Groundbreaking research presented at the International Myeloma Society 21st Annual Meeting has shed new light on the progression and treatment of multiple myeloma (MM) precursor conditions, offering hope for earlier intervention and better patient outcomes.
Understanding Disease Progression Through Genomics
Scientists have made significant strides in understanding the genomic evolution of multiple myeloma and its precursor conditions. "The genome of [MM] is actually very old. By the time we have overt [MM], it's [been accumulating mutations] for 30 years," explained Dr. Irene Ghobrial from Harvard Medical School's Dana-Farber Cancer Institute. This insight has revealed that while MM shows 30 years of genomic development, MGUS (Monoclonal Gammopathy of Undetermined Significance) represents about 15 years of genomic evolution.
Risk Progression and Population Impact
MGUS, characterized by the presence of monoclonal proteins in blood, shows a consistent 1% annual risk of progression to MM. In contrast, Smoldering Multiple Myeloma (SMM) carries a more significant 10% annual risk of progression to MM, particularly in the first five years after diagnosis. The phase 2 iStopMM study revealed that SMM affects approximately 0.5% of the general population over 40 years old, with 3,725 cases identified among 80,000 participants.
Advances in Risk Stratification
Recent developments in whole genome sequencing of circulating tumor cells have identified crucial genetic markers, including translocations and structural variants in both MGUS and SMM. These findings have led to the development of a "myeloma-like" genomic model that effectively differentiates between high- and low-risk SMM patients.
Treatment Breakthroughs for SMM
While MGUS typically requires monitoring rather than treatment, emerging evidence supports early intervention for high-risk SMM patients. The PETHEMA study, led by Dr. María-Victoria Mateos, demonstrated remarkable results using lenalidomide and dexamethasone (ReDex) in high-risk SMM patients, showing:
- 82% reduction in end organ damage risk
- 70% decrease in mortality risk
- Similar efficacy with lenalidomide monotherapy
Future Directions and Ongoing Research
Multiple clinical trials are currently investigating immunotherapy approaches for high-risk SMM, including:
- The phase 3 Aquila trial
- The Ithaca study
- The DETER-SMM trial
These studies aim to develop potential curative approaches and improve progression-free survival rates.
Role of Immune System in Disease Progression
Dr. Madhav Dhodapkar from Emory University's Winship Cancer Institute highlighted the immune system's crucial role in disease progression: "Patients with [MM] make more cytokines, particularly inflammatory cytokines compared to the MGUS counterparts." This understanding has led to the development of an "immune age calculator" that may help improve risk stratification and disease progression predictions.
Clinical Implications and Recommendations
Experts now recommend continued observation for intermediate or low-risk disease patients while advocating for early intervention in high-risk patients using regimens such as lenalidomide or ReDex for 1-2 years post-diagnosis. The 2/20/20 risk stratification model has emerged as a valuable tool for identifying high-risk patients with a 50% two-year progression risk.
