Table 3. Summary of SPM cumulative incidence and significance at 3 years according to pathway and treatment received.
| SPM incidence at 3 years according to treatment |
Incidence |
|||||
|---|---|---|---|---|---|---|
| Whole trial | P-valuea | TE | P-valuea | TNE | P-valuea | |
| Induction (104 SPMs) | ||||||
| Whole trial cohort all SPM (%) | 3.8 | — | — | — | ||
| Lenalidomide induction (%) | 3.7 | >0.05 | 2.7 | 0.114 | 5.9 | 0.548 |
| Thalidomide induction (%) | 3.4 | 1.5 | 5.9 | |||
| Maintenance (58 SPMs) | ||||||
| Lenalidomide±vorinostat maintenance (%) | 8.9 | 0.011 | 5.8 | 0.1 | 12.9 | 0.053 |
| Observation only (%) | 4.0 | 2.0 | 6.3 | |||
| TNE ⩽74 years observation only (%) | — | — | 6.1 | 0.511 | ||
| TNE ⩽74 years lenalidomide±vorinostat (%) | 9.7 | |||||
| TNE >74 years observation only (%) | — | — | 6.5 | 0.049 | ||
| TNE >74 years lenalidomide±vorinostat (%) | 17.3 | |||||
| SPM incidence per 100 person-years according to induction | ||||||
| Overall | 1.6 | — | 1 | — | 2.5 | — |
| Thalidomide induction | — | 0.8 | 2.7 | |||
| Lenalidomide induction | — | 1.2 | — | 2.3 | — | |
| SPM incidence per 100 person-years according to maintenance | ||||||
| Overall | 2.2 | — | 1.2 | — | 3.6 | — |
| Active observation | — | 0.8 | — | 2.2 | — | |
| Lenalidomide | 1 | — | 5.5 | — | ||
| Lenalidomide+vorinostat | 2.4 | — | 2.9 | — | ||
| Cycles all | Cycles TE | Cycles TNE | |
|---|---|---|---|
| Number of cycles of therapy received in all SPM patients | |||
| Median number of induction cycles (range) | 6 (1–14) | CTD=6 (3–8) | CTDa=6 (1–8) |
| RCD=5 (4–14) | RCDa=6 (1–8) | ||
| Median number of maintenance cycles (range) | 14 (1–48) | 14 (1–42) | 14 (1–48) |
| mg all (range) | mg TE (range) | mg TNE (range) | |
|---|---|---|---|
| Total induction drug doses received in all SPM patients | |||
| Median total cyclophosphamide dose per patient | 6000 (0–16 000) | 6000 (3100–12 000) | 6400 (0–16 000) |
| Median total dexamethasone dose per patient | 960 (80–4000) | 1280 (640–4000) | 960 (80–1280) |
| Median total thalidomide dose per patient | 14 000 (800–32 000) | 15 000 (6300–32 000) | 12 000 (800–28 000) |
| Median total lenalidomide dose per patient | 2100 (165–7350) | 2100 (1240–7350) | 2118 (165–3150) |
| Total maintenance drug doses received in all SPM patients | |||
| Median total lenalidomide maintenance dose per patient | 3080 (180–21 105) | 3448 (210–13 075)b | 2940 (180–21 105) |
| TNE overall mg (range) | TNE ⩽74 years mg (range)c | TNE >74 years mg (range) | |
| TNE median total lenalidomide maintenance dose per patient according to age | 2940 (180–21 105) | 3360 (180–21 105) | 2273 (840–17 430) |
Abbreviations: CTD, cyclophosphamide, thalidomide and dexamethasone; RCD, cyclophosphamide, lenalidomide and dexamethasone; SPM, second primary malignancy; TE, transplant eligible; TNE, transplant non-eligible.
There was a significant difference between SPM incidence at 3 years in patients receiving lenalidomide-based maintenance compared with patients being observed only for the whole trial cohort (P=0.011). There was also a significant difference in SPM incidence in patients >74 years, enrolled to the TNE pathway who received lenalidomide maintenance in comparison with the observation group (P=0.049).
Overall trial SPM incidence per 100 person-years is 1.6. Transplant eligible patients have a lower total SPM incidence in comparison with the TNE patients (1.0 versus 2.5). Incidence rates per 100 person-years according to induction therapy were 0.8 and 1.2 for patients receiving thalidomide versus lenalidomide in the TE pathway. The TNE pathway patients receiving thalidomide or lenalidomide induction had incidence rates per 100 person-years of 2.7 and 2.3, respectively.
Fifty-eight patients developed a second malignancy whilst in the maintenance phase of the trial resulting in an incidence rate (IR) of 2.2 per 100 person-years. Eighteen patients developed an SPM following maintenance randomisation in the TE arm and 40 in the TNE arm with an IR per 100 patient-years of 1.2 and 3.6, respectively. The lowest incidence was observed in patients being observed only, with TE and TNE IR per 100 patient years of 0.8 and 2.2, respectively. Patients receiving lenalidomide alone or in combination with vorinostat had incidence rates of 1.0 and 2.4 per 100 patient years, respectively, in the TE pathway, and 5.5 and 2.9, respectively, in the TNE pathway.
The number of induction cycles received was comparable between groups with a median of 6 cycles for CTD, CTDa and RCDa, and 5 cycles for RCD. Total doses of trial drugs received at induction and maintenance was also comparable between SPM patients according to pathway and age. Patients >74 years in the TNE pathway who received lenalidomide maintenance and developed an SPM did not receive greater doses of trial drug in comparison to those <74 years.
Fine and Gray.
Total dose of lenalidomide maintenance received was not available for one patient in the TE pathway.
Total dose of lenalidomide maintenance received was not available for one patient ⩽74 years in the TNE pathway.