Photo courtesy of NIH
Assessing certain genetic abnormalities and a patient’s International Staging System (ISS) stage can reveal patients with high-risk multiple myeloma (MM), according to research published in the Journal of Clinical Oncology.
Investigators said this method can identify a majority of newly diagnosed MM patients who will relapse or die prematurely.
The team began this work by performing whole-exome sequencing on the 463 patients enrolled in the Myeloma XI trial.
This revealed 15 genes that were significantly mutated—IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3.
The investigators noted that mutations in the RAS (43%) and NF-κB (17%) pathways were common but proved prognostically neutral.
On the other hand, mutations in CCND1 and DNA repair pathway alterations—TP53, ATM, ATR, and ZNFHX4 mutations—were associated with poor survival.
For example, 2-year overall survival (OS) was 38.1% in patients with CCND1 mutations and 80% in those without them (P=0.005). Likewise, 2-year OS was 50% in patients with ATM mutations and 80.3% in those without them (P=0.01).
Conversely, mutations in IRF4 and EGR1 were associated with superior survival. Two-year OS was 100% in patients with IRF4 mutations and 79% in those without them (P=0.05). And 2-year OS was 100% in patients with EGR1 mutations and 78% in those without them (P=0.04).
In a multivariable analysis, an ISS stage of III, TP53 variants, CCND1 mutations, ATM and ATR mutations, amp(1q), and MYC translocations were independently associated with OS.
An ISS stage of III, age older than 70 years, t(4;14), MYC translocations, TP53 variants, ATM and ATR mutations, and ZFHX4 mutations were independently associated with progression-free survival (PFS).
In an attempt to predict PFS and OS accurately in newly diagnosed MM patients, the investigators combined the genetic risk factors they identified—mutations and copy number and structural abnormalities (CNSAs)—with clinical information captured by the ISS.
This led to 3 prognostic groups. Patients in group 1 (low-risk) had ISS I/II and no mutations/CNSAs. Patients in group 2 (moderate-risk) had ISS III with no mutations/CNSAs or ISS I/II/III with 1 mutation/CNSA. And patients in group 3 (high-risk) had 2 mutations/CNSAs regardless of their ISS.
The investigators said classifying patients in this way can identify 83% of patients who will relapse prematurely and 92% of patients who will die prematurely.
“Our study has identified genetic features which can identify those patients whose myeloma is likely to prove aggressive and to progress quickly,” said study author Gareth Morgan, MD, PhD, of The Institute of Cancer Research, London in the UK.
“We hope our study ultimately paves the way for genetic testing to pick out the minority of patients with myeloma with a poor prognosis, who might benefit from the most intensive possible treatment.”
