NEW ORLEANS—As new drugs are introduced to the armamentarium against multiple myeloma, researchers continue to search for the best combination regimens and dosing for specific patient subpopulations.
In previously untreated patients over age 65, for example, a prospective, multicenter, randomized Phase III study from Spain has shown that reduced-intensity induction with either of two bortezomib-prednisone regimens—bortezombi-melphalan-prednisone (VMP) and bortezomib-thalidomide-prednisone (VTP)—produced similar results with no loss in efficacy.
“A less intensive induction therapy followed by a maintenance therapy is very effective in elderly untreated myeloma patients,” said the senior editor of the report presented here at the ASH Annual Meeting, Maria-Victoria Mateos, MD, PhD, Attending Physician in the Hematology Department of Hospital Universitario Salamanca in Spain.
The regimens in this study from the Spanish Myeloma Group were modified for reduced intensity, following a lead from the recent VISTA (“Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone”) trial, which found VMP significantly superior to melphalan and prednisone alone.
The two regimens in the trial differed in toxicity profiles, however, as VMP was associated with higher hematologic toxicity and infections. On the other hand, VTP was associated with cardiologic complications.
Another finding was that maintenance therapy with either bortezomib/thalidomide (VT) or bortezomib/prednisone (VP) markedly improved the quality of responses with a good safety profile.
“The combination of these induction and maintenance schedules seems to overcome the [usually] poor prognosis” of these patients, Dr. Mateos said.
The study was presented as Abstract #3 in the Plenary Scientific Session, and afterwards, ASH 2009 President Nancy Berliner, MD, Chief of Hematology at Brigham and Women's Hospital and Professor of Medicine at Harvard Medical School, was asked for her opinion: “It was determined that an akylating agent should be the best partner for bortezomib in induction therapy in elderly untreated multiple myeloma patients, and established the value of maintenance therapy in an elderly population,” she said.
“Most clinical studies have been inadequate [for this patient population] because the standard-of-care for myeloma has been auto-transplants following induction therapy, and that prevents or disallows an alternative that can prolong the survival of elderly patients.”
Outcomes for Modified Schedules
Dr. Mateos reported that the modified induction schedules had similar overall response rates (80% for VMP and 81% for VTP) for the 260 patients analyzed on an intent-to-treat basis. Complete remission rates after induction therapy were 20% for VMP and 27% for VTP.
But there was a clear difference in the toxicity profiles: The VMP group had a higher incidence of neutropenia and infections, but some patients in the VTP group experienced the development of cardiac toxicity.
And the frequency of Grade 3/4 peripheral neuropathy was 5% in the VMP group.
Maintenance therapy with either VT or VP markedly improved the quality of responses in the 178 patients receiving maintenance therapy. Complete responses increased from 23% to 42%, with no significant differences in response rates between the VT and VP treatment arms.
In addition, both maintenance regimens resulted in an acceptable toxicity profile.
Cost & Safety
Dr. Mateos said she considered bortezomib the best choice for induction in elderly untreated patients based on safety but also cost, since melphalan is less expensive than thalidomide. But she suggested that based on the results of this trial, that lenalidomide might be explored rather than thalidomide in this setting, in order to decrease toxicity still further.
Melphalan-prednisone has been the standard of care for multiple myeloma patients who cannot receive a stem cell transplant, she explained.
“Our first question [in this new trial] was, which agent is the best partner for bortezomib in induction therapy, an alkylating agent—melphalan—or an immunomodulatory therapy—thalidomide.”
‘Clear & Compelling’
The moderator of a news conference that featured Dr. Mateos's study, Richard A. Van Etten, MD, PhD, Professor of Medicine at Tufts University School of Medicine and Chief of the Division of Hematology/ Oncology and Director of the Tufts Medical Center Cancer Center, said afterwards that he considered the results of the trial to be clear and compelling: ”First, they found that altering the dosage of the regimen could reduce toxicity in these older patients, particularly neurotoxicity; and second, that an alkylating agent, melphalan, was a better choice to combine with bortezomib than thalidomide.”
Dr. Van Etten said the message he takes home from this presentation is that “in elderly patients with myeloma, the combination of melphalan with these two other drugs and the change in schedule of the bortezomib should be strongly considered.”
He explained that in the past, melphalan was to be avoided in these myeloma patients because it is highly toxic to stem cells and compromises the chances of a successful stem cell harvest. “Now, though, the playing field has been changed because of these new agents, principally lenalidomide and bortezomib, being moved up front, and it's no longer clear that transplant would prolong survival in patients getting these new agents. So that needs to be readdressed.”
The Chairman and Medical Director of the International Myeloma Foundation, Brian G.M. Durie, MD, asked after the meeting to comment on Dr. Mateos's study, though, was underwhelmed, saying that he did not think it would have all that much impact.
“One of the crucial issues in myeloma is how intensive induction should be and what is the ideal duration,” he said in a telephone interview. “Dr. Mateos's patients in both study arms were randomized to maintenance, and all patients had equal duration of therapy, so this doesn't really help answer the question about duration or the need for maintenance.”
Dr. Durie said he would like to get away from the word maintenance—“It implies that the patient is in complete remission and then is given treatment to prevent relapse. But another concept is that of ongoing active treatment, as in the Mateos study.
“Patients were not in remission but were receiving ongoing active therapy, and the question then is the duration of ongoing active therapy.”
The two combination regimens in this trial were active and producing good results, Dr. Durie continued, but he pointed out that high response rates were also being reported in many other bortezomib (Velcade) studies at this meeting.
“One Velcade study, the EVOLUTION trial, had a 100% response rate, so the response rates in Dr. Mateos's study were certainly by no means the best with Velcade combinations, or even other combinations. This study is not game changing,” he said.
Dr. Durie went so far as to question why this study was even chosen as a plenary presentation: “I was puzzled about that,” he said. “We [at the International Myeloma Foundation] interviewed 50 or 60 myeloma investigators as part of our activities at ASH, and we asked that question.
“And we got mixed answers, many saying that Dr. Mateos's study was interesting but it was not a treatment-changing abstract.”
Hear Maria-Victoria Mateos talk more about her research in a “Live from ASH” OT Broadcast News podcast (Program #2) available at oncology-times.com and on iTunes.