Lenalidomide, Particularly When Combined With Oral Melphalan, Increases Risk of Second Primary Hematologic Malignancy in Myeloma Therapy


Key Points

  • Lenalidomide was associated with a higher risk of second hematologic primary malignancies, mainly reflecting increased risk when used in combination with melphalan.
  • No increased risk was associated with use of lenalidomide in combination with dexamethasone or cyclophosphamide. 

Lenalidomide (Revlimid) has been associated with risk for second primary malignancies in patients with myeloma. In a meta-analysis of individual patient data reported in The Lancet Oncology, Palumbo et al found that lenalidomide was associated with a significantly increased risk of second primary malignancies, reflecting an increased risk of second hematologic malignancies that was driven mainly by use of lenalidomide in combination with oral melphalan.

Study Details

The meta-analysis included data from seven phase III trials of lenalidomide treatment that recruited patients with newly diagnosed multiple myeloma between January 2000 and December 2012. Patient data, including age, sex, date of diagnosis, allocated treatment and received treatment, duration of treatment and cause of discontinuation, maintenance treatment, date of first relapse, date of second primary malignancy diagnosis, type of second primary malignancy, date of death or last contact, and cause of death, were obtained by direct collaboration with the principal investigators of the trials.

Of the 3,218 included patients who received treatment, 2,620 had received lenalidomide and 598 had not (all receiving melphalan-based regimens). A regression model of subdistribution hazards for clustered data was applied to assess the effect of lenalidomide on the cumulative incidence function of second primary malignancies, accounting for heterogeneity across studies. The multivariate analysis also adjusted for concomitant treatments, age, and sex.

Increased Risk of Hematologic Malignancy

The 5-year cumulative incidence of all second primary malignancies was 6.9% in the lenalidomide group vs 4.8% in the no lenalidomide group (hazard ratio [HR] = 1.55, P = .037). Whereas there was no significant difference between groups in cumulative 5-year incidences of solid second primary malignancies (3.8% vs 3.4%, HR = 1.1, P = .72), there was increased risk of hematologic second primary malignancies in the lenalidomide group (3.1% vs 1.4%, HR = 3.8, P = .029).

Increased Risk With Lenalidomide/Oral Melphalan

On multivariate analysis, compared with no lenalidomide (melphalan-based regimens), lenalidomide plus dexamethasone was associated with reduced risk of second solid malignancy (HR = 0.63, P = .016), with no significant differences in risk observed for lenalidomide in combination with intravenous melphalan, oral melphalan, or cyclophosphamide. Compared with no lenalidomide (melphalan-based regimens), lenalidomide plus oral melphalan was associated with a nearly fivefold increase in risk for second hematologic malignancy (HR = 4.86, P < .0001), with no significant differences in risk observed for lenalidomide in combination with dexamethasone, intravenous melphalan (HR = 2.21, P = .304), or cyclophosphamide.

The investigators concluded, “Patients with newly diagnosed myeloma who received lenalidomide had an increased risk of developing haematological second primary malignancies, driven mainly by treatment strategies that included a combination of lenalidomide and oral melphalan. These results suggest that alternatives, such as cyclophosphamide or alkylating-free combinations, should be considered instead of oral melphalan in combination with lenalidomide for myeloma.”

Antonio Palumbo, MD, of Azienda Ospedaliera Città della Salute e della Scienza di Torino, is the corresponding author for The Lancet Oncology article.

The study was funded by Celgene Corporation. For full disclosures of the study authors, visit

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