Advances in Hematologic Malignancies
Issue 10, Spring 2019
— Mark Bustoros, MD, and Irene Ghobrial, MD
Multiple myeloma (MM) is an incurable plasma cell neoplasm and the second most common adult hematologic malignancy, with 30,000 estimated new cases and 12,000 estimated deaths in 2016. MM is always preceded by two precursor
asymptomatic states known as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM).
One of the main concepts of cancer prevention and interception is to identify high-risk individuals and asymptomatic patients and then provide different approaches to prevent progression to overt malignancy.
MGUS is present in 3 percent and 5 percent of the U.S. Caucasian population aged 50 and 70 years, respectively, and could progress into MM at a rate of 1.5 percent per year. The incidence or prevalence of SMM is unknown, but it carries a higher chance
of progression into MM, reaching around 10 percent per year. Some patients rapidly progress from SMM to MM, while others remain indolent without progression over their lifetime. Unfortunately, our current understanding of the mechanism and the
biological factors that lead to disease progression remains incomplete.
In the past, clinical risk scores for assessing the risk of progression in SMM patients have been proposed, including Mayo Clinic and the Spanish (PETHEMA) risk models[5, 6]. These models have their advantages and limitations, warranting the development
of new precise risk models to address the unmet needs in SMM. Moreover, with the progress in the field of genome sequencing, a model that includes genomic biomarkers is needed to identify different molecular and biological subgroups in this heterogeneous
We previously presented, for the first time, data on the mutational profile of SMM patients, where we observed that mutations in KRAS or NRAS genes, as well as translocations or copy number alterations in MYC oncogene, are significant
risk factors and associated with a shorter time to progression to symptomatic myeloma. Similar results were also reported by later studies from other groups[8, 9]. These findings illustrate the importance of including genomic biomarkers that reflect
the biology of SMM in the new models, and not just biomarkers that measure tumor burden.
Early intervention in high-risk SMM began with a randomized clinical trial from the Spanish myeloma group on observation vs. treatment with Revlimid and Dexamethasone (RD). Results showed a superior PFS and OS in the treatment arm after a median follow
up of 75 months. Progression to multiple myeloma occurred in 86 percent vs. 39 percent of patients in the observation and treatment groups, respectively. Although the trial outcomes were not endorsed here in the U.S., we started a phase II trial
of Elotuzumab-RD (ERD) in high-risk SMM, followed by another phase II trial with Ixazomib-RD (IRD). The final data of the ERD trial was presented at ASH 2018, showing a 36 months PFS of 95 percent, where none of the patients clinically progressed
to symptomatic MM. Moreover, results of the interim analysis of 29 patients in the IRD trial showed deep response in patients who had at least 4 cycles of therapy, where 56 percent of the patients achieved complete or very good partial response
(CR and VGPR).
Other important ongoing initiatives and research domains in MM are the PROMISE and PCROWD studies. PROMISE study is the first
screening study in the U.S. for high-risk individuals who are of African American descent or any individual with a family history of MGUS, SMM, or MM. PCROWD is a nationwide tissue banking study for patients with MGUS and SMM diagnosis, in order to
help in understanding the mechanism of progression over time.
The field of precursor conditions of MM and other blood cancers is continuing to evolve, and studies in that field are essential for identifying high-risk patients who could benefit from therapeutic intervention to ultimately improve MM future outcomes.