Genetic Abnormalities in Smoldering Myeloma Could Indicate Higher Risk of Disease Progression

Patients with smoldering myeloma whose disease harbors select genetic abnormalities may be an indicator that they could be at a higher risk for developing multiple myeloma, according to results of a study published in the Journal of Clinical Oncology.¹

Specifically, results showed that patients with smoldering multiple myeloma who had select MAPK pathway mutations, MYC amplifications or translocations, or TP53 mutations or deletions were more likely to advance to multiple myeloma.

“We found that the genomic alterations with smoldering multiple myeloma are essentially the same as full-fledged myeloma,” co-lead study author Romanos Sklavenitis-Pistofidis, MD, a postdoctoral fellow at Dana-Farber Cancer Institute, stated in a press release.² “This suggests that by the time smoldering multiple myeloma is diagnosed, most of the molecular abnormalities found in myeloma have already occurred.”

Modern prognostic models are not known to accurately predict disease progression for patients with smoldering myeloma, the investigators noted in the study, since those initially determined to be of low- or intermediate-risk still experience disease progression. Therefore, stronger prognostic markers should be identified to determine at-risk patients who are in need of treatment earlier in their disease course to prevent progression.

“As a group, patients with smoldering myeloma have a 10% annual risk of developing myeloma, but it’s difficult to determine which are at the greatest risk, so our goal was to understand the heterogeneity within [smoldering myeloma] and explore which genetic alterations could predict the high-risk group,” said lead study author Mark W. Bustoros, MD, an instructor of Dana-Farber Cancer Institute, in the press release.

In the analysis, researchers utilized next-generation sequencing to analyze 214 bone marrow samples from patients with smoldering multiple myeloma. The median age was 62 years (range, 34-85) and were stratified based on risk of disease progression (low-, intermediate-, and high-). Those who experienced multiple myeloma symptoms at diagnosis, such as hypercalcemia, renal impairment, anemia, or bone lytic lesions, were excluded from the analysis.

Two types of sequencing were utilized during the analysis, including whole-exome sequencing (WES) on 72 matched tumor-normal samples and targeted deep sequencing on 48 samples. WES was also used to analyze an additional 94 tumor-only samples.2 The median follow-up time was 6.2 years.

Findings revealed that 36% of patients (n = 76) harbored IgH translocations, which is ordinarily seen in multiple myeloma. More commonly present in the patient population, however, were somatic copy number alterations (SCNAs), in 88% of patients (n = 189).

Additionally, the median mutation density observed in patients with smoldering multiple myeloma was 1.4 mutations/megabase, while 55% of samples (118) had single nucleotide variants (SNVs) in genes, which is another common abnormality in multiple myeloma. Among those 118 patients, 46% experienced alterations in MAPK pathways (KRAS, NRAS, BRAF, and PTPN11), while 10% of patients (n = 21) experienced alterations to DNA repair pathways (17p deletion, TP53, and ATM SNVs). Additionally, among the subjects analyzed, SNVs were found to be present in genes of nuclear factor-kB (22%), protein processing (21%), and cell cycle pathways (6.7%).

To further define genomic biomarkers of disease progression, the researchers identified a subset of patients (n = 85) who did not receive treatment prior to multiple myeloma progression. The median time to progression (TTP) was 3.9 years. Results showed that 62% of patients (n = 53) had progressive disease and 38% (n = 32) were asymptomatic.

Between the observed genomic abnormalities, patients with MYC aberrations (translocations or amplifications) were noted as having the smallest median TTP (8.4 vs 51.6 months; P<.001). Those with MAPK pathway mutations had the second lowest TTP (14.4 vs 60 months; P<.001), followed by patients with DNA repair pathway alterations (15.6 vs 50.4 months; P = .004). While both MAPK pathway mutations and MYC alterations corresponded with higher bone marrow infiltration at diagnosis (P = .001 vs. P<.001), MAPK mutations were the only abnormality that showed significant correlation with M-protein levels (P<.001).

From analyzing these data, researchers created a predictive genomic model by assessing which independent risk factors impacted the progression of smoldering multiple myeloma to multiple myeloma. These included MYC gene aberrations, MAPK (KRAS, NRAS, SNVs) alterations, and DNA repair pathway alterations.

Next, researchers created an external validation cohort of 72 patients with smoldering multiple myeloma. Of this cohort, all of whom had their tumor DNA previously sequenced, 47 patients progressed to multiple myeloma at a median TTP of 5 years. The findings from this external cohort corroborated the study's overall data, as patients with any of the aforementioned genomic alterations (n = 47) were found to have a higher risk of progression at 2.5 years vs 10 years (P = .001).

Additional findings showed that the the majority of mutations could be linked to aging signatures, along with an equal contribution of adenosine-induced deaminase and catalytic polypeptide-like signatures.

Based on these findings, the investigators concluded that using genomic sequencing on tumors after a patient is diagnosed with smoldering multiple myeloma stands as an improved strategy for identifying a patient's risk of progression, as well as opening the avenue of early treatment.

“Ideally, our biological model could be combined with the traditional clinical models to get the best indication of a patient’s risk of progression,” the authors concluded in the press release. “Patients identified as being high-risk could then be closely monitored for signs of advancing disease or participate in clinical trials of agents that aim to slow or stop progression.”

References

1. Genomic test accurately identifies patients with smoldering multiple myeloma at high risk of developing myeloma, study finds. News Release. Dana-Farber Cancer Institute. June 9, 2020. Accessed June 10, 2020. https://bit.ly/2ZWkeRz
2. Bustoros M, Sklavenitis-Pistofidis R, Park J, et al. Genomic profiling of smoldering multiple myeloma identifies patients at a high risk of disease progression [published online ahead of print May 22, 2020]. J Clin Oncol. doi:10.1200/JCO.20.00437