Gene Expression Studies Offer Insight Into Myeloma Regimen's Efficacy

Alessandra Di Bacco, PhD

An analysis of c-MYC expression in relapsed myeloma identified subgroups of patients with improved response to the combination of an immunomodulator and a proteasome inhibitor, according to data from a randomized trial presented during the 2016 ASH Annual Meeting.1

Patients in third or fourth relapse had improved progression-free survival (PFS) with a combination regimen of ixazomib (Ninlaro) and lenalidomide (Revlimid), as did patients who relapsed after 1 prior regimen and did not undergo autologous stem cell transplant. All 3 groups of patients had high expression of c-MYC.

In contrast, patients who received 1 prior regimen and then relapsed after stem cell transplant had low c-MYC expression and did not derive the same benefit from the ixazomib/lenalidomide combination.

The explanation for the disparity in response and PFS remains unclear but appears to involve increased cellular differentiation possibly influenced by treatment history, lead author Alessandra Di Bacco, PhD said.

“Ixazomib/lenalidomide provides benefits in both high and low c-MYC subgroups, although the benefit is more pronounced in patients with high c-MYC—expressing tumors,” said Di Bacco, an associate director at Millennium Pharmaceuticals in Cambridge, Massachusetts. “The expression of c-MYC does not explain the PFS effects observed in posttransplant relapsed tumors, suggesting the presence of additional factors influencing their behavior.”

The findings came from an exploratory gene-expression study involving bone marrow aspirate samples from participants in the TOURMALINE-MM1 randomized trial.2 The trial involved 722 patients with relapsed, refractory, or relapsed/refractory myeloma and a treatment history that included 1 to 3 prior systemic regimens.

The patients were randomized to lenalidomide paired with either ixazomib or placebo. The primary endpoint was PFS, and the efficacy analysis showed significant prolongation of PFS in patients treated with ixazomib (20.6 vs 14.7 median PFS).

Bone marrow specimens were available for 419 (58%) of the patients. Investigators focused on c-MYC expression because of its role in cellular processes that include proliferation, differentiation, and protein synthesis.

“In multiple myeloma, MYC expression is related to poor prognosis, and it plays a role in the transformation from monoclonal gammopathy of uncertain significance to myeloma,” said Di Bacco. “Published data have previously suggested a link between MYC levels and sensitivity to proteasome inhibitors.”

Investigators evaluated the impact of c-MYC expression on PFS, using median expression for the study population as the cutoff to define high and low levels of expression. They also examined c-MYC expression by treatment history.

Overall, c-MYC expression did not significantly affect PFS (P =.98). However, investigators found a significant impact of treatment among patients with high c-MYC (P =.024). In the subgroup of patients with high expression, patients randomized to ixazomib had significantly better PFS, associated with a 59% reduction in the hazard for progression or death (95% CI, 0.26-0.65; P =.00011).

Continuing their analysis, investigators found higher c-MYC expression in patients who had received 2 or 3 prior therapies versus those who had received a single prior systemic regimen (P =.011). Patients with 1 prior therapy had a median PFS of 20.6 months with ixazomib and 16.6 months with placebo, a nonsignificant difference (HR, 0.88; 95% CI, 0.65-1.20).

Among patients in third or fourth relapse, median PFS was not reached in the subgroup that received lenalidomide plus ixazomib compared with 12.9 months for patients treated with lenalidomide and placebo (HR, 0.58; 95% CI, 0.40-0.84; P = .0033). Additionally, the more treatment-experienced patients derived a PFS benefit from the addition of ixazomib regardless of c-MYC expression level. However, the difference from placebo achieved statistical significance only in the subgroup of patients with high c-MYC expression (HR, 0.36; 95% CI, 0.18-0.72; P =.00269).

Investigators separated patients with 1 prior systemic regimen according to transplant status. A subsequent analysis showed that patients who did not undergo stem cell transplant derived a PFS benefit if they had high c-MYC expression (P =.0146) but not with low expression. In contrast, patients who had 1 prior systemic regimen and then relapsed after a stem cell transplant did not benefit from ixazomib, regardless of c-MYC expression. In general, patients who underwent stem cell transplant had lower levels of c-MYC expression.

In an effort to explain the transplant-related disparity, Di Bacco pointed to evidence identifying CD19 and CD81 as markers of B-cell differentiation. Three patterns of expression in myeloma provide an extent of differentiation: CD19+/CD81+, less differentiation; CD19-/CD81+, intermediate; CD19-/CD81-, increased differentiation.

Analysis of bone marrow from TOURMALINE-MM1 participants showed that myeloma relapse after stem cell transplant was associated with increased levels of CD19 or CD81, indication less differentiation.

Di Bacco said investigators have developed a working hypothesis that transplant alters the biology (CD19/CD81) of myeloma. Patients who relapse after 1 prior therapy and stem cell transplant have less-differentiated tumors. Additionally, relapse after 1 systemic regimen without stem cell transplant, or after 2 or 3 prior regimens, is associated with increased tumor differentiation.

“Immunodulatory drugs and proteasome inhibitors appear to target different clones, with lenalidomide preferentially targeting low c-MYC—expressing tumors and proteasome inhibitors targeting high c-MYC–expressing tumors and more differentiated tumors,” said Di Bacco. “This might explain, in part, their synergistic action and the increased benefit observed with ixazomib and lenalidomide.”

References

1. Di Bacco A, Bahlis NJ, Munshi NC, et al. Higher c-MYC expression is associated with ixazomib-lenalidomide-dexamethasone (IRd) progression-free survival (PFS) benefit versus placebo-Rd: biomarker analysis of the phase 3 tourmaline-MM1 study in relapsed/refractory multiple myeloma (RRMM). Presented at: 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 243.
2. Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Eng J Med. 2016;374:1621-1634.