NEW YORK—Questions still remain about whether consolidation therapy and minimal residual disease (MRD) testing should be used for monitoring and treatment of multiple myeloma, according to experts who participated in a debate at the Great Debates & Updates in Hematologic Malignancies meeting here. The nearly 200 members of the audience heard Suzanne Lentzsch, MD, PhD, and Sagar Lonial, MD, discuss treatment strategies based on MRD test results and tackle the question of whether treatment should be stopped if sustained MRD-negativity is achieved, or whether it is more prudent to consider some consolidation therapy.
Suzanne Lentzsch: Yes
Lentzsch noted that there are multiple options to test for minimal residual disease, and the issue with the variety of tests is their sensitivity and reliability.
“This debate has similarities to whether cure equals aiming for MRD versus control equals acceptance of MRD-positivity. If you argue in favor of cure, you have to favor MRD. If you favor control, you have to accept MRD-positivity.”
She asked: “Why in contrast to the situation with all other cancers are we okay with partial remissions in myeloma?” Cure is possible in myeloma, but only with eradication of MRD. “The proof of principle has been shown by allotransplant trials. Autograft-allograft patients survive longer than double-autologous transplant patients,” she said.
Lentzsch emphasized the importance of good clinical response: “Newer myeloma drugs provide a better clinical response, and up to 100 percent partial responses. Clinical response to therapy impacts overall survival [OS] and progression-free survival [PFS]. Median PFS almost doubles for those with clinical responses.”
Why stop at complete response (CR), when myeloma is still responding, but not eradicated? she asked. Among patients achieving CR, flow cytometry and MRD-negativity have an impact on overall. Those who show sustained stringent CRs do better in the long run. A landmark, two-year analysis showed that sustained stringent complete responses to therapy do impacts overall survival, she said.
Myeloma genetics and MRD status also have an impact. Hyperdiploidy patients with certain transformations (11, 14 or 6, 14) survive longer than those with other transformations or deletions, she said.
A variety of studies show that MRD negativity improves PFS, and most show a benefit in OS. Lentzsch provided a summary of the most relevant studies based on multicolor flow cytometry (MFC) detection of MRD in multiple myeloma.
“It should be noted that albeit most of the published results were obtained by former and less sensitive MFC approaches, the persistence of MRD is consistently associated with a significantly shorter PFS and often OS, as compared with MRD-negative patients,” Lentzsch said.
Depth of response is related to time to tumor progression. “If we go for a PR, only deep remission is a precondition for achieving long-term remission. If we go for MRD-negativity, then consolidation reduces residual tumor burden,” she said, noting that polymerase chain reaction (PCR)-negativity increases in patients who receive two cycles of consolidation.
In summary, Lentzsch said: “For younger patients diagnosed with multiple myeloma who are transplant ineligible, with novel treatments, deeper responses can be achieved in more patients. Deeper responses mean better survival. MRD-negativity is the only way to achieve cure. “Why not aim for a cure and MRD-negativity? MRD-negativity needs to be achieved and maintained.”
The best method for MRD-negativity needs to be defined, but there are multiple options, she concluded.
Sagar Lonial: No
Lonial took a different tack in his talk and rephrased the question to “Does MRD status influence the use of consolidation therapy or duration of therapy?” His answer was an emphatic “No.”
He asked: “Should we use consolidation and MRD to define duration of therapy, or use the MRD test to determine who remains on MRD therapy? If we want to talk about curing myeloma, it is not okay to stop therapy at a certain point.”
Response matters in myeloma, Lonial emphasized: “CR predicts long-term outcome in immunofixation-negative young and elderly patients and in MRD-negative young patients. Depth of response correlates with OS. PFS also goes according to the quality of the response.”
But all CRs are not the same. “More patients in true CR achieve a molecular CR. We are able to identify a subset of patients with better long-term outcome.”
Lonial described the evolution of the definition of CR. “Initially, CR was defined as a 75 percent reduction in the M protein. European Society for Blood and Marrow Transplantation (EBMT) criteria moved this to elimination of detectable protein by serum protein electrophoresis and immunofixation. International Myeloma Working Group criteria moved this to EBMT plus normal free-light and negative standard flow. This is the so-called ‘stringent CR,’” he said. “Stringent CR gives a superior result than conventional CR.”
Getting to MRD also matters. Patients who achieve a molecular flow CR do better, but they are not cured. “Whether the patient achieves a CR, a stringent CR, or a molecular flow CR, it is not okay to not send the patient on to consolidation or to continue maintenance therapy,” he said.
Studies show that flow cytometry predicts outcomes post-autotransplant. “MPF is better, even among CR patients. The depth of response does not tell you it is okay to stop treatment. Patients continue to relapse five, six, or seven years out even after they achieve flow negativity. If the goal is a cure, you can't stop therapy.”
The best method to assess MRD is next-generation sequencing. “Next-generation sequencing identifies patients who do better, but it is still not yet sufficiently powerful enough to say stop therapy or whether a patient does not need consolidation,” he said.
Myeloma patients relapse even after positron emission tomography (PET) scans. “PET scans tell us better or worse outcome, but, again, do not tell us whether we can stop therapy,” Lonial said. Studies of the impact of post-autologous stem cell transplantation (ASCT) PET/CT negativity on clinical outcomes show complete FDG suppression at PET/CT after ASCT leads to longer PFS and OS. “PET/CT is a reliable technique for predicting long-term outcomes,” he said.
Lonial noted that the impact on survival of achieving an immunophenotypic response after high-dose chemoradiotherapy followed by ASCT is independent of the induction regimen.
He described the outcome of myeloma patients in molecular response after therapy with bortezomib, thalidomide, and dexamethasone. “After consolidation, the CR rate is 50 percent and the metabolic clearance rate is 25 percent. The duration of CR more than six years is around 50 percent, with a five-year CR duration of 50 percent and 10-year CR duration around 30 percent.”
MRD can be used to stratify the CR population into two groups, with strikingly different prognosis, Lonial continued. “Higher levels of sensitivity translate into improved prediction of time to tumor progression. The tumor level is like a dose-response curve.”
Summing up, he said: “Despite new methods, whether MRD is assessed by flow cytometry, PCR, or next-generation sequencing, we do not see plateaus in the survival curves, so stopping therapy may not make sense. Consolidation therapy, even in the context of MRD-negative disease, may continue to offer benefit. We cannot use current methodology to determine duration or intensity of therapy.”
Before the debate, more than three-quarters of the audience members voted in favor of using consolidation and MRD testing to monitor treatment. But Lonial's argument persuaded about one-quarter of them to change their votes to No.
In the question-and-answer session, a participant asked about the value of MRD-negativity in high-risk myeloma patients. “The difficulty in high-risk myeloma is that these patients achieve CR about as often as standard-risk patients, but the duration of response is not as good,” Lonial said, noting that there is not as much MRD-negativity in high-risk patients.
Lentzsch added that patients with MRD-negativity have better outcomes—perhaps because their disease is more sensitive to treatment. “Patients with adverse prognostic markers do poorly,” she said.
Another participant asked what should clinicians do if MRD-negativity does not predict when to stop therapy? “This is a subjective decision,” said Lonial. “I continue therapy unless it becomes too toxic.” Lentzsch said. “MRD-negativity is not ready for prime time. We haven't agreed on a test method yet. It is not useful to guide treatment right now.” She added that low activity on a PET/CT scan “may not be helpful either.”
Lonial noted that his center uses both MFC and PET/CT scans.