Molecular Profiles Differ Between High-risk Smoldering Myeloma, Newly Diagnosed Multiple Myeloma

CHICAGO — A proportion of patients, at least, with high-risk smoldering myeloma have different molecular profiles compared with patients with newly diagnosed multiple myeloma, results from a study presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting showed.¹

Smoldering myeloma is a poorly defined precursor state to multiple myeloma; however, recent treatment studies targeting patients with smoldering myeloma have been conducted and have demonstrated promising clinical outcomes, including a prospective clinical trial evaluating carfilzomib plus lenalidomide and dexamethasone (CRd). In that study, results showed that 62% of patients with newly diagnosed multiple myeloma achieved a near complete response or better² and 94% of the 17 patients with smoldering myeloma had stringent complete responses.

In contrast, there is little information available on the biology of smoldering myeloma. Therefore, researchers sought to conduct whole exome sequencing and RNA sequencing of plasma cells from the participants of the CRd trial to provide novel insights on tumor cell biology. Sequencing was performed in 39 patients with newly diagnosed multiple myeloma and in 17 patients with high-risk smoldering myeloma.

Among patients with newly diagnosed multiple myeloma,  the researchers found a median of 53 mutations per patients vs 52 among those with smoldering myeloma.

“The median number of somatic mutations was similar in newly diagnosed multiple myeloma and high-risk smoldering myeloma patients,” said lead investigator Sham Mailankody, MBBS, medical oncologist and hematologist at Memorial Sloan Kettering Cancer Center in New York, NY.

Researchers also observed previously reported recurrently mutated genes in patients with multiple myeloma (BRAF, DIS3, FAM46C, IDH1, INTS12, IRF4, KRAS, NRAS, PRDM1, TP53, TRAF3, CYLD, RB1, ACTG1, LTB, HIST1H1E and MAX) in 44% of those with newly diagnosed disease; however, only 2 non-synonymous mutations were detected among these genes in 1 patient with high-risk smoldering myeloma (P=.005).

When analyzing the mutational landscape by treatment response among patients with multiple myeloma, investigators found that 32% of the 22 patients who obtained a complete response and 59% of the 17 patients who did not obtain a complete response had recurrently mutated genes.

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“Mutational profile was associated with depth of treatment response in newly diagnosed patients,” Dr Mailankody explained. “Importantly, high-risk smoldering myeloma patients lack significantly recurrent myeloma mutations, which is suggestive of treatment responsive disease biology in high-risk smoldering myeloma.”

These findings could ultimately impact risk determination and timing of therapy initiation among patients with high-risk smoldering myeloma.

“Our results support clinical studies focusing on early treatment initiation in high-risk smoldering myeloma patients,” Dr Mailankody concluded.        

Reference

1. Mailankody S, Korde N, Roschewski MJ, et al. Genetic plasma cell signatures in high-risk smoldering myeloma versus multiple myeloma patients. .J Clin Oncol. 2016; 34 (suppl; abstr 8003).
2. Korde N, Roschewski M, Zingone A, et al. Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 2015;1(6):746-754. doi:10.1001/jamaoncol.2015.2010.