NEW YORK CITY—Second primary malignancies are a known risk of treatment of multiple myeloma, and studies in the literature point the finger at certain anticancer agents. But recent research supports a hypothesis that some patients with hematologic diseases may be predisposed to second malignancies.
There is evidence that the risk of second malignancy may be related not only to therapy but also to host or disease biology, said Ola Landgren, MD, PhD, Senior Investigator in the Multiple Myeloma Section of the National Cancer Institute, speaking here at the Lymphoma & Myeloma International Congress on Hematologic Malignancies.
Concerns about second malignancies and myeloma are not new, he noted, but three clinical trials suggesting that lenalidomide might increase the risk of second primary malignancies renewed that concern, particularly for patients undergoing maintenance treatment. Research is also showing that having a plasma cell disease itself increases the risk, he said, and there may be an additive effect from therapy.
Landgren said that in a study he and colleagues conducted analyzing a large Swedish database of myeloma patients and patients with monoclonal gammopathy of undetermined significance (MGUS) (Blood 2011;118:4086-4092), the incidence of acute myeloid leukemia and myelodysplastic syndrome increased in both myeloma and MCUS patients compared with that in the general population.
“IgG/IgA MGUS patients had an increased risk of AML/MDS, but IgM MGUS patients did not, and the greatest risk was among MGUS patients with M-protein concentrations greater than 1.5 g/dL,” he said. “This doesn't prove there is a relationship, but it highly suggests there is some disease-related underlying risk, because none of these patients had received therapy.”
And ongoing research at the NCI is finding evidence of myeloid abnormalities at baseline in patients with smoldering myeloma in the absence of exposure to therapy, pointing to some kind of precursor MDS, he said.
Discuss Risk with Patients
“For the group of patients where these second cancers happen, it is devastating,” Landgren said. “The good thing is, it is very unlikely to happen.”
He said clinicians should tell patients the facts—that there are plusses and minuses, that treating with lenalidomide has been found in three trials to prolong the time before the disease gets active again, but that unfortunately, there is an increased risk for second malignancy—“The tradeoff has to be discussed with the patient.”
The three randomized myeloma studies suggesting a link between lenalidomide and second malignancy were presented at the 2010 American Society of Hematology Annual Meeting. The European IFM 2005-02 study by Attal and colleagues—subsequently published earlier this year in the New England Journal of Medicine (2012;366:1782-1791) showed that lenalidomide maintenance after stem-cell transplantation significantly prolonged progression-free and event-free survival compared with placebo.
But the incidence of second primary hematologic cancers was 4.2 percent in the lenalidomide group versus 1.7 percent in the placebo group, and the incidence of patients with at least one second primary cancer was 8.5 vs. 3.6 percent, respectively.
In the second study, the CALGB 100104 trial by McCarthy et al (NEJM 2012;366:1770-1781) studied lenalidomide maintenance therapy after stem-cell transplantation. The treatment group had significantly longer time to progression and significantly increased overall survival, but treatment was associated with a rate of second primary hematologic cancers of 3.5 vs. 0.4 percent for placebo.
And in the MM-015 trial by Palumbo and colleagues (NEJM 2012;366:1759-1769), progression-free survival more than doubled for patients with newly diagnosed myeloma ineligible for transplantation who received lenalidomide maintenance. But the three-year rate of invasive second primary tumors was seven percent in the two lenalidomide-treated groups vs. three percent without lenalidomide.
Still, meeting co-chair Ruben Niesvizky, MD, Director of the Multiple Myeloma Service at New York Presbyterian Hospital-Weill Cornell Medical Center, said he thought concern about second malignancies and lenalidomide is being overstated.
“I think the culprit is genotoxic therapy such as melphalan, doxorubicin, etoposide, and cisplatin—all those drugs cause leukemia and secondary cancers,” he said in an interview. “The deleterious effect of lenalidomide and the development of secondary malignancies have not been seen in individuals who take just lenalidomide.”
Similarly, meeting chair Morton Coleman, MD, Clinical Professor of Medicine and Director of the Center for Lymphoma and Myeloma at New York Presbyterian Hospital-Weill Cornell Medical Center, said he believes that in some patients a predisposition for myeloproliferative diseases could be fueled by alkylating agents.
“Some myeloma patients have some element of myelodysplasia, and if you give an alkylator with Revlimid [lenalidomide] you just uncover more of that predisposition,” he said in an interview. In those second malignancies, use of lenalidomide is usually in combination with or following the use of alkylating agents—“It looks like it's not just Revlimid, but rather Revlimid with an alkylating agent.”
He said his institution has a study with BiRD (biaxin-Revlimid-dexamethasone), which does not use alkylating agents—“And we haven't seen a preponderance of second malignancies, with the exception perhaps of some skin malignancies.”
Even so, things need to be kept in perspective, he said: Regardless of whether Revlimid is or is not used, the incidence of second malignancies does not have a major impact on overall survival. “Everything is a risk-vs-benefits ratio. If you can make a compelling case for using maintenance Revlimid, I think you might get more hematologic malignancies, but it really doesn't matter in terms of the overall survival of the patients.”
On the other hand, he said, a case might be made for using another agent such as bortezomib instead of lenalidomide in patients who have had alkylators.