NEW YORK CITY—A renowned hematologist says he has tempered his goal of seeking a complete response (CR) in every patient with multiple myeloma.
“CR is not necessarily a surrogate for survival in multiple myeloma,” says Bart Barlogie, MD, PhD, Director of the Myeloma Institute for Research and Therapy and Professor at the University of Arkansas Medical Center.
In fact, patients with multiple myeloma who show no response to chemotherapy and stem cell transplant have longer overall survival than patients who achieve a complete response that is not sustained, he said in a presentation here at the Lymphoma & Myeloma meeting.
Dr. Barlogie spoke of “this obsession with CR I used to share, but no longer share across the board.” He said he held the earlier view of CR as he entered the myeloma field from the acute leukemia field, where there was virtually no complete remission—“and the first necessary step to get anywhere is truly complete remission.”
But “as we get older we may actually become more flexible,” he added candidly, to the appreciation of the audience.
In his presentation, “The Pursuit of Cure in Multiple Myeloma,” Dr. Barlogie compared the outcomes of the Total Therapy trials TT1, TT2, and TT3 to show that improvement in the CR rate does not translate into longer overall survival.
“Just the observation of CR by itself may not be that meaningful,” he said.
There are good reasons for using complete response as a surrogate for myeloma survival, Dr. Barlogie said. CR rates helped prove that the melphalan dose-response effect with peripheral blood stem cell transplant was effective, with CR rates of up to 50% and with longer overall survival. CR is also an independent favorable variable in multiple myeloma on multivariate analysis.
And CR has been critical for overall survival in the context of high risk as defined by gene expression profiling, as well as an important means of identifying new agents in end-stage multiple myeloma, such as thalidomide and bortezomib.
But there are caveats, he said. Patients can have low CR rates in multiple myeloma that evolves from smoldering disease and yet have superb overall survival. And adverse factors associated with overall survival, such as rapid regrowth, can still occur with high CR rates.
Dr. Barlogie also noted that the higher CR rate in the TT2 trial regimen that included thalidomide did not translate into longer CR duration or overall survival, whereas bortezomib as used in TT3 did not increase CR rates but it did extend CR duration and overall survival.
“As many of the new drug trials are focusing so strictly on early CR endpoints, this bothered me somewhat, so we looked for another surrogate and that was a sustained CR,” Dr. Barlogie said. The researchers used “sus-CR” status for patients in the TT2 trial who achieved a CR after treatment and who had not suffered a relapse by the time point of three years after initiation of treatment.
Five years later—after a total of eight years—patients categorized as sus-CR in that trial had a 90% survival rate.
The shortest survival outcome in that trial was in patients who achieved a CR but then relapsed within three years.
Paradoxically, intermediate survival rates were seen in patients who never achieved a complete response. “These are probably the ones who have more benign myeloma, coming out of a smoldering, accumulating disease rather than a proliferative disease.”
Dr. Barlogie said CR outcome cannot be predicted upfront yet, and he and colleague John D. Shaughnessy, Jr., PhD, Professor of Medicine at the University of Arkansas, are researching a gene-array profile that would identify de novo patients who might still be in CR at three years.
Dr. Barlogie said that based on TT1 data, he anticipates that multiple myeloma patients might achieve a 10-year continuous complete remission rate in TT3 above 50%. He anticipated that the 10-year survival rate would rise from 35% in TT1 to 45% in TT2, and to 60% in TT3.
And the anticipated 10-year continuous CR rates would increase from 25% in TT1 to 40% in TT2, and to 55% in TT3.
“In view of rare relapses beyond 10 years, [that rate] can be equated with cure,” he said.
The Total Therapy regimens were adapted from the St. Jude approach to childhood acute lymphoblastic leukemia, Dr. Bart Barlogie explained. Total therapy implies intent to cure through the use of all available active agents and modalities upfront, rather than in sequence.
“Multiple myeloma is marked by unusually profound genomic chaos, and is more similar to solid tumor malignancies than other hematologic malignancies. It is important to bring to bear all of the facets that may have activity in order to get complete remission—that is, profound tumor mass reduction as early and as fast as possible.”
He said genomic chaos is likely the reason that the disease can resist targeted therapies aimed at unique molecular signaling pathways.
Dr. Barlogie stressed rapid initiation of therapy for multiple myeloma.
“In the presence of cytogenetic abnormalities, and probably more importantly in high risk [cases] as defined by gene array, you'd better get your treatment in on time,” he said.
The backbone of the Arkansas approach, as Dr. Barlogie calls it, has been a tandem MEL-Tx regimen that exploits melphalan's dose-response effect in multiple myeloma.
In the proposed TT4 trial, the program for high-risk disease is dose-dense and dose-intense VDT-PACE for six cycles with stem cell boosts.
“Through such rapidly recycled combination therapy on a 21-day cycle, multiple myeloma re-growth can be markedly reduced vis-à-vis MEL-Tx,” he said.
This schedule will avoid “these six, eight, ten weeks of no therapy that you end up with when you give high-dose melphalan, when a patient has to recover from mucositis.”
Cytotoxic vs Cytostatic
In remarks to Dr. Barlogie after the presentation, meeting chair Morton Coleman, MD, said he fully agreed with a comment Dr. Barlogie made that some novel agents may be cytotstatic rather than cytocidal.
“I know when we had the BLT-D [Biaxin-low dose thalidomide-dexamethasone] program, it was important to maintain patients on thalidomide, because once you stop the therapy the disease would come back very rapidly,” Dr. Coleman said. “So it is probably more than just a CR—I think the type of drug you use is very important.”
Dr. Coleman asked Dr. Barlogie why some of his multiple myeloma regimens still use doxorubicin (Adriamycin).
“Doxil seems to work, while Adriamycin's activity seems to be marginal,” Dr. Coleman said.
Dr. Barlogie said he does not use Doxil in this setting because of the mucositis. “When you do the native compound you can just stop it whenever you think it's worthy of stopping,” he said. “But once the pegylated stuff is in, I've given basically three or four days of the drug.”
He said in these cases he administers Adriamycin by continuous infusion to mimic a low-dose level—3 to 5 mg/m2, in patients who have “a burnt-out bone marrow” with platelets in the 20,000 to 30,000 range due to impaired stem cell reserve.
“We do this together with Velcade and thalidomide and rapamycin, and we can get a 50 percent partial and a 30 percent complete remission in this setting,” he said.