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Lenalidomide-Associated Risk for SPMs Appear Isolated to MM

January 26, 2023

February 2023

Leah Lawrence

Leah Lawrence is a freelance health writer and editor based in Delaware.

Second primary malignancies (SPMs) detected while on lenalidomide treatment seem to occur only in patients with multiple myeloma (MM), according to a literature review and meta-analysis published in Lancet Haematology.

Lenalidomide has changed the landscape of MM treatment, and patients diagnosed with the disease are living longer with its use, according to study researcher Konstantinos Lontos, MD, of the University of Texas MD Anderson Cancer Center in Houston. As overall survival (OS) for any malignancy increases, so does the risk of treatment-associated SPMs.

“Lenalidomide use has historically been associated with increased risk of SPM, but most of these studies have been in [MM],” Dr. Lontos said. “As the indications for lenalidomide are expanding to diseases other than myeloma, it is important to look at the risk of lenalidomide-induced SPM across all disease types.”

To do that, Dr. Lontos and colleagues conducted a literature review and meta-analysis of randomized controlled trials that reported SPMs in patients treated with lenalidomide. Trials had at least one patient group treated with lenalidomide and one non-lenalidomide group, and included studies had a follow-up of at least 12 months. Thirty-eight studies met these criteria for a total of 14,058 patients. Eighteen studies were in patients with MM.

Looking at all included malignancies, the risk ratio (RR) for SPM with lenalidomide use was 1.16 (95% CI 0.96-1.39). Risk for SPM varied across disease type. The RR for trials of patients with MM was 1.42 (1.09-1.84). There was an increase in both hematologic and solid tumor SPM, and this increase was seen in patients regardless of transplantation status.

In contrast, there was no increased risk for SPM in patients with lymphoma or chronic lymphocytic leukemia (RR=0.90; 95% CI 0.76-1.08) or in those with myelodysplastic syndromes (RR=0.96; 95% CI 0.23-3.97).

Dr. Lontos said the researchers were unsure why the increased risk of SPM was isolated to patients with MM. Some hypotheses include modulation of the lenalidomide effect by myeloma drugs such as melphalan and genetic polymorphisms that increase the probability of developing myeloma but at the same time influence the lenalidomide effect.

“We also know that malignancies can affect the body in a systemic way and not just in their microenvironment,” Dr. Lontos said. “Myeloma could be systemically preparing the ground for lenalidomide to exert its pro-tumorigenic effect. Finally, we should always consider the chance that this result is purely due to bias because physicians are more likely to look for SPM in myeloma than lymphoma … because of prior literature.”

Of the 38 trials, about half (55%) had low risk for bias, a third (32%) had unclear risk of bias, and only 13% had high risk for bias.

The results are also limited by the fact that reporting of SPM was inconsistent in the included studies. Additionally, the researchers looked at published reporting of SPMs and did not obtain patient-level data. Finally, Dr. Lontos and colleagues acknowledged that “death is a competing event with the development of SPM,” meaning that “the [OS] benefit seen in multiple studies in the lenalidomide treatment group could have confounded the risk of developing SPM.”

Despite these potential limitations, Dr. Lontos said the results of the analysis could be significant for several reasons. The results should reassure clinicians using lenalidomide for other indications, but they should also inform physicians treating patients with MM that SPM can be increased even in the non-transplant setting.

In addition, the results educate the community that lenalidomide can increase solid tumor incidence and not only hematologic malignancies, and they set a precedent for each drug’s effect to be investigated in a specific disease context.

Any conflicts of interest declared by the authors can be found in the original article.


Saleem K, Franz J, Klem ML, et al. Second primary malignancies in patients with haema-tological cancers treated with lenalidomide: a systematic review and meta-analysis. Lancet Haematol. 2022;9(12):E906-E918.


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