Patients with Smoldering Multiple Myeloma (SMM) are currently followed until clinical progression to Multiple Myeloma (MM). Two randomized Phase III clinical trials have shown that early therapeutic intervention in patients with high-risk SMM can prolong progression-free survival (PFS) and in one instance overall survival (OS). Identifying patients at high risk of progression is needed for prompt therapeutic intervention.
A new study led by Drs. Getz (Massachusetts General Hospital) and Ghobrial (Dana-Farber Cancer Institute) and published in the Cancer Cell journal, explores the use of single-cell RNA-sequencing on bone marrow and peripheral blood samples from patients with high-risk Smoldering Multiple Myeloma (SMM) to examine changes at diagnosis and post-therapy. Findings of this study were also presented at the 19th International Myeloma Society Annual Meeting.
“We demonstrated that the similarity of a patient’s bone marrow immune cell composition to that of age-matched healthy individuals can be harnessed for prognostication, as patients whose immune microenvironment is the least similar tended to have longer progression-free survival (PFS). Based on this observation, we hypothesized that at least some of the changes in immune cell composition we observe in patient bone marrow may simply reflect the immune system’s reactivity against the tumor. We found that cytotoxic T cells from such individuals were more likely to be part of expanded T cell clones and exhibited an expression profile consistent with senescence and exhaustion, demonstrating that this subgroup of individuals may be more likely to show signs of antigen experience and chronic antigen stimulation” says first author of the study, Dr Romanos Sklavenitis-Pistofidis.
“Furthermore, we observed that on average, the similarity of a patient’s bone marrow immune cell composition to that of healthy individuals increased at the end of treatment, suggesting that immunotherapy may indeed lead to normalization of the immune microenvironment. We termed this state post-therapy immune normalization (PIN) and showed that patients who achieved it had significantly longer PFS. If validated in larger randomized trials with different regimens and different patient populations, PIN may enable further risk stratification of patients at the minimal residual disease (MRD) state and ultimately help identify patients who may experience longer PFS and individuals who may need protracted maintenance therapy.”, Dr Sklavenitis-Pistofidis adds.
Lastly, they showed that peripheral blood immune cell composition mirrored that of the bone marrow so well that a classifier trained to identify the presence of myeloma based on bone marrow immune cell composition alone was able to correctly classify nearly all peripheral blood samples. These results suggest that key immune biomarkers may be measurable in peripheral blood, which may enable regular immune profiling in patients with SMM and thus, the development of improved risk stratification models.
Dr Sklavenitis-Pistofidis is currently an Instructor in Medicine in the Department of Medical Oncology at DFCI, HMS, and the Broad. His research focus is to determine genetic and immunological causes of disease progression from premalignant states, such as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma or Waldenstrom’s Macroglobulinemia, to full-blown malignancy, with the goal of developing novel clinical-grade assays to improve risk stratification and patient outcome.