Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial

Abstract

We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.

Figure 1

Consort diagram outlining the treatment pathway for all 104 SPMs confirmed as trial-related.

Figure 2

(a) Overall trial-related SPM incidence. The 1-, 2- and 3-year cumulative incidence of all SPM is 0.7%, 2.3% and 3.8% at 1, 2 and 3 years, respectively, for the whole trial. (b) Overall-trial related SPM incidence excluding NMSC. The 1-, 2- and 3-year cumulative incidence of all SPM when non-invasive malignancies are excluded is 0.6%, 1.8% and 2.9%, respectively, for the whole trial.

Figure 3

(a) TE pathway SPM incidence according to induction. Three-year SPM CI was 2.7% and 1.5% for the RCD and CTD induction groups, respectively; Fine and Gray P=0.014. n=756 RCD and 753 CTD. (b) TNE pathway SPM incidence according to induction. Three-year SPM CI was 5.9% and 5.9% for the RCDa and CTDa groups, respectively; Fine and Gray P=0.548. n=611 RCDa and 612 CTDa.

Figure 4

(a) Whole trial SPM incidence according to maintenance received. Three-year CI was 8.9% and 4.0% for the len and active observation maintenance groups, respectively; Fine and Gray P=0.011. n=820 len±vori and 540 active observation. (b) TE pathway SPM incidence according to maintenance received. Three-year CI was 5.8% and 2.0% for the len and active observation maintenance groups, respectively; Fine and Gray P=0.097. n=495 len±vori and 313 active observation. (c) TNE pathway SPM incidence according to maintenance received. Three-year CI was 12.9% and 6.3% for the len and active observation maintenance groups, respectively; Fine and Gray P=0.053. n=324 len±vori and 228 active observation. len, lenalidomide; vor, vorinostat.

Figure 5

(a) TNE patients >74 years old receiving maintenance. Overall 3-year CI was 17.3% and 6.5% for the len and active observation maintenance groups, respectively; P=0.049. n=144 len and 103 obs. (b) TNE patients ⩽74 years old receiving maintenance. Overall 3-year CI was 9.7% and 6.1% for the len and active observation maintenance groups, respectively; P=0.511. n=180 len and 125 obs. len, lenalidomide; obs, observation.