Introduction: Lenalidomide (LEN) is structurally similar to thalidomide and induces high response rates in multiple myeloma (MM). Recently several randomized trials (IFM 2005-02, CALGB 100104) have shown that LEN maintenance given after autologous stem cell transplant (ASCT) in newly diagnosed MM patients resulted in significant prolongation of the progression-free survival. Unfortunately in both trials an increased rate of second cancers with a high concern for the development of MDS/AML was observed. Therefore the goal of this study was to evaluate the bone marrow and corresponding cytogenetic data of patients treated with LEN alone or in combination for early signs of MDS.
Methods: To investigate the role of ASCT and alkylators such as bendamustine in combination with LEN in the development of MDS we evaluated
- newly diagnosed MM patients treated with LEN and dexamethasone alone (LD alone) (n=14)
- pre treatment, after 6-9 cycles, at follow up
- newly diagnosed MM patients treated with LEN and dexamethasone followed by ASCT (LD+ASCT) (n=18)
- pre treatment, after 3-4 cycles, 3 months after ASCT, at follow up
- relapsed MM patients treated with LEN, bendamustine and dexamethasone (BLD) (n=8)
- pre treatment, at the end of treatment after median 6 cycles (4-8 cycles), at follow up
We evaluated 110 bone marrow specimens (aspirate smears and biopsy) and the corresponding peripheral blood films and cytogenetic studies, including classical and myeloma-related FISH studies, in 40 MM patients. Review of morphology and cytogenetic studies were performed independently of each other.
Results: In the LD alone arm, 5 out of 14 (36%) patients showed mild, non-specific erythropoietic and megakaryopoietic dyspoiesis pre-treatment. Those changes were also found in 6 of 14 (43%) and 4 of 6 (67%) of patients after 6-9 cycles and at further follow up (median follow up 14 months; range 12-28.5), respectively. One patient developed MDS 13 months after start of treatment that was characterized by frank megakaryocytic dysplasia, ring sideroblasts and an abnormal clone 46,XX,t(4;11)(q31;p15)/46,XX. This patient had no karyotypic abnormalities related to MDS prior to treatment.
In patients treated with LEN for 4 cycles followed by ASCT (LD+ASCT), 1 of 16 patients (6%) showed mild megakaryocytic dyspoiesis pretreatment. Mild megakaryocytic dyspoiesis was present in 2 of 17 (12%) and 3 of 16 (19%) patients after 4 cycles of LEN and at 3 months post ASCT, respectively. At further follow up in 8 patients (median 12.5 months, range: 10-22), dysmegakaryopoietic signs were no longer detected. Only one patient was found to have a potentially significant clonal cytogenetic abnormality post LD+ASCT that could not be attributed to myeloma – 46,XY,t(2;17)(p23;q11.2)/46,XY. The t(2;17) persisted in the subsequent bone marrow evaluation, but was no longer present in the next evaluation.
In relapsed and heavily pretreated MM patients (median 3 prior treatments; range 2-9) receiving BLD, 5 of 7 patients (71%) showed mild non-specific dyspoiesis prior to treatment involving either erythroid, megakaryocytic or granulocytic lineages. Mild non-specific erythropoietic and/or megakaryopoietic dyspoiesis was found in 7 of 8 (88%) and 2 of 4 (50%) of patients at end of treatment and at further follow up (median 14.5 months; range 12-23), respectively.
Overall, frank morphologic dysplasia was not detected in any patient except the one (from LD alone) who developed MDS.
Conclusion: In summary the careful longitudinal reevaluation of 110 bone marrow samples and corresponding cytogenetic studies treated with LEN alone, in combination with ASCT or bendamustine did not show increased signs of early or overt MDS. It is of note that many MM patients showed mild dyspoiesis even before treatment. The development of MDS in one patient (2.5%) suggests that longer follow up is needed for all patients. To our knowledge this is the first study that re-evaluated longitudinal bone marrow samples for early signs of MDS before clinical symptoms are overt.