Myeloma XI Trial – Second Primary Malignancy Interim Report in Newly Diagnosed Multiple Myeloma (NDMM) Patients

Background: Past studies have linked lenalidomide to an increased risk of second primary malignancy (SPM) and in-particular a higher incidence of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Such studies in which oral melphalan was used in combination with lenalidomide resulted in haematological SPM incidence of between 3.0-11.4% at 5 years. More recently, meta-analysis has suggested that lenalidomide in combination with other agents such as cyclophosphamide and dexamethasone does not result in an increased rate of SPM development. Here we report the incidence of SPM in Myeloma XI, the largest randomised trial to date in-which lenalidomide is used as both an induction and maintenance treatment option.

Methods: Myeloma XI is a phase III, randomised, multi-centre, parallel group design, open-label trial comparing thalidomide, lenalidomide and bortezomib combinations and lenalidomide as maintenance treatment in newly diagnosed symptomatic myeloma patients.

The trial has both transplant eligible (TE) and transplant non-eligible (TNE) pathways. NDMM patients are entered into the TE pathway if they are deemed fit/young enough to tolerate high dose therapy. Those who enter the TNE pathway receive attenuated doses of chemotherapy agents. Patients in the TE pathway will receive high dose melphalan supported by autologous stem cell transplantation if they achieve a very good partial response or better following induction or, if appropriate following pre-transplant consolidation. Pre-transplant consolidation with bortezomib is protocol treatment for patients with refractory disease or no change post-induction whereas for patients with a sub-optimal response (MR/PR) randomisation to bortezomib versus observation alone is compared. Both pathways include maintenance with lenalidomide, lenalidomide and vorinostat or monitoring only.

Since May 2010, 2745 patients have been recruited with over 950 patients enrolled for more than 2 years since initial induction randomisation. A total of 1225 patients have entered maintenance with 720 receiving lenalidomide maintenance either as a single agent or in combination with vorinostat.

Results: Thirty three patients (1.2% of entrants) have developed a second primary malignancy since enrolment. One patient developed a haematological SPM (CML) whilst on the trial (0.04%). This occurred in a patient being treated on the TE pathway who had received lenalidomide containing induction and had undergone 24 months of lenalidomide maintenance. The remaining 32 SPM cases were solid or non-invasive skin cancers with an incidence of 1.16%. Cumulative incidence of all SPMs is 0.53%,1.00% and 1.70% at one, two and three years respectively. Median overall time to SPM development from induction is 15.4 months (range 1.6 – 38.4).

Approximately half the patients who developed an SPM (54.5%, n=18) received lenalidomide induction therapy with a median time to SPM development of 10.2 months (2.1 – 26.5) in the TE group (n=8) and 19.9 months (1.6 - 37.6) in the TNE group (n=10). Fifteen patients (45.5%) received thalidomide induction with a median time to SPM development in the TE group (n=2) of 10.1 months (7.7-12.4) and 21.3 months (3.7 – 38.4) in the TNE group (n=13).

Over two thirds of SPM patients (70%) were being treated on the TNE pathway. The average age at the time of SPM development was 76.7 and 65.9 for the TNE and TE pathways respectively. The majority of SPMs were observed during maintenance (52%, n=17) with 94% (n=16) of these patients receiving lenalidomide. Of the remaining patients, 27% developed an SPM during induction (n=9), 12% (n=4) following bortezomib and 9% (n=3) following induction but prior to maintenance randomisation.

Conclusions: The Myeloma XI trial has so far reported very low overall SPM incidence. Concerns of an increased incidence of haematological malignancy in earlier trials containing lenalidomide in combination with oral melphalan have not been reproduced here. The findings support recent meta-analysis that suggests lenalidomide in combination with cyclophosphamide or dexamethasone is not associated with an increased haematological SPM risk. It is however noted that the majority of patients who developed an SPM during maintenance were on lenalidomide and thus this will need to be monitored closely as the trial continues.

On behalf of the NCRI Haemato-oncology subgroup