NEW YORK—Oral proteasome inhibitors and immunotherapy may be the future of maintenance for multiple myeloma, but what is the best form of maintenance now—proteasome inhibitors or immunomodulatory drugs (IMiDs)? Or do some patients not need maintenance? Three myeloma experts debated this topic here at the 2015 Lymphoma & Myeloma meeting.
All three experts agreed that the goals of maintenance therapy in myeloma are to reduce the risk of relapse and extend progression-free survival (PFS) and overall survival (OS). Maintenance of response is achieved following a new treatment with the administration of drugs for a prolonged time period. Therapy must be convenient, safe, and well-tolerated over the long-term, and not prevent the use or reduce the efficacy of other future treatments.
James Berenson, MD: Proteasome Inhibitor Maintenance
James Berenson, MD, President and CEO, Institute for Myeloma and Bone Cancer Research in West Hollywood, CA, took up the cause for proteasome inhibitor maintenance. He began by noting that “only one study of lenalidomide maintenance, with or without steroids, has shown an OS benefit. Three studies show improvements in PFS, but no difference in OS.”
A new meta-analysis of 7,730 multiple myeloma patients from 18 phase 3 trials shows a PFS improvement in both transplant and non-transplant patients, as well as when patients are stratified for both lenalidomide and thalidomide treatment. “However, there is no OS benefit, and no benefit in either transplant or non-transplant patients or for either lenalidomide or thalidomide,” Berenson said. Grade 3/4 adverse events show increased thromboembolic events, peripheral neuropathy, neutropenia, and infection.
Berenson said “there are fairly consistent results showing improvement in PFS with lenalidomide maintenance; however, inconsistent results showing improvement in OS. There are no studies that show using lenalidomide for patients responding to non-IMiD-containing regimens is effective in terms of PFS or OS.”
There are a few randomized trials of bortezomib as a maintenance drug, but inadequate trial design makes it hard to determine the impact of bortezomib itself in the maintenance setting, he said. One trial of bortezomib as maintenance therapy in multiple myeloma compared bortezomib-melphalan-prednisone-thalidomide plus bortezomib-thalidomide maintenance with bortezomib-melphalan-prednisone alone in newly diagnosed elderly myeloma patients. After a median follow-up of 54 months, the 3-year PFS was superior with the bortezomib-based maintenance therapy (51%) compared to without it (32%), and OS was also superior, he said.
Berenson noted that treatment discontinuation due to adverse events was higher with the bortezomib-based maintenance therapy regimen, in particular in those patients over age 75.
“The landmark analysis after nine cycles found a 52 percent reduced risk of progression with bortezomib maintenance, irrespective of response and in patients under age 75, but not in patients age 75 and older,” Berenson said. “This was not a randomized look at the data and we have no clear-cut answer from this trial.” Prognostic factors included response, age, staging, and cytogenetic abnormalities.
In the phase 3 PETHEMA/GEM trial, bortezomib as maintenance therapy in previously untreated multiple myeloma patients found those who responded before maintenance did better. After median follow-up of 34.9 months from onset of maintenance therapy, the addition of bortezomib to thalidomide maintenance resulted in significantly longer PFS as compared to thalidomide or interferon. There was no difference in OS. Bortezomib maintenance conferred a significant PFS advantage in patients with low-risk, but not high-risk, cytogenetics, he said.
In summary, Berenson said: “Lenalidomide maintenance therapy with or without steroids is well-tolerated and improves PFS, but not OS among multiple myeloma patients (also with thalidomide) and in both the transplant and non-transplant settings. There are no data showing activity after induction with other drugs. Bortezomib-responding patients tolerate its long-term use as maintenance therapy, and responses deepen during maintenance therapy. However, its efficacy in term of PFS or OS has not been clearly demonstrated due to trial design limitations. Oral proteasome inhibitors, such as ixazxomib, now in clinical development, offer convenience, which makes them more ideal as maintenance drugs.”
Antonio Palumbo, MD:Immunomodulatory Maintenance
Antonio Palumbo, MD, Chief, Myeloma Unit, at the University of Torino in Torino, Italy, stated that maintenance with IMiDs was best. Pointing to his own studies, Palumbo said, “If we give continuous treatment of IMiDs instead of fixed-duration therapy, we can delay tumors, and there is a PFS and OS advantage.”
