Second Malignancies in Total Therapy 3 Trials for Newly Diagnosed Multiple Myeloma: Influence of Lenalidomide Versus Thalidomide in Maintenance Phases

Recent data from IFM, CALGB and GEMIMA trials suggest that utilizing lenalidomide as maintenance therapy is associated with a higher incidence of second cancers, including both hematologic and solid malignancies. Two successive Total Therapy 3 (TT3) trials, one employing as maintenance thalidomide (TT3A, n=303) and the other lenalidomide (TT3B, n=177), after tandem transplants offered the opportunity of investigating whether lenalidomide therapy was associated with greater probability of inducing second malignancies. Patients & Methods: The details of TT3A and TT3B trials and patient outcomes have been reported previously. Briefly, both employed identical induction therapy with 2 cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone plus 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide), followed by melphalan 200mg/m2-based tandem autologous transplantation and 2 cycles of dose-reduced VTD-PACE consolidation. Maintenance consisted of VTD in the first year and TD for years 2 and 3 in TT3A, while TT3B employed VRD for all 3 years. All patients had signed an informed consent in keeping with institutional and federal guidelines. For the purpose of this analysis, the MM data base was interrogated for the development of CA-2 arising after protocol initiation and after start of maintenance therapy in TT3 trials. This was based on frequently scheduled positron emission tomography (PET) scanning, performed at baseline and on average every 3 months in the first year and semi-annually thereafter. For the early detection of potential MDS or AML, all bone marrow examinations included metaphase karyotyping and, when indicated because of pathological or clinical suspicion, inter-phase fluorescence in situ hybridization (FISH) for the detection of MDS- and AML- associated abnormalities. Chi-square and Fisher's exact tests were used to compare baseline characteristics between protocols. Univariate and multivariate Cox proportional hazard regression were used to model associations between baseline covariates and onset of second malignancy. Furthermore, the Kaplan and Meier method was used to model cumulative incidence of second malignancy from the initiation of maintenance therapy. Results: TT3B patients had notably higher proportions of patients with ISS III disease and GEP70-high risk as compared to TT3A patients. There was an incidence of 16 new second primary cancers on TT3A over the entire period of observation with 7 solid tumors and 9 hematologic malignancies. We only observed 2 new second primaries on protocol TT3B (1 solid, 1 hematologic malignancy). There were no differences in cumulative incidence of hematologic CA2 or solid CA2 between the protocols from the initiation of maintenance therapy on the two TT3 trials (Figure 1). Cox regression analysis identified old age (> 66yrs) and high Kappa FLC levels (>168 mg/dl) as the only factors negatively associated with timing of onset of a second malignancy, when modeled from initiation of maintenance therapy. MDS associated cytogenetic abnormalities (MDS-CA) can occur as either transient or persistent anomalies on serial bone marrow analyses in post-transplant MM patients in absence of cytopenias or morphologic evidence of MDS, as previously reported. The 4-year incidence of MDS-CA in TT3B was significantly higher than TT3A. It remains to be seen whether such MDS-CAs progress to overt clinical MDS and therefore need to be followed prospectively. Conclusion: Our study has the great advantage containing large cohorts of patients who underwent treatment that only differed in the maintenance regimen. Furthermore we did not have to rely on multiple different methods of detecting incidental CA2 but rather obtained PET scans in regular intervals thus avoiding underreporting of CA2s. In terms of treatment our aproach can be best compared to the IFM 2005-02 and CALGB 100104 who both included HDT and HSCT. Overall we had a significant lower incidence of CA2 in the treatment arms than these comparable trials. Taken together, the data suggest that there are no discernable differences in CA-2 when combining different IMiDs with BZ/D as maintenance strategy. There is, however, a higher incidence of MDS karyotypic abnormalities, both transient and persistent, in patients who remain on the Bz/D/Len maintenance after having undergone autologous stem cell transplantation on TT3B.

Barlogie:Celgene, Genzyme, Novartis, Millennium: Consultancy, Honoraria, Patents & Royalties.