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The outcome for myeloma patients has significantly improved over the last decade, mainly due to the introduction of new drugs with a singular mechanism of action, such as thalidomide and lenalidomide (revlimid), both immunomodulatory drugs (IMIDs), and the proteasome inhibitor bortezomib (velcade).1 In this article, we will briefly review the treatment of newly diagnosed patients stratified according to age (above or below 65–70 years of age) and transplant or non-transplant candidate status.
The combination of vincristine, doxorubicin and dexamethasone (VAD) has long been the gold standard as a preparatory regimen for young newly diagnosed multiple myeloma (MM) patients who are candidates for autologous stem cell transplant (ASCT), with partial response (PR) rates ranging between 52 and 63% and complete response (CR) rates of 3–13%. However, novel drug combinations appear to be superior to VAD, such as regimens to decrease tumour burden pre-transplant (Trx). Three randomised trials have compared thalidomide (T)-based regimens (T + Dex or TAD or T + VAD) versus either high-dose DEX or VAD as an initial therapy in transplant-eligible patients.2–4 In all studies, thalidomide combinations were superior to conventional induction treatment, although the response rate (>PR) obtained with T + Dex (63%) was lower than that achieved with TAD or T + VAD (80%, but CR rates are usually <10%). The MRC group has compared cyclosphophamide + TD versus cyclophosphamide + VAD (CVAD) as an induction regimen before transplant; the thalidomide arm was significantly superior, with a response rate (RR) of 87 versus 75% including 20 versus 12% CRs, respectively. In studies evaluating bortezomib (Bz) combination therapy, data from both a French randomised trial comparing Bz + Dex versus VAD and an Italian trial comparing Bz-TD versus TD show superiority of Bz regimens both before and after transplant, with 80 versus 94% >PR including 15 versus 32% CR, respectively. These results are consistent with several previous pilot studies. In terms of lenalidomide (Len), two large randomised studies have shown that the majority of patients (>85%) respond to Len + Dex induction, but probably a minimum of six cycles would be required to achieve a substantial number of CRs.5 Novel agents did not affect stem cell collection, although for lenalidomide it is recommended to collect the cells after no more than four to six cycles using cyclophosphamide with G-CSF. In summary, current results indicate that novel induction regimens are superior to VAD.
High-dose therapy (HDT) (usually based on melphalan 200mg/m2) followed by ASCT prolonged overall survival (OS) compared with standard-dose therapy (SDT) in prospective randomised trials conducted by French (Francophone Myeloma Intergroup [IFM]) and English (Medica Research Council [MRC]) groups and has provided evidence for a more than 10-year survival rate in at least a subset of patients.6,7 Nevertheless, the US study (Southwest Oncology Group [SWOG] 9321), the French MAG91 study and the Spanish PETHEMA-94 trial, although confirmed the benefit of ASCT in terms of response rate and event-free survival (EFS), did not find superiority in terms of survival compared with SDT.8,9 These discrepancies can be, at least in part, explained by: differences in study design (the Spanish study randomised patients responding to initial therapy while, in the others, randomisation was performed 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.