NEW YORK—The still-unresolved issue of the length and type of maintenance therapy for patients with multiple myeloma who have completed induction therapy, undergone autologous stem cell transplantation (ASCT), and have consolidation therapy was the topic of a debate here at the Great Debates & Updates in Hematologic Malignancies meeting.
Suzanne Lentzsch: Maintenance for Two Years Only
Suzanne Lentzsch, Associate Professor of Clinical Medicine in the College of Physicians and Surgeons of Columbia University and Director of the Multiple Myeloma and Amyloidosis Program at New York Presbyterian Hospital, started by noting noted that the purpose of maintenance therapy for multiple myeloma (MM) is to prolong the duration of remission and life expectancy. “This requires periodic follow-up to monitor toxicity and response. The patient must have disease that is in remission—undetectable or at a low level—and must have recovered from all previous toxicities.”
In addition, maintenance agents must have minimal toxicity or at least not overlap with the toxicity of the induction regimen, and need to have convenient dosing and a convenient route of administration.
Problems with Maintenance Therapy
There are problems with maintenance therapy, she said: “Induction therapy followed by ASCT alone will cytoreduce, but not cure, most MM patients. Can maintenance therapy prevent disease progression? Convert partial responses to complete responses? Improve overall survival? Everybody gets the drug, but not everybody gets the benefit. You can ‘burn’ an effective drug.
There is also treatment fatigue. And some patients stay in remission without maintenance.”
She defined an ideal maintenance strategy as one that significantly improves outcomes with minimal side effects and with preservation of response to salvage. To maintain an ideal strategy, “we need to limit maintenance to two years,” she said.
Thalidomide Maintenance Trials
She supported her argument with data from maintenance clinical trials. Thalidomide maintenance trials, for example, show improvement in progression-free survival (PFS) in all trials, but most show no significant improvement in overall survival (OS).
Lenalidomide maintenance following lenalidomide consolidation was tested by French researchers in the IFM 2005-02 Phase III randomized, placebo-controlled trial of 614 myeloma patients. PFS was significantly improved with lenalidomide maintenance (41 months) compared with use of placebo (24 months). Overall survival was not significantly different. Adverse events after randomization in the treated population show more grade 3 and 4 neutropenia in the lenalidomide group (51%) compared with the placebo group (18%). Plus, there were more hematologic cancers, including at least one second primary cancer, in the lenalidomide group, she pointed out.
The conclusion is that “lenalidomide maintenance after transplantation significantly prolonged PFS and event-free survival among patients with MM. But four years after randomization, OS was similar in the two study groups.”
CALB 100104 Trial
The U.S. CALGB 100104 trial investigated lenalidomide maintenance after transplant in 460 patients with multiple myeloma. PFS was significantly higher in those who received lenalidomide treatment (46%) compared with placebo (27%). Overall survival improved with lenalidomide, but despite being significant, there was only an eight percent benefit, she noted.
Among lenalidomide-treated patients, there were considerable hematologic toxicities, including neutropenia, thrombocytopenia, and lymphopenia. The risk of second primary cancers was also significantly greater with lenalidomide compared with placebo.
The conclusions of CALGB 100104, Lentzsch said: “In patients who had undergone stem-cell transplantation, lenalidomide maintenance therapy improved PFS and OS, though at the expense of increased hematologic toxicity and second malignant tumors.
“In all of the lenalidomide maintenance Phase III trials, significant toxicity increased with lenalidomide from about 15 to 50 percent. And in Phase III trials of lenalidomide maintenance after ASCT, there is no doubt about improved PFS with maintenance, but there is only a slight or no OS difference.”
Another study, the Italian GIMEMA RV-MM-PI-209 trial of autologous transplantation and maintenance therapy in 399 myeloma patients, found similar results: PFS was improved significantly with maintenance, but there was no difference in OS. Again, there were increased Grade 3 and 4 adverse events. The combination of lenalidomide and melphalan significantly increased the risk of second primary malignancies.
The conclusion from the GIMEMA RV-MM-Pl-209 trial is that “lenalidomide maintenance, as compared with no maintenance, after high-dose melphalan plus stem-cell transplantation or melphalan-prednisone-lenalidomide [MPR] significantly prolonged PFS, but not OS.”
Summing up, Lentzsch said: “Maintenance with novel agents significantly improves PFS. Maintenance after transplant does not significantly increase OS in most of the randomized trials. Hematologic toxicity issues are critical. Hematologic secondary malignancies significantly increase with lenalidomide, with further increases with oral melphalan.”
