NEW YORK—With increased depth of response from current myeloma therapies, there is an increasing pattern of increased overall survival, said Ajai Chari, MD, Associate Professor of Medicine and Director of Clinical Research of the Multiple Myeloma Program at Mount Sinai Medical Center. “Even in this era of novel therapeutics, the quality of response correlates with progression-free survival. We need to move past current criteria for complete response (CR).”
Chari argued why autologous stem cell transplant (ASCT) is needed for patients with multiple myeloma during a debate here at the Lymphoma & Myeloma 2015: International Congress on Hematologic Malignancies. Tomar Mark, MD, MSc, Assistant Professor of Medicine in the Division of Hematology/Oncology at New York-Presbyterian Weill-Cornell Medical College in New York, took the opposing side of the argument.
“We have such good therapy upfront, we may be able to go from induction to maintenance to achieve minimal residual disease (MRD)-negativity. Should we transplant patients who achieve CR or MRD-negative status? No. Must we use transplant as a means to get people into CR or MRD negative status? No,” Mark said.
Yes, Transplant Is Needed for CR and MRD
A meta-analysis of the impact of MRD status on survival outcomes in patients who achieve CR found that MRD-negativity reduced the hazard ratio of progressive disease by 56 percent. “The majority of MRD-positive patients progressed by six years, whereas nearly half of MRD-negative patients remained progression-free,” Chari said, during the debate.
For overall survival post-ASCT, MRD-negative status reduced the hazard of death by 53 percent.
In MRD-negative patients, the five-year overall survival was 78 percent and median overall survival was not reached, as compared to 60 percent overall survival and a median 82 months overall survival in MRD-positive patients.
The best overall survival was seen in patients with favorable cytogenetics and MRD-negativity, Chari said, adding that in a multivariate analysis, “there was not enough to justify looking at Fluorescence in situ Hybridization (FISH) as a surrogate for MRD.”
A Phase II study examined extended carfilzomib-lenalidomide-dexamethasone therapy plus ASCT in newly diagnosed patients with multiple myeloma. With deferred ASCT, this regimen “has shown excellent responses in newly diagnosed multiple myeloma with unprecedented stringent CR of 55 percent and also three-year disease control rate of 79 percent.” On the other hand, 45 percent of patients do not achieve stringent CR and 21 percent relapsed in three years, he noted.
This success led to an extended carfilzomib-lenalidomide-dexamethasone plus ASCT study that looked at the role of transplant after four cycles of induction using this combination in 62 patients. That study demonstrated that depth of response matters and increases with transplant plus therapy, he said.
With ASCT, the stringent CR rate was 22 percent and MRD-negativity was 60 percent. With consolidation, those rates improved to 71 percent for stringent CR and 85 percent for MRD-negativity. At the end of carfilzomib-lenalidomide-dexamethasone therapy, the stringent CR was 87 percent and all patients achieved MRD-negativity. “This small study provides initial insight into the role of transplant. Stringent CR is not a cure,” he said.
Chari added that these unanswered questions remain: Who should be tested for MRD? What is the specificity of MRD testing? What is the role of MRD with the integration of gene expression profiling?
“The best MRD test is yet to be determined,” he said. “There are questions about molecular assays of peripheral blood and in PET/MRI negative patients given the limitations of a single bone marrow sample.The impact of the new era of myeloma therapies is still unknown.”
Among outstanding issues are the significance of a monoclonal antibody-associated CR and the role of interference assays. Chari said he hoped that personalized medicine would see the use of MRD to guide treatment intensity.
“Response depth by conventional criteria correlates with overall survival post-ASCT. Unprecedented depth with novel agent combinations requires improved measures of response depth,” he noted. And, r even patients who achieve stringent CRs with highly active carfilzomib-lenalidomide-dexamethasone therapy still relapse.
“MRD-negativity post-ASCT correlates with progression-free survival and overall survival. ASCT plus consolidation with carfilzomib-lenalidomide-dexamethasone resulted in the biggest improvements in stringent CR and MRD negativity,” Chari said. “As the data now stand, transplant is still a necessity to achieve stringent CR and MRD negativity.”
Transplant is a Tool,Not a Necessity
“Myeloma is not curable. The role of maintenance is to deepen response,” Mark said arguing the opposing side of the debate.
Mark agreed there was no debate that MRD status is important because it can lead to a survival benefit. “People in CR do better if they achieve MRD-negativity. This leads to longer progression-free survival,” he said.
He said he wondered why stem cell transplant is still recommended for patients in CR: “Stem cell transplant has an overall survival benefit. The caveat is that this data is old; very few patients (5-10 percent) achieve CR. Does remission deepen for CR? Patients who upgrade their response do better with transplant,” Mark said.
Stem cell transplant deepens treatment response, but he wondered whether a remission deeper than CR matters for transplant. “Patients who achieve CR before transplant do not get this benefit after transplant. The impact of response to induction to achieve CR is pre-transplant, not CR post-transplant,” he said.
“Do you need a transplant if you achieve CR with induction therapy?” he asked. One study took a retrospective look at 758 consecutive patients at MD Anderson Cancer Center undergoing induction followed by ASCT within one year of diagnosis. The landmark analysis based on response at two years after start of therapy found patients who upgraded their response with ASCT obtained a survival benefit. Patients with a CR prior to ASCT did not achieve a longer overall survival, he noted.
“Do we need transplant to get patients into CR or MRD-negativity?” Mark asked. “It is now possible to achieve CR and MRD-negativity with chemotherapy alone in an increasing fraction of people. This has proven to be possible with BiRd (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) and carfilzomib-lenalidomide-dexamethasone—and certainly will become more the norm.”
He suggested that for a patient with CR prior to transplant, “there is no reason to consolidate with high-dose melphalan.”
With BiRD therapy, response deepens over time outside of transplant. “A good deal of patients who achieve CR also achieve MRD-negativity without transplant,” he said, adding that for BiRD therapy and carfilzomib combinations maintaining MRD-negativity is the key to prolonged responses.
In conclusion, Mark said: “CR and MRD-negativity is the goal for all patients. Increasingly more patients can reach MRD-negativity status without the use of ASCT. Achievement of CR prior to transplant gives an equal outcome to CR post-transplant.” He noted that transplant studies with MRD detection may strengthen or disprove this conclusion.
“Continuing induction chemotherapy may be all some people need,” said Mark. “I agree that some patients need to get to transplant to achieve CR or MRD-negativity, but the choice is not a necessity. Transplant is a tool, not a destination.”
During the Q&A at the end of the debate, Antonio Palumbo, MD, of the University of Torino in Torino, Italy, suggested that fit myeloma patients should go to transplant. “Transplant always increases CR and MRD-negativity. Today, we don't have a tool to clearly overcome the need for transplant to increase CR,” he said.
“We have to use risk-adapted therapy,” Chari added. “First, you need to clear up MRD deficiency.”
Palumbo also noted that “when you have a resistant patient, the best thing to do is to switch therapy.” Melphalan plus transplant is one potential switch, he said.
And Mark added: “In the community, a patient with very good partial response to initial therapy is a perfect patient to send to transplant.”
In general, “high-risk myeloma patients are not well-served,” Chari said. “Primarily, it's low- and intermediate-risk patients who are served. Transplant itself is not enough to overcome high-risk disease. We need to do better in these patients.”
An audience survey before and after the debate showed that Mark made a convincing argument. Beforehand, nearly half (48 percent) of the audience believed transplant was a necessity to achieve CR or MRD-negativity; afterward, nearly half (43 percent) no longer thought so.