Lenalidomide (len) has been linked to an increased risk of second primary malignancy (SPM) and in-particular acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Haematological SPM (hSPM) incidence in patients receiving len is highest in those also exposed to oral melphalan, resulting in an apparent hSPM incidence of between 3.0-11.4% at 5 years. More recently, meta-analysis has suggested that when used in combination with other agents e.g. cyclophosphamide there is no increased rate of hSPM. Here we report SPM rates in Myeloma XI, the largest randomised trial to date in-which len is used as an induction and maintenance therapy.


Myeloma XI is a phase III, randomised, multi-centre, parallel group design, open-label trial comparing thalidomide (thal), len and bortezomib combinations and len as maintenance treatment in NDMM patients. The trial includes transplant eligible (TE) and transplant non-eligible (TNE) pathways. TE patients received high dose melphalan supported by autologous stem cell transplantation if they achieved a very good partial response or better. Patients in both pathways were randomised to maintenance with len (+/- vorinostat) or active observation. Since May 2010, 2745 patients have been recruited with over 1170 patients enrolled for more than 2 years. A total of 1367 patients have entered maintenance with 836 randomised to len (median 6 cycles (range 1-42)).


Following central committee review of 87 reported SPMs in 84 patients, 69 cases in 67 patients were confirmed (incidence rate (IR) 2.45%). The median time to SPM development from induction is 15.6 months (range 1.2 - 42.5). The cumulative incidence of all SPMs is 0.65% (95% CI 0.35, 0.97), 1.84% (1.26, 2.41) and 3.41% (2.49, 4.43) at one, two and three years respectively, Figure 1. Of SPM patients, 44 (65.7%) were treated on the TNE pathway (IR 3.6%) and 23 (34.3%) on the TE pathway (IR 1.5%). The average age at the time of SPM was 75.1 and 65.9 for the TNE and TE pathways respectively.

Thirty seven (56%) patients received len induction with a median time to SPM development of 11.7 months (1.2 - 25.3) in the TE group (n=15) and 18.2 months (3.4 - 30.8) in the TNE group (n=22). The remaining 30 patients (44%) received thal induction with a median time to SPM development in the TE group (n=8) of 31.3 months (6 - 43.1) and 12.6 months (3.4 - 38.4) in the TNE group (n=22).

Of the patients who developed an SPM 40 (59.7%) did so following maintenance randomisation. The incidence was highest in those receiving len based maintenance (n=34, IR 4.2%). In the observation arm 6 patients developed an SPM (IR 1.1%). The median time to SPM development from maintenance randomisation is 20.32 months in those receiving len and 15.61 months in the observation only group. 28 of the 40 SPM cases that occurred following maintenance were in the TNE pathway with 24 patients receiving len.The overall incidence of SPM development in TNE patients receiving len maintenance is 7.4%. In the TE patients 12 SPM cases developed following maintenance randomisation with 10 patients receiving len. The overall incidence of SPM in the TE patients treated with len maintenance is 2.0%. Of the remaining patients, 22 (32.9%) developed an SPM during induction and five (7.5%) following induction but prior to maintenance.

Eight patients developed a hSPM (IR 0.29%), MDS (n=4), AML (n=2), CML and Hodgkin's Lymphoma. Of these patients four received len induction and seven received len based maintenance. Median time to SPM development for hSPM was 18.2 months (5.9 - 42.5). The remaining 61 SPM cases (59 patients) were solid tumours or non-invasive skin cancers (IR 2.15%).


The overall incidence rates of SPM are low and an increased rate of hSPM was not seen. The highest SPM incidence was observed in patients receiving len maintenance enrolled to the TNE arm (n=24, IR 7.4%). Advanced age is likely to be a contributing factor but it may be related to treatment duration, which is longer in this group. It is also important to note that 37.5% (n=9) of these cases were non-invasive skin cancers. Committee review of all reported SPMs led to the rejection of 18 cases (20.7%). The commonest reason for rejection was because the malignancy pre-dated trial entry (n=12). We, therefore, recommend incorporating a review process for all trials where SPMs are considered to accurately assess the impact of treatment on SPM development and to prevent the false inflation of SPM figures.


Jones:Celgene: Other: Travel support, Research Funding. Off Label Use: Lenalidomide and vorinostat as maintenance therapy for myeloma. Pawlyn:Celgene: Honoraria, Other: Travel support; The Institute of Cancer Research: Employment. Kaiser:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; BristolMyerSquibb: Consultancy; Chugai: Consultancy; Janssen: Honoraria. Davies:Takeda-Milenium: Honoraria; Onyx-Amgen: Honoraria; University of Arkansas for Medical Sciences: Employment; Celgene: Honoraria. Gregory:Janssen: Honoraria; Celgene: Honoraria. Boyd:Celgene: Honoraria, Other: Travel; Janssen: Honoraria, Other: Travel. Owen:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Jackson:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Morgan:University of Arkansas for Medical Sciences: Employment; CancerNet: Honoraria; MMRF: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Weisman Institute: Honoraria.

Author notes


Asterisk with author names denotes non-ASH members.

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