followed by ASCT’ approach may be challenged by the optimal results obtained with ‘long-term’ treatment with novel combinations (i.e. Len + Dex). Although a randomised trial comparing these two approaches would be most interesting, the transplant approach induces a very high CR rate (a goal in all haematological malignancies) and patients enjoy a long-term period free of treatment with an excellent quality of life.
Regarding tandem ASCT,10–12 its use will decrease for two reasons:
according to the IFM and Italian experiences, only patients achieving a less than ‘very good’ partial response with the first transplant benefit from the second; and a similar benefit is obtained upon using thalidomide as consolidation/maintenance therapy. By contrast, a second transplant at relapse may be increasingly used, provided that the duration of the response to first transplant has lasted for more than two to three years.
Maintenance
The third step in this sequence of treatment is maintenance. Interferon and/or corticosteroids have shown little benefit and have been abandoned. The availability of novel agents (particularly those in oral formulations – thalidomide and lenalidomide) has renewed the concept of maintenance in an attempt to prolong the duration of response after transplant.13–15
The IFM group has shown that
thalidomide maintenance after tandem ASCT is significantly superior to no maintenance or pamidronate alone in terms of EFS (52, 36 and 37% at three years, respectively) and OS (87 versus 74% at four years). This superiority has been confirmed by an Australian study comparing thalidomide plus prednisone versus prednisone alone. Of note, the Arkansas group has also observed that the use of thalidomide as part of the induction and maintenance phase was associated with longer EFS, but only translated into an OS benefit for a subset of patients with high-risk cytogenetics. Similarly, the MMRC group has reported a short survival after relapse for patients receiving maintenance with thalidomide. This raises an important concern about whether the continuous use of novel agents may induce more resistant relapses. Moreover, the benefit of thalidomide maintenance for patients who are already in CR, as well as for those with poor cytogenetics, is not well established: the IMF and MMRC groups showed no benefit for patients with deletion 13q and 17p (detected by fluorescent in situ hybridisation [FISH] analysis), respectively, while, as mentioned above, in the Arkansas study there was a survival advantage for patients with abnormal cytogenetics
82
treated with thalidomide. Accordingly, although randomised trials are required to define the role of long-term maintenance (greater than one year), a short treatment with thalidomide would be justified in patients who have not achieved CR post-ASCT. Moreover, it is possible that the better tolerance of lenalidomide will facilitate its use in maintenance programmes.
Allogeneic Transplant
Allogeneic transplantation remains the only curative therapeutic approach in MM patients. However, it is associated with a high transplant-related mortality (TRM) of up to 30–50% as well as morbidity, mainly due to chronic graft-versus-host disease (GvHD). Accordingly, it should be used in carefully defined situations and, preferably, within the context of clinical trials. In order to decrease TRM, different reduced-intensity conditioning regimens (RIC) have been developed (allo-RIC), mainly based on fludarabine and melphalan or fludarabine plus radiotherapy (2Gy).16–18
TRM decreases
to 15–25%, but this is associated with a higher incidence of relapses. In a prospective randomised trial, the French group compared double ASCT with ASCT followed by allo-RIC among patients displaying poor prognostic features (high B2 microglobuline and monosomy of chromosome). Unfortunately, there were no event-free survivors at five years either after double ASCT or after ASCT followed by allo-RIC. Similar results have been reported by the Hovon group. By contrast, both the Italian and the EBMT groups, using a similar approach, have described an improvement in terms of OS among patients receiving ASCT followed by allo-RIC compared with double autologous transplant. The Spanish group has recently reported a trend towards a longer PFS in favour of allo-RIC, but with a similar OS. Differences in patient characteristics, GvHD prophylaxis and conditioning regimens could contribute to explaining these discrepant results. Moreover, unfortunately, a high proportion of patients develop extra-medullary relapses without bone marrow involvement, indicating that, although the disease may be under control in the bone marrow milieu, extra- medullary spread may occur.
In order to use allo-Trx as rescue therapy, a prerequisite is to obtain either complete remission or a ‘very good’ partial response before transplant, as most patients with active disease will not benefit from this procedure. Once again, transplants should be performed by experienced groups and within clinical trials. Donor lymphocyte infusions (DLI) given for relapsed myeloma following allogeneic transplantation induce responses in 30–50% of patients, but unfortunately the long-term efficacy is limited. Interestingly, the combination of DLI with thalidomide, lenalidomide or bortezomib may improve the response rate and contribute to modulating the immune response, although further studies are required to confirm these data.
Treatment Options for the Elderly Patient Not Suitable for Stem Cell Transplantation
Melphalan + prednisone (MP) has been the gold standard for over 40 years; however, recent results based on the combination of MP with either thalidomide or bortezomib, and probably also with lenalidomide, indicate that there are now new standards of care for elderly MM patients.19–21
Five randomised trials have compared T+MP (MPT) versus MP. In all these studies both the RR and CRs were significantly higher in the MPT arm (RR 57–76% for MPT versus 31–48% for MP, CR 7–16% for
EUROPEAN ONCOLOGY
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