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Lenalidomide-based regimens in elderly MM
between treatment arms was the most frequent grade ≥3 neutropenia in the R arm compared to RP, which did not translate into a higher infection rate. One of the possible explanations of this finding is based on the effect of pred- nisone on neutrophils.13 Glucocorticoid therapy inhibits L- selectin expression on neutrophils that are more prone to enter the bloodstream, delays the migration of circulating neutrophils into tissues, produces a direct antiapoptotic effect on these cells and prompts the release of young neu- trophils from the bone marrow leading to an increased peripheral blood neutrophil count.
While dose discontinuation was not different in the RP and R arms, patients treated with R alone more often required dose reductions, which slightly impaired the effi- cacy of maintenance treatment.
The treatment goal in elderly MM patients is not a trivial issue and international guidelines suggesting personalized treatment according to patients’ frailty status are currently based on expert opinions, without the availability of high- quality evidence.8,9 With all the limitations of a post-hoc analysis, this is the first analysis to show that fit patients benefit from a full-dose triplet regimen while intermediate- fit and frail patients benefit from gentler regimens.
Indeed, fit patients treated with MPR induction showed a statistically significant PFS advantage over those treated with CPR or Rd. Intermediate-fit and frail patients did not show any PFS benefit from one regimen over the others.
A higher hematologic adverse event rate was noted with MPR induction compared to induction with the other regimens.
After the protocol amendment, introduced because of negligible adverse events, the dose of cyclophosphamide was increased. Nevertheless, despite the amendment, cyclophosphamide could still have been underdosed as compared to the dose delivered in other cyclophos- phamide-containing regimens used in younger patients.14,15 This issue could have mitigated the impact on PFS of the addition of cyclophosphamide to lenalidomide-steroid doublets even in fit patients.
Hematologic adverse events were not dependent on patients’ frailty status, while the rate of non-hematologic adverse events was correlated to the fitness status but not to the type of induction regimen. Indeed, physicians’ lim- itations to treat frail patients effectively are based on the patients’ reduced organ function reserve leading to a high- er rate of non-hematologic toxicity, rather than on the hematologic toxicity that is mainly dependent on the treatment itself, as observed with the melphalan-contain- ing regimen in this study.
As expected, frail patients experienced the highest dis- continuation rate due to toxicity, and discontinuation was more frequent among patients receiving the alkylator-con- taining regimens than among those treated with the Rd doublet. It is, therefore, reasonable to support the choice of a full-dose alkylator-containing triplet regimen in fit patients, in order to prioritize the efficacy. Conversely, intermediate-fit and frail patients could benefit from a gentler regimen, since a better safety profile should be pur- sued in the absence of an advantage in PFS or OS.
In the FIRST trial, a retrospective proxy algorithm (which calculated data from questionnaires on medical history and quality of life) was used to estimate the IMWG Frailty Score.16 In that post-hoc analysis, continu- ous Rd was compared to an alkylator-containing triplet regimen; however, differently from our analysis, the novel agent used in the control arm was the first-generation immunomodulatory drug thalidomide. Indeed, in that analysis continuous Rd produced longer PFS and OS com- pared to melphalan-prednisone-thalidomide across all frailty subgroups, with the greatest benefits observed in fit patients. No lenalidomide-containing triplet regimens were included in that trial.
Despite the limitations of inter-trial comparisons, Rd induction produced a shorter PFS in our study than in the FIRST study (26 months with continuous Rd and 21 months with Rd given for 18 months).17 Of note, in that trial Rd was given for a fixed duration of 18 months or continuously, while in our trial Rd was given only for 9 months as induction treatment and then both mainte- nance regimens included lenalidomide given at a lower dose (10 mg instead of 25 mg) and lower steroid doses or no steroids at all, depending on the treatment arm. The same observation, with the same limitations of inter-trial comparisons, can also be applied to the control arm of the more recent MAIA study, in which a median PFS of 31.9 months was obtained with continuous Rd (even longer than the PFS obtained in the FIRST study with an identical regimen).18
However, the role of continuous, full-dose treatment vs. full-dose induction followed by low-dose maintenance in frailty-defined populations of elderly patients remains an open issue.
Recently, initial results from a randomized phase III trial comparing continuous Rd vs. Rd induction followed by lenalidomide maintenance (Rd-R) in intermediate-fit patients were reported.19 Notably, in this population of patients, continuous Rd did not produce an advantage in PFS compared to Rd-R (15.5 months vs. 18.3 months). On the
Table 4. Grade ≥3 hematologic adverse events, non-hematologic adverse events, treatment discontinuation and toxic deaths during maintenance treatment according to patients’ frailty status.
Treatment arm (n)
Frailty Score class (n)
Hematologic AE G ≥3, n (%)
Non-hematologic AE G ≥3, n (%)
Discontinuation due to AE, n (%)
DeathduetoAE,n(%) 2(2) 1(2) 2(5) 2(2) 2(3) 4(8)
Fit (101)
Frail (40)
Fit (91)
Intermediate-fit (58)
Frail (49)
Lenalidomide (R) (n=204)
Intermediate-fit (63)
Lenalidomide-prednisone (RP) (n=198)
24 (24) 12 (12) 16 (16)
13 (21) 5 (8) 9 (14)
9 (22) 5 (12) 11 (28)
10 (11) 12 (13) 14 (15)
6 (10) 9 (16) 16 (28)
10 (20) 7 (14) 11 (22)
AE: adverse events; G: grade; n: number; %: percentage.
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