There is not much difference between IMiDs and proteasome inhibitors, he said. “Lenalidomide maintenance leads to PFS improvement. A meta-analysis of a combination of thalidomide-lenalidomide-bortezomib shows an OS benefit. One regimen is not superior to another. For efficacy data, bortezomib is not clearly superior to IMiDs, but it does require injections every 15 days and there is some peripheral neuropathy.”
He also noted two recent studies of carfilzomib combinations, ASPIRE (carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone) and ENDEAVOR (carfilzomib-dexamethasone versus bortezomib-dexamethasone), also found a PFS advantage to continuous therapy.
“Carfilzomib-lenalidomide is an option in maintenance,” Palumbo said. “There is no issue with peripheral neuropathy, which may represent an alternative.” He noted that infusion of carfilzomib is only for the short-term.
The next advance may be an oral proteasome inhibitor, ixazomib, shown to be compatible with lenalidomide in combination. “Evidence suggests this is an interesting drug, but there is not enough data yet. We must wait for two major randomized trial comparisons of ixazomib versus placebo in transplant and non-transplant eligible patients.” He noted that one of the common adverse events with ixazomib is diarrhea, but there is less peripheral neuropathy and hematologic toxicity.
The most friendly treatment approach, Palumbo said, is lenalidomide maintenance. This may need dose reduction, but there is no major peripheral neuropathy or non-hematologic toxicity. “I believe it is the best available agent,” he said. “Several studies show a clear benefit of 12 to 18 months improvement in remission prolongation.”
In conclusion, Palumbo said: “Lenalidomide has extensive efficacy, it's an oral drug, has no peripheral neuropathy side effects, and there is extensive data. Ixazomib in the future may be major competition, but the phase 2 data is too early and gastrointestinal toxicity may represent an issue. There is limited value for intravenous drugs.”
He added that monthly exposure to monoclonal antibody in the future might represent an alternative to IMiDs as a maintenance approach.
Sundar Jagannath, MD: No Maintenance
Sundar Jagannath, MD, Director, Multiple Myeloma Program, and Professor of Medicine at Tisch Cancer Institute at Mount Sinai Medical Center in New York, debated that no maintenance is necessary.
“The purpose of maintenance therapy is to prolong remission duration and life expectancy without compromising quality of life,” Jagannarth said.
Strategies for maintenance include low-intensity chemotherapy to eliminate or suppress the minimal residual disease; immunotherapy with antibodies or checkpoint inhibitors; and vaccines.
Clinical controversies include when to provide maintenance—after maximum tumor cytoreduction has been achieved post-transplant with fixed-durations or in non-transplant patients with variable doses? Is PFS a surrogate endpoint for OS? What is best for high-risk patients?
“PFS is not a primary endpoint for OS,” Jagannarth stated flatly. “There is minimal change, about 25 percent, in paraprotein, which has little impact on OS. A median absolute increase in PFS by six to nine months has no impact on OS. Post-progression therapy influences OS.”
He offered evidence on why maintenance improves PFS but not OS. “Altering the tumor population induces drug resistance, and altering the microenvironment leads to evolution of aggressive clones and myelodysplastic syndrome.”
He agreed with Palumbo that continuous therapy is better than fixed-dose therapy. “Continuous therapy gives better outcomes. Induction of more than 12 months leads to no further improvement in the complete response (CR) rate. Adding a proteasome inhibitor does increase CR,” Jagannarth said.
Jagannarth concluded: “We should provide chemotherapy maintenance to treat until there is maximum tumor cytoreduction after a minimum of 12 months. Good risk patients need no maintenance. High-risk patients need continuous therapy. Post-transplant, consider second transplant or consolidation if the patient achieves less than very good partial response (VGPR). Also consider maintenance for a patient not in VGPR or better.”
The future of maintenance is immunotherapy, Jagannarth said. He believes a new paradigm may develop from the use of elotuzumab, checkpoint inhibitors, and vaccines.
Debate responses: Before the debate, two-thirds of the audienc e believed that IMiDs were the best maintenance therapy and one-quarter voted for proteasome inhibitors. No one voted for no maintenance. However, after hearing the three speakers, the votes changed dramatically: Only 10 percent said proteasome inhibitors, 42 percent IMiDs and now 30 percent chose no maintenance.