Do patients with smoldering multiple myeloma require treatment?
That is the question that researchers are hoping to answer in an ongoing randomized phase 3 trial, which is looking at Revlimid (lenalidomide) compared with observation in patients with asymptomatic high-risk smoldering multiple myeloma (NCT01169337).
If the answer is yes, it would represent a fundamental paradigm shift in how oncologists approach the disease, Madhav Dhodapkar, principal investigator of the Yale University cohort of the trial and clinical research program leader in the Hematology Program at Yale Cancer Center, said in an interview with CURE.
“A portion of patients with smoldering myeloma do progress to clinical myeloma, which requires significantly more therapy,” said Dhodapkar. “It is very important for us to know if using Revlimid early on will actually prevent progression to clinical myeloma, and actually lead to improved outcomes. If it does, it will change the standard of care.”
The study is taking place at 588 locations throughout the United States, Ireland and Puerto Rico with an estimated enrollment of 224 patients. In the experimental arm, patients will receive Revlimid daily for 21 days with a repeat course every 28 days in the absence of disease progression or unacceptable toxicity.
Patients in the control arm will be observed until progression to clinical myeloma. Primary endpoints of the study include progression-free survival (PFS) over a period of up to 10 years and incidence of grade 3 or higher toxicities.
The diagnosis of asymptomatic high-risk smoldering multiple myeloma must be confirmed by a bone marrow plasmacytosis that shows at least 10 percent plasma cells or sheets of plasma cells at any time before initiating study treatment. The test must include marrow obtained by aspiration or biopsy within four weeks prior to randomization.
This confirms the diagnosis of smoldering myeloma, which is critical to the accuracy of the study, Sagar Lonial, the principal investigator of the overall trial, said in an interview with CURE.
The International Myeloma Working group updated the criteria for the diagnosis of multiple myeloma in October 2015, moving numerous patients who were previously defined as having smoldering myeloma into the clinical myeloma category.
None of the patients in this trial were part of the group that was reclassified to clinical myeloma in 2015; however, it is possible that some patients who have demonstrated response to treatment in past studies were misdiagnosed as having smoldering myeloma when they actually had clinical myeloma, said Lonial, who is professor and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine, and chief medical officer at Winship Cancer Institute.
“In our trial, I am not concerned about a misclassification, because we’ve performed bone surveys and MRIs on every patient and that allows us to really tease this issue out,” he said. “However, there have been trials, including a Spanish trial conducted three years ago, where this may have been an issue.”
The trial in question was a randomized phase 3 trial, published in 2013, which investigated Revlimid and dexamethasone versus observation in 119 patients then defined as having high-risk smoldering myeloma.
After a median follow-up of 40 months, the median time to progression was not yet reached in the treatment group compared with 21 months in the observation group. The three-year survival rate was also higher in the treatment group, at 94 percent versus 80 percent.
Because of the changes in the definition of smoldering myeloma, these results may not be accurate, said Lonial.
“In that analysis, there was a very early difference in overall survival (OS) and I think a lot of that difference was that there are probably some patients who didn’t fit into smoldering category. Since they were just observed and not treated, they didn’t do very well,” he said. “I think what we are eventually going to end up doing is not treating smoldering myeloma, but actually moving patients who may require earlier treatment into the myeloma category.”
It is possible that patients who are at intermediate or high risk for progression to clinical myeloma should be treated earlier. However, prior to the conclusion of his trial, there are no data to currently suggest that, said Lonial.
The trial is still accruing; therefore, oncologists are encouraged to enroll eligible patients. Around 50 to 60 patients still need to be enrolled. The longest a patient at this time has been on Revlimid within the trial is 3.5 years.
Questions still remain to be answered regarding whether or not smoldering myeloma patients should be treated. It will take more trials to fully answer that question, said Lonial.
“What we are really trying to understand is why there are patients who received Revlimid and did really well, but also patients in the observation arm who did better than we would have predicted,” said Lonial. “Even if we really tease out those who need treatment and we treat them, PFS or remission may not be the right endpoint. We really need to start looking at OS in the long-term, and we will need a bigger study for that.”