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    • br Methods The Spanish GEM MAS

    2019-06-10


    Methods The Spanish GEM05MAS65 trial lasted from March, 2006 to October, 2008 and included 260 patients from 63 Spanish centers. At study entry, every patient was aged 65 years or older and had newly diagnosed, untreated, symptomatic, measurable MM. These patients had received a homogeneous induction treatment consisting either in bortezomib, melphalan, and prednisone (VMP) or bortezomib, thalidomide, and prednisone (VTP). Design of the study and treatment arms have been extensively described elsewhere [9–11]. Briefly, patients were upfront randomized to receive induction with 6 cycles of VMP or VTP. One hundred and seventy eight patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone (VP, n=87) or bortezomib plus thalidomide (VT, n=91) [9–11]. As of December 31st, 2013, 164 patients of the GEM05MAS65 trial had suffered disease relapse or progression. One hundred and forty-five (88%) received second line therapy and form the basis of this hsp90 inhibitor study. Nineteen (12%) patients were excluded due to asymptomatic relapse at time of analysis (11 patients), no data at relapse (6 patients) and early death after relapse without receiving second-line therapy (2 patients) (Fig. 1).
    Results
    Discussion In this study, every patient received front-line therapy with bortezomib as part of the GEM2005MAS65 trial and 50% of them also received thalidomide during the induction regimen. It has been hypothesized that by the exposure to novel agents in relapsed or refractory multiple MM, more resistant subclones may survive under the selective stress of the agents, explaining the more aggressive forms of relapse [14]. Our findings, however, do not support this hypothesis. In fact, an asymptomatic increase in the monoclonal component along with the reappearance of the classical CRAB symptoms were the most commonly forms of relapse (113 patients, 78%) and only 32 (22%) patients developed aggressive relapse. This pattern of relapse is similar to that observed in younger patients who received induction with conventional chemotherapy followed by autologous transplantation [6–8]. Thus, the type of relapse might be more related with disease biology such as the intraclonal heterogeneity recently reported in MM [15,16]. However, additional studies are needed to try to clarify whether exposure to regimens including one or more novel drugs during induction will increase the risk of more resistant disease at time of relapse. The overall and CR rate after relapse were 51.7% and 11%, respectively and not influenced by the type of regimen administered in the front-line therapy (VMP or VTP). However, achievement of CR after relapse was associated to a significantly longer OS when compared with those patients who obtained less than CR (28.3 vs. 14.8 months; P=0.04). In newly diagnosed MM patients an association between achieving deep levels of remission and long-term survival has been proved confirming this parameter as a valid surrogate marker of the treatment efficacy [18] but the value of the depth of response in the relapse setting has been less investigated [19]. Our results, however strongly suggest that CR should also be a valid objective of any therapeutic strategy even in patients in relapse. Median PFS after first relapse in the overall series was 8.84 months with no differences between VMP and VTP and shorter than the corresponding figure observed with the use of lenalidomide and dexamethasone in first relapse by other groups [17]. However, microfilaments must be noted that these results were achieved at a time when novel agents were rarely used upfront, and results might be different in patients who received novel agents as first-line treatment like those included in our study. Although direct comparisons are not possible, the PFS observed in our study was similar to that recently reported with bortezomib and dexamethasone [20] but shorter than that observed with different three-drug regimens such as bortezomib, dexamethasone, and panobinostat [20] or lenalidomide, dexamethasone, and carfilzomib [21] suggesting that a triple combination may be more effective for this subgroup of patients. However, it should also be highlighted that median age at time of relapse was much higher in our series than in other studies dealing with MM patients in relapse a fact that also may explain the shorter duration of PFS observed in our study [14,17,20,21].