Early intervention for high-risk smoldering multiple myeloma (HR-SMM) has been shown to achieve deeper and more prolonged responses compared to newly diagnosed multiple myeloma (NDMM).¹ However, clinical risk stratification models used to identify high-risk patients change over time, leading to heterogeneity in the inclusion criteria and disease biology.¹ It is thus unclear whether the favorable outcomes of interventional studies for HR-SMM are due to the treatment of less aggressive diseases or inaccuracy in the clinical definition of HR-SMM.¹

To better contextualize the results of SMM intervention trials, genome profiling of treated HR-SMM patients from two parallel intervention studies was performed to compare against the genomes of NDMM patients.¹ In the ASH Annual Meeting & Exposition 2023, Dr. Benjamin Diamond from the Sylvester Comprehensive Cancer Center, University of Miami, Florida, United States, presented findings from the comparison.¹

Whole genome sequencing (WGS) analysis was performed in a phase II trial where HR-SMM patients were treated with carfilzomib, lenalidomide, and dexamethasone (KRd) and subsequently maintained on lenalidomide only (/R) (n=27), which was compared with the WGS of NDMM patients treated with KRd with or without daratumumab (±D) (n=60).¹ Whole exome sequencing (WES) was performed in the E-PRISM trial where HR-SMM patients had been treated with elotuzumab and lenalidomide with or without dexamethasone (n=27), which was compared with the WES of NDMM patients from the CoMMpass trial (n=701).¹

It was noted that the two groups of HR-SMM patients had heterogeneous characteristics due to the wide variety of clinical risk criteria, resulting in different mutational signature profiles.¹ One of the major differences between the HR-SMM and NDMM cohorts was the level of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) activity.¹ High frequency (82%-85%) of APOBEC presence was previously reported among patients with progressive precursor conditions.¹ In the WGS analysis, the APOBEC mutational signature contribution was significantly lower (p=0.001) in the KRd/R-treated HR-SMM cohort (44%) at almost half of the APOBEC mutational signature contribution in the KRd±D-treated NDMM cohort (87%).¹ Similarly, the WES analysis revealed that the E-PRISM HR-SMM cohort also had a lower APOBEC mutational signature contribution by two-thirds compared to the CoMMpass NDMM cohort (15% vs 45%; p<0.001).¹ The low APOBEC mutational signature contribution observed in these HR-SMM cohorts suggests that these patients may have had less aggressive disease and were less likely to progress to active disease.¹

Genomic features including structural variants, mutational signatures, copy number variants (CNVs), and single nucleotide variants (SNVs) were also investigated in the study.¹ Looking at a combination of 139 driver gene mutations and CNVs at driver loci, HR-SMM patients had less complex genomic features compared to NDMM patients.¹ In particular, HR-SMM patients showed more gain or amplification of chromosome 1q, MYC amplification, RAS pathway mutations, inactivation of tumor suppressor genes, and APOBEC activity compared to NDMM patients.¹ When HR-SMM and NDMM patients were pooled and grouped according to prognostic outcomes and sustained minimal residual disease (MRD) negativity, HR-SMM patients with fewer genomic features had more similar outcomes as NDMM patients who had lower risk, while HR-SMM patients with more genomic features were more similar to NDMM patients with higher-risk.¹

Additionally, the researchers identified genomic alterations associated with clinical or biochemical disease progression and sustained MRD negativity in the KRd/R-treated HR-SMM cohort.¹ Genomic lesions like chromosome 1q gain or amplification, inactivation of HIST1H2BK and MAX, 13q14.2 deletion, t(4;14) translocation, APOBEC alterations, and chromothripsis were associated with poorer outcomes.¹ Having 2 or more of these genomic features was significantly associated with progression of disease (p=0.034).¹

In summary, HR-SMM patients treated in two parallel triplet intervention studies were heterogeneous based on their clinical risk scores.¹ Compared to NDMM patients, HR-SMM patients are less genomically complex and have genomic profiles similar to benign precursor conditions or indolent MM.¹ However, patients with complex genomic features may have relatively poor outcomes despite triplet intervention.¹ These results thus support the use of genomics to better identify SMM patients at high risk of progression who may benefit the most from early intervention, given the heterogeneity and flux of clinical risk scores.¹