The potential risks of continuous maintenance treatment, she said, include:
- Adverse events related to long-term treatment;
- Reduced quality of life;
- Impact on subsequent therapeutic options;
- Continuous follow-up with office visits/labs; and
- Possible reduced survival after relapse from selection of resistant clones and availability of non-cross-reacting agents.
“Maintenance exposes all patients to the side effects of prolonged treatment, and this could lead to an explosion of costs without proven benefit for survival. Maintenance therapy should be given for only two years, since common wisdom dictates that PFS by itself may not justify continuous therapy for all patients.
“Either a survival or quality-of-life benefit needs to be shown to justify toxicities, costs, and potential overtreatment,” Lentzsch concluded.
Ruben Niesvizky:Continuous Maintenance
Ruben Niesvizky, MD, Director of the Center for Multiple Myeloma at New York Presbyterian Hospital-Cornell Medical Center, made the case for continuous maintenance. “Maintenance has to be taken by its word: If we maintain patients for two years, this is likely to induce relapses. We are not going to cure patients.”
Several trials of post-ASCT maintenance show that immunomodulatory agents, such as thalidomide, improve PFS and OS, he said. “We have to take into account survival when considering maintenance. Immunomodulatory drugs are the main agents to improve PFS.”
The great challenge with thalidomide is long-term tolerance. Some 30 to 40 percent of patients discontinue treatment—thus eliminating the ability to incorporate the goals of consolidation and induction therapy, he said.
Niesvitzky was the lead author of the BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) trial, which added clarithromycin to lenalidomide and dexamethasone and resulted in high complete and overall response rates in treatment-naïve symptomatic MM patients (Blood 2008;111:1101-1109).
“The longer we used the combination, the deeper the response and the more robust the outcome,” he said. “We continued therapy as long as toxicity allowed.” The tendency was to discontinue therapy due to intolerance.
The results showed that lenalidomide maintenance could be maintained for 24 cycles. “The only cohort to achieve molecular remission was on lenalidomide maintenance.”
In an update of the BiRD trial published five years later (Blood 2013; 121:1982-1985), patients continued lenalidomide therapy for more than six years, with an overall four-year survival rate of 82 percent. “There is no question that continuing therapy is tolerable and can be used long-term,” Niesvitzky said.
Other studies have shown that PFS is not affected by transplant after lenalidomide. “After transplantation, both young and fit patients and even elderly patients can be maintained.”
Niesvitzky also cited a few of the same clinical trials that Lentzsch did: The French IFM 2005-02 trial showed “consolidation improved CR/very good partial response from 58 to 69 percent, and PFS from 23 to 41 months,” he said, noting that overall survival is not yet different between the lenalidomide and placebo groups.
In the CALGB 100104 study, the median time to progression was 42.3 months with lenalidomide and 21.8 months with placebo. And while there was no overall survival difference, “there may have been a difference between the two arms, which may no longer be present due to crossover,” he said.
Newest Maintenance Trial
The newest maintenance trial is a 2014 Italian study of 402 patients randomized to receive MPR or melphalan at 200 mg/m2 (MEL 200) with or without maintenance. In the first randomization, the results show that MPR led to a PFS of 24 months and five-year overall response rate of 62 percent compared with the PFS and five-year OS in MEL 200 PFS of 38 months and 71 percent.
In the second randomization of lenalidomide maintenance or no maintenance, patients on maintenance had a complete response rate of 23 percent versus 19 percent for those on no maintenance. In the maintenance group, PFS was 37 months and five-year OS was 75 percent compared with 26 months and 58 percent among the no-maintenance patients. “This is a strong argument for long-term lenalidomide,” Niesvizky said.
“Younger or older patients over age 60, those with CR or no CR—all show higher PFS with maintenance,” he said. The only patients who do not benefit long-term from lenalidomide maintenance are those with poor-risk cytogenetics, which is the minority of patients. The best candidates, he said, have transplant followed by lenalidomide maintenance.
In addition, lenalidomide maintenance slows down clonal tiding, which allows for longer PFS: “Faster clonal evolution interrupts therapy. Those who do not recover immunity have clonal sensitivity and relapse.”
In conclusion, Niesvizky said: “Patients who receive maintenance have improved PFS and OS. In Europe, the recommendation is continued maintenance with lenalidomide or bortezomib for MM patients.”
Before the debate, three-quarters of the audience voted that they considered two years of maintenance to be sufficient for multiple myeloma patients. Afterwards, that percentage was reduced somewhat, to approximately two-thirds, showing, though, that most of the audience still preferred shorter-term rather than continuous maintenance therapy.