Sagar Lonial, MD
Five years from now multiple myeloma will have a therapeutic backbone consisting entirely of combinations of novel agents, a leading myeloma researcher predicted.
The combinations will involve immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies. Stem-cell transplantation will retain a role in treatment of myeloma, but its role in the era of monoclonal antibodies will likely be a topic of multiple clinical trials.
“We will sequence patient samples after two to four cycles of therapy in order to understand the specifics of the remaining clone and how to target it,” Sagar Lonial, MD, chief medical officer at Winship Cancer Institute of Emory University said in a presentation at the 2015 Society of Hematologic Oncology annual meeting.
“This will guide maintenance therapy. Once patients become MRD [minimal residual disease] negative, they will be randomized to continue or stop therapy based on their genetics at presentation.”
Current therapeutic approaches based on diagnostic tissue specimens may help guide treatment over the short term but may not reveal that clone that will be present at relapse, Lonial said. Recent studies have shown that myeloma is a disease consisting of both normal and malignant-cell biology, and treatment should target both types of biology.
“MRD, in and of itself, does not indicate cure, but is needed on the path to cure,” he said.
In the not-to-distant future, RNA sequencing will become standard diagnostic testing at the initial evaluation of a patient with myeloma, replacing both fluorescence in situ hybridization and gene expression profile. RNA sequencing at presentation may not be reflective of myeloma genetics at relapse, so reassessment will be required when the disease burden has decreased and will be helpful in guiding maintenance therapy, said Lonial.
Three classes of drugs will form the basis of initial treatment for all patients: immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies. On the basis of biomarker or mutation findings, some patients might receive other classes of therapy. Potential options might include histone deacetylase inhibitors; kinesin spindle protein inhibitors; Myc-targeted therapy; and agents targeting the apoptosis pathway, CRM, or Akt.
MRD assessment will continue to have a role in treatment decisions, but the impact of MRD status on the disease course will likely depend on genetic risk.
“High-risk multiple myeloma needs to get to MRD negative to improve outcomes,” said Lonial. “Standard-risk myeloma may be less important unless you’re striving for cure.”
MRD status has demonstrated the ability to stratify patients who achieve complete response into two groups who have strikingly different prognoses, he continued. Patients who achieve both complete response and MRD status have significantly better survival as compared with patients who have complete response but remain MRD positive (Blood
However, different degrees of MRD will further risk-stratify patients. Those patients with the deepest responses will have the best survival, but patients with different levels of MRD positivity will also differ in terms of survival, improving as MRD status moves closer to MRD negativity.
Tests that reliably predict response to treatment will become increasingly important in the management of myeloma. The need for ongoing evaluation makes simplicity a key characteristic for any test. Recently, investigators in a multicenter study reported that a potential blood test for evaluating patients’ MRD had shown promise in a preliminary clinical evaluation (Clin Lymphoma Myeloma Leuk
PET/CT imaging also has shown promise as a means of predicting long-term outcomes in myeloma. For example, complete FDG suppression on PET/CT after autologous stem cell transplantation has been associated with improved progression-free and overall survival (Blood
Making optimal use of new therapeutic options, sequencing technology, and testing capabilities will offer the best opportunity yet to achieve cure in multiple myeloma, said Lonial.