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S. Bringhen et al.
other hand, event-free survival (progression or death from any cause/lenalidomide discontinuation/hematologic grade 4 or non-hematologic grade 3-4 adverse events) was signifi- cantly better in the Rd-R arm than in the continuous Rd arm.
These results suggest that at least in intermediate-fit eld- erly patients with NDMM, treatment intensity during the maintenance phase can be de-escalated with no negative impact on outcome.
The EMN01 trial enrolled patients from 2009 to 2012; thereafter, less toxic and more effective combinations began to be available. For instance, the addition of borte- zomib to Rd led to a clinically meaningful improvement in PFS and OS in NDMM patients without intent for imme- diate ASCT, irrespective of the patients’ age.20 In NDMM patients, the addition of the anti-CD38 monoclonal anti- body daratumumab to bortezomib-melphalan-prednisone or Rd doubled PFS, with mild and manageable toxicity.18,21 Besides, studies exploring the addition of a monoclonal antibody to the bortezomib-Rd combination are ongoing with very promising early results.22
Contextualizing our data, quadruplet or triplet regimens containing monoclonal antibodies, immunomodulatory drugs and/or proteasome inhibitors may be the best choic- es for fit, elderly patients. However, there is still the need for safety and efficacy data on selected intermediate-fit and frail populations receiving new combinations at full or reduced doses. As an example, in the MAIA trial, continu- ous daratumumab-Rd significantly prolonged PFS com- pared to continuous Rd, but a higher incidence of infec- tions and a lower lenalidomide cumulative dose due to dose reduction/discontinuation were noted in the daratu- mumab-Rd arm.23 Regarding maintenance, data about combinations of monoclonal antibodies plus immunomodulatory drugs outside of the context of con- tinuous therapy are not currently available in elderly patients. In the experimental arm of the ALCYONE trial, daratumumab monotherapy after induction therapy with the daratumumab-bortezomib-melphalan-prednisone quadruplet was well tolerated and improved the duration and depth of response.24 A longer follow-up of these two studies will inform us about the safety of monoclonal anti- body maintenance and the feasibility of long-term treat- ment with monoclonal antibodies plus immunomodulato- ry drugs in elderly patients.
Our analysis has some limitations. The trial was
designed to show superiority of a three-drug induction regimen over a two-drug induction regimen in the overall population, and thus the study power was not enough to detect a statistically significant difference in the frailty subgroups. However, the outcome differences between treatment arms in fit patients were high enough to reach significant levels.
Moreover, our analysis based on the frailty status was not pre-specified, but the geriatric assessment adopted to calculate the IMWG Frailty Score was obtained from the enrolled patients before the start of therapy. Although patients’ allocation to treatment arms was not stratified by IMWG Frailty Score, the stratification by age led to a uni- form distribution of fit, intermediate-fit, and frail patients across treatment arms.
In conclusion, this trial showed that the triplet MPR pro- longed PFS compared to gentler regimens in elderly fit but not in intermediate-fit and frail MM patients. In interme- diate-fit and frail patients, in the absence of differences in terms of efficacy, safety must be prioritized. Maintenance with lenalidomide-based regimens led to good outcomes with a good safety profile.
These data provide the basis for personalized treatment according to a patients’ frailty status. Different combina- tions of new-generation immunomodulatory drugs, protea- some inhibitors and monoclonal antibodies should be eval- uated in fit, intermediate-fit and frail patients to confirm these observations. Novel compounds with a good safety profile in combination with a lenalidomide-based mainte- nance treatment should also be explored in elderly patients.
Role of the funding source
The EMN01 study (NCT01093196) was sponsored by Fondazione Neoplasie Sangue [FO.NE.SA.] ONLUS (Italy) and supported by funding from Celgene, which had no role in the study’s design, data collection, data analysis, data interpretation, writing of the report or publication of this contribution. The corresponding author had full access to all the data in the EMN01 study and had final responsibility for the decision to prepare and submit this man- uscript for publication, together with the other authors.
Acknowledgments
We thank all the patients who participated in the study, the nurses Silvia Boscolo and Concetta Calicchio and the data man- agers Antonella Fiorillo and Elena Tigano.
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