New Analysis of Somatic Alterations Identifies Low-Risk Multiple Myeloma Subgroup

Mehmet Kemal Samur, PhD

A new study has identified genomic factors that appear to correlate with a better risk profile and better progression-free survival (PFS) among patients with multiple myeloma (MM). The findings, though preliminary, could someday lead to better patient empowerment and stratification.¹

Corresponding author Mehmet Kemal Samur, PhD, of Harvard Medical School and the Dana-Farber Cancer Institute, and colleagues, noted in the report published in the Journal of Clinical Oncology that despite major advances in the treatment of MM, the cancer remains incurable. However, he and his colleagues said that genomic characterization of the disease using wholegenome sequencing (WGS) or targeted sequencing in large numbers of patients with MM has created the potential to better understand somatic mutations as well as their functions.

“WGS has now made it possible to interrogate causal processes underlying genomic heterogeneity in newly diagnosed MM,” Samur and colleagues wrote. “This heterogeneity in MM, as in other cancers, reflects changes in cellular pathways in the MM clone, as well as the tumor microenvironment, which promote MM cell growth and drug resistance, as well as overcoming immune surveillance.”

In their study, Samur and colleagues analyzed deep WGS data from theIFM/DFCI 2009study published in 2017.²The new analysis centered on 183 patients who were newly diagnosed with MM and were treated with one of 2 therapeutic combinations: lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD), or RVD along with autologous stem cell transplant (RVD+ASCT). The investigators used clinical data alongside the genetic analysis in hopes of finding links to patient prognosis.

The analysis showed that MM subgroups experience significantly different mutational load and processes. By examining the timeline of when mutational processes are activated, the investigators were able to identify 2 distinct models of acquisition of the mutational changes identified upon diagnosis, Samur and colleagues wrote.

“Virtually all MM subgroups have activated DNA repair–associated signature as a prominent late mutational process, whereas APOBEC signature targeting C>G is activated in the intermediate phase of disease progression in high-risk MM,” they wrote.

One subgroup was genomically identified that had low DNA damage (defined as a low genomic scar score [GSS; ≤5] with chromosome 9 gain). Those patients, which comprised 17% of the total study population, had a 100% estimated survival rate at 69 months (log-rank P <.0001). The superior outcome of patients with low GSS and chromosome 9 gain was validated in an independent data set of 577 patients who showed a 5-year survival probability rate of 93% (log-rank P <.0001).

“This subgroup allowed us to distinguish patients with low- and high-risk hyperdiploid MM and identify patients with prolongation of progression-free survival,” they wrote. “Genomic characteristics of this subgroup included lower mutational load with significant contribution from age-related mutations as well as frequent NRAS mutation.”

Samur told Targeted Oncology that the finding was in line with earlier research, including a study by the International Myeloma Working Group, which found that 15% of patients achieve very-long-term remission.³

“Our observation in our data was 17%, and this was in line with previous observational studies,” he said. “With all the new therapeutic options becoming available to patients with multiple myeloma and new research that has been and will be done, we hope that that fraction of patients with multiple myeloma who do well will increase.”

Samur and colleagues said the subgroup’s superior results were independent of International Staging System stage and minimal residual disease status.

“Importantly, our study shows that, in addition to traditional risk markers, we can use genomic markers such as low GSS and gain9 to identify true low-risk groups,” Samur and colleagues wrote. They added that while hyperdiploidy has traditionally been seen as a marker of superior outcomes, only 31% of patients with hyperdiploid multiple myeloma fell into their “good-risk” group, suggesting that low GSS is an important component of risk category.

Though the broader study had 2 treatment arms, Samur and colleagues said the overall survival of patients in their subgroups was not significantly impacted by whether they received RVD or RVD+ASCT. PFS was not statistically significantly different in the subgroups, with the exception of the “good-risk” subgroup. In that subgroup, RVD+ASCT led to superior PFS (P <.006), the same result as was found in the overall 2009 study.

Samur said the sample size in his group’s analysis was too small to be the basis of clinical decisions, however. He said larger follow-up studies would be needed.

In the meantime, Samur said he hopes to provide broad access to the classifications to better inform and empower patients.

“Although this won’t affect the treatment options and plan any time soon, it would give caregivers additional information about their patient’s genome and risk status, as well as it may also help reduce the stress patients would have to handle if they are in the low-risk group,” he said.

_References:

_{1. Samur MK, Aktas Samur A, Fulciniti M, et al. Genome-Wide Somatic Alterations in Multiple Myeloma Reveal a Superior Outcome Group. J Clin Oncol. Published online July 20, 2020. doi:10.1200/JCO.20.00461}

_{2. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750}

_{3. Usmani SZ, Hoering A, Cavo M, et al. Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project. Blood Cancer J. 2018;8(12):123. doi:10.1038/s41408-018-0155-7}