Patients with multiple myeloma and CHIP often have worse outcomes following autologous stem cell transplant, study finds

• Overall survival and progression-free survival following transplant tends to be shorter than in patients without CHIP
• Use of immunomodulatory therapy following transplant is linked to longer disease response and survival regardless of CHIP status

Patients who have both multiple myeloma and clonal hematopoiesis of indeterminate potential (CHIP) – a symptomless condition associated with poor outcomes in other hematologic cancers – tend not to survive as long after a transplant with their own stem cells than patients with myeloma who don’t have CHIP, a new study by Dana-Farber Cancer Institute investigators shows.

The study, published online today by Nature Communications, also found that, regardless of their CHIP status, patients with myeloma who are treated with immunomodulatory drugs (thalidomide and lenalidomide) post-transplant are likely to live longer, and have more time before the disease worsens, than those who don’t receive such drugs.

“Our findings indicate that the presence of CHIP at the time of transplant is a risk factor for faster disease progression in patients with multiple myeloma undergoing autologous stem cell transplant,” said study first author Tarek H. Mouhieddine, MD, of Dana-Farber and the Broad Institute of MIT and Harvard. “This might suggest that patients should be screened for CHIP in advance of a transplant, but our data also show that immunomodulatory therapy after a transplant is safe regardless of CHIP status.”

Multiple myeloma, a cancer of plasma cells in the bone marrow, is usually treated in newly diagnosed patients with drugs known as protease inhibitors and immunomodulatory drugs followed by high-dose chemotherapy and an autologous stem cell transplant. Unless otherwise contraindicated, most patients continue to receive immunomodulatory drugs as maintenance therapy until the disease worsens.

CHIP is one of several recently identified precursor conditions for hematological cancers. It is diagnosed in people whose blood is found to contain certain genetic mutations but who are otherwise healthy. Those with CHIP have a 0.5-1% risk of developing a non-plasma cell hematologic malignancy such as acute myeloid leukemia and myelodysplastic syndrome and are at heightened risk for cardiovascular disease and stroke.

For the new study, researchers sequenced the DNA of stem cells collected for transplant in 629 patients with multiple myeloma. They found that 136 of them had CHIP.

In tracking the patients, investigators found that those with CHIP lived a median of 5.3 years after transplant, significantly less than the 7.5 years for those without CHIP. Patients with CHIP also had a shorter progression-free survival, the period before the disease worsens.

As expected, the researchers found that patients who received immunomodulatory maintenance therapy had a longer median survival – 8.5 years – than those not receiving such therapy – 5.6 years. However, among patients who didn’t receive this type of maintenance therapy, those with CHIP had a significantly shorter median survival of 3.6 years versus 6.6 years in those without CHIP mutations.

Encouragingly, the researchers found that myeloma patients with CHIP who undergo a transplant were not at an elevated risk for myeloid cancers that can develop years later as a result of the therapies used to treat myeloma.

The senior author of the study is Irene M. Ghobrial, MD, of Dana-Farber and the Broad Institute.  Co-authors are Adam S. Sperling, MD, PhD, Robert Redd, MS, Christopher J. Gibson, MD, Marzia Capelletti, PhD, Daisy Huynh, Kalvis Hornburg, Henry Dumke, Cody J. Boehner, Chia-Jen Liu, MD, PhD, Saud H. Al Dubayan, MD, Brendan Reardon, Eliezer M. Van Allen, MD, Chip Stewart, PhD, Robert L. Schlossman, MD, Nikhil C. Munshi, MD, Kenneth C. Anderson, MD, David P. Steensma, MD, Jacob P. Laubach, MD, MPP, Paul G. Richardson, MD, Jerome Ritz, MD, Robert J. Soiffer, MD, and Donna S. Neuberg ScD, of Dana-Farber; Jihye Park, PhD, Mark Bustoros, MD, Romanos Sklavenitis-Pistofidis, MD, Sabrin Tahri, MD, and Benjamin L. Ebert, MD, PhD, of Dana-Farber and the Broad Institute; Salomon Manier, MD, PhD, of Dana-Farber and the University of Lille, Lille France; Amin H. Nassar, MD, of Dana-Farber and Brigham and Women’s Hospital; Lorenzo Trippa, PhD, of Dana-Farber and Harvard T.H. Chan School of Public Health; Matthew Leventhal, of the Broad Institute; Muhieddine M. Itani, MD, of Massachusetts General Hospital; Jonathan J. Keats, PhD, of Translational Genomics Research Institute, Phoenix, Ariz.; Shaadi Mehr, and Daniel Auclair, PhD, of the Multiple Myeloma Research Foundation; and Gad Getz, PhD, of Massachusetts General Hospital and the Broad Institute.

The research was supported by grants from the Multiple Myeloma Research Foundation, Adelson Medical Research Foundation, Stand Up to Cancer, and the Leukemia and Lymphoma Society.