NEW YORK—Maintenance therapy after remission in multiple myeloma is a controversial topic, and a very topical question was asked in a debate here at the Lymphoma & Myeloma International Congress: Is maintenance necessary, and if so, which is most beneficial—with immunomodulators or with proteasome inhibitorsl?
Sergio A. Giralt, MD, Chief of the Adult Bone Marrow Transplant Service and Acting Chief of the Myeloma Service at Memorial Sloan-Kettering Cancer Center, argued for maintenance, and said immunomodulators would be his choice.
James R. Berenson, MD, Medical and Scientific Director of the Institute for Myeloma and Bone Cancer Research in Los Angeles, took the “no” position, but spoke more to which agents would be recommended if one must use maintenance, concluding that a proteasome inhibitor would be preferred.
Yes, and Maintenance with IMiDs
“The answer to the question is yes, and the right choice is lenalidomide,” Giralt began, as he launched into his argument citing three trials he said should guide clinicians and change the way they practice.
These large, randomized trials showed that in the context of autologous stem cell transplantation, the use of lenalidomide maintenance is associated with a significant progression-free survival benefit that is measured in almost two years, he said.
* The Phase III IFM 2005-02 trial tested lenalidomide as consolidation/maintenance post-autologous stem cell transplantations (Attal et al: Blood 2009;114: ASH Annual Meeting, Abstract 529, and Attal et al: JCO 2010; 28: ASCO Annual Meeting, Abstract 8018).
* CALGB 100104, a placebo-controlled randomized trial of maintenance lenalidomide after melphalan 200 and transplant (McCarthy et al: NEJM 2012;366:1770-1781). An update at the International Myeloma Workshop in January 2013 showed an overall survival rate of 70 percent—five years among the 229 patients in the placebo arm compared with 80 percent of 231 patients in the lenalidomide arm.
* And in the GIMENA MEL200 vs. MPR trial led by Antonio Palumbo (Boccadoro et al: ASCO 2013 Abstract 8509)), lenalidomide maintenance was associated with a 48 percent reduced risk of disease progression and a 38 percent reduced risk of death.
These trials showed that progression-free survival was prolonged with stem cell transplant therapy after lenalidomide, regardless of response or prior exposure to lenalidomide, Giralt said. “Data are emerging from these trials that the benefit of maintenance may be greater when started earlier after transplant.”
The trials all showed tolerability, although an increase in second primary malignancy was a concern.
“For now, lenalidomide should be considered the standard of care,” Giralt said.
In comments after the debate, Giralt said it is important to remember that maintenance lenalidomide is associated with an increase in second primary malignancies. Nevertheless, he said he thought lenalidomide maintenance will ultimately improve survival, “and if that's the case, it should become the standard of care.”
Giralt said the bar for survival among myeloma patients today is set very high, “approaching 60 percent at five years—numbers we've never seen before. If you consider that in the first transplant trials median survival was five years or less, and now we're talking about median survivals that haven't been reached, it's easy to see that proteasome inhibitors, IMiDs, high-dose melphalan and lenalidomide maintenance have changed the course of this disease.”
No, But Maybe Use a Proteasome Inhibitor
Berenson said he uses maintenance therapy for certain patients with myeloma, and that the question here really is what roles the different drugs can play.
Besides maintaining the response achieved following treatment while being convenient and safe, maintenance therapy should not prevent the use or reduce the efficacy of other future treatments, he said. “These patients live for many, many years, and they need the opportunity to avail themselves to get new drugs—that is hopefully not reduced by the maintenance treatment,” he said.
Clinical trials do not offer a great deal of guidance, he added. Most data from clinical trials of maintenance are from the frontline setting, and no trials have compared maintenance until relapse vs. a fixed time, although some trials have used both.
And there is very little data from randomized trials comparing different maintenance regimens as the only randomization.
Bisphosphonates have antitumor effects in myeloma and synergize with other anti-myeloma drugs. In the IFM (Intergroupe Francophone du Myeloma) 99-02 study, maintenance with pamidronate and thalidomide showed a survival advantage while single-agent pamidronate did not.
And in the MRC Myeloma IX trial, maintenance with zoledronic acid and chemotherapy significantly improved the relative risk of death by 16 percent over use of clodronate with chemotherapy.
Berenson also cited a trial using bortezomib as maintenance: the VMPT-VT vs. VMP trial (Palumbo et al: ASH 2012; Abstract 200).
While it is difficult to tease out the effects of thalidomide in the VMPT-VT arm, Berenson said, the VMPT-VT arm (bortezomib-melphalan-prednisone-thalidomide) that included maintenance with bortezomib-thalidomide did show a 52 percent reduced risk of disease progression irrespective of the response (complete or partial) in patients younger than 75, suggesting that the role of maintenance is positive.
The role of maintenance therapy in myeloma with novel agents has not been clearly defined due to limitations in trial design, Berenson said, but long-term use appears to be safe with bortezomib and steroids. Meanwhile, better trial designs are needed, to clarify the role of maintenance therapy in myeloma, regarding:
* Specific drugs;
* Single agents vs. combinations;
* Doses and schedules; and
* Length of therapy—fixed vs. to progression—and to which endpoints—progression-free survival or overall survival.
Currently in the Clinic
Berenson concluded with an outline of maintenance therapy as used in his clinic:
Maintenance is used for all patients with myeloma responding in both the frontline and salvage setting;
Drugs are continued until progressive disease; however, doses may have to be reduced or discontinued due to toxicity; and
Drugs are continued that were part of the treatment regimen except chemotherapy.
New agents are not introduced during maintenance.
“We like to say ‘the devil you know is better—and shown to be effective—than the one you don't,’” he said. “If you are adding new drugs you are doing new therapy.”
Steroids are used with equivalent dose intensity to 160 mg of dexamethasone per month, although oral methylprednisolone every other day is preferred, alone or with intravenous dexamethasone every other week.
Bortezomib is given at 1.3 mg/m2 subcutaneously every other week.
“We do use the IMiDs, but we use them in patients who have responded to IMiD-based regimens.” The lenalidomide dosage is 10 mg for 14 days, or for 21 out of 28 days, depending on what was used in the prior regimen. Thalidomide is used at 50-100 mg daily, tapered with the onset of neuropathy.
Zoledronic acid is continued monthly.
Pre/Post Debate Audience Survey
Meeting attendees were able to vote on the debate question before and after via the Internet from a tablet or phone in the meeting room. More voters favored Giralt's recommendation of immunomodulators, while fewer said they would give no maintenance: