The number of approved agents in multiple myeloma has skyrocketed in recent years, leading to significant improvements in survival, but questions remain regarding the optimal duration of treatment. Although traditionally limited to a fixed number of cycles due to accumulating toxicity, novel agents with less severe toxicity profiles offer the possibility of prolonged maintenance therapy, but just how long should initial treatment last? At the 2019 National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies, Yvonne A. Efebera, MD, MPH, and Nina Shah, MD, debated the advantages of fixed vs continuous maintenance therapy for multiple myeloma.1
Dr. Efebera: Time-Limited Myeloma Therapy
According to Dr. Efebera, Associate Professor at The Ohio State University Comprehensive Cancer Center–James Cancer Hospital and Solove Research Institute, postinduction consolidation and treatment improve survival, but the appropriate length of maintenance therapy remains unknown.
“Clearly, there is a benefit for maintenance therapy, but we have yet to determine when enough is enough.”— Yvonne A. Efebera, MD, MPH
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A meta-analysis comparing continuous vs fixed-duration therapy in three randomized trials, including one autologous stem cell transplantation (ASCT) study and two nontransplant studies, found that patients receiving continuous maintenance therapy had a median progression-free survival of 32 months vs 16 months with fixed-duration treatment (nine cycles of induction) and no maintenance therapy.2
“Clearly, there is a benefit for maintenance therapy, but we have yet to determine when enough is enough,” said Dr. Efebera. “There is no randomized trial comparing 1 year of maintenance therapy vs 3 years vs 5 years vs until disease progression.”
As Dr. Efebera explained, the closest study to date is a joint effort between the Intergroupe Francophone Myelome (IFM) trialists group and the Dana-Farber Cancer Institute.3 This trial randomly assigned patients with multiple myeloma to receive induction therapy with three cycles of lenalidomide, bortezomib, and dexamethasone (RVD) and then consolidation therapy with either five additional cycles of RVD or high-dose melphalan plus stem cell transplantation followed by two additional cycles of RVD. Although all IFM patients received maintenance therapy with lenalidomide for 1 year due to concerns of secondary primary malignancy, patients enrolled at Dana-Farber received continuous maintenance therapy.
The results from Dana-Farber have not yet been published, but the IFM results showed a median progression-free survival of 50 months in the transplantation arm and 36 months in the nontransplantation arm, with 4-year overall survival of 81% and 82%, respectively. “These findings do not really differ from the randomized study of maintenance vs placebo, but hopefully, we’ll have some information from the U.S. study soon,” said Dr. Efebera.
Physical and Financial Toxicities
Even with a shorter duration of maintenance, however, safety data have shown significant toxicities. An analysis by Attal et al found that more than one-third of patients on lenalidomide maintenance experienced grade 3 or higher neutropenia, and 58% of patients had grade 3 or higher hematologic toxicity compared with 22% on placebo.4 A meta-analysis by McCarthy et al also showed that nearly 30% of patients on maintenance lenalidomide had treatment-emergent adverse events, and approximately 30% had to be taken off study.5
With the monthly cost of lenalidomide exceeding $8,000, financial toxicity should be another cause of concern, said Dr. Efebera, who noted that some patients will be on maintenance therapy for up to 7 years. A study of quality-adjusted life years (QALY) associated with maintenance identified 5.72 QALY for patients on lenalidomide vs 4.61 QALY for patients with no maintenance, but the incremental cost-utility ratio was more than $300,000. As Dr. Efebera explained, this high ratio adds uncertainty about the maximum duration of treatment.
“Quality of life is clearly affected on maintenance therapy,” said Dr. Efebera, who noted that 54% of patients experience cognitive decline. “Chemo brain is no joke.”
Future Research
To provide a more definitive answer regarding the appropriate treatment length, Dr. Efebera proposed randomly assigning patients to 3, 5, or 7 years of lenalidomide maintenance following four cycles of induction and ASCT or eight cycles of induction for transplant-ineligible patients. “Investigators were able to pull this off in breast cancer, so we can do this in myeloma, too,” concluded Dr. Efebera.
Dr Shah: Longer Duration of Therapy Still Better
According to Dr. Shah, a hematologist/oncologist and Associate Professor of Medicine at the University of California, San Francisco Health, continuous treatment until disease progression or tolerance offers patients with myeloma the best survival advantage.
“We know that the depth of response is important in myeloma, and the more you treat, the deeper the response you get.”— Nina Shah, MD
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“We know that the depth of response is important in myeloma, and the more you treat, the deeper the response you get,” Dr. Shah explained. “This is one of the ideas not only behind transplant consolidation but also maintenance therapy: to potentially increase the proportion of patients who test negative for minimal residual disease, which will then theoretically translate to a greater progression-free survival.”
The IFM study was not powered to show an improvement in overall survival, noted Dr. Shah, but CALGB (Alliance) 100104, which assessed lenalidomide vs placebo maintenance after single autologous stem cell transplantation for multiple myeloma, demonstrated improvements in progression-free and overall survival for patients who received lenalidomide maintenance.6 As Dr. Shah reported, Alliance’s study design favored the increased use of immunomodulatory drugs, and the duration of maintenance therapy approached 3 years vs 2 years on the IFM study, which could account for the overall survival advantage.
Nevertheless, as the question has not been studied in a prospective manner, said Dr. Shah, the appropriate duration of maintenance therapy must be teased from retrospective data. One retrospective analysis compared patients who had received lenalidomide maintenance for less than 12 months vs 12 to 24 months vs more than 24 months. The investigators reported an improvement in progression-free survival associated with longer therapy.6
“Of course, this type of analysis is always biased,” said Dr. Shah, “but it looks like receiving longer maintenance therapy is better.”
Despite the survival advantage, however, Dr. Shah acknowledged drawbacks associated with prolonged maintenance therapy—namely, secondary primary malignancies. “Secondary primary malignancies are obviously more prevalent in patients who receive lenalidomide maintenance than in those who do not,” she said. “This is a really important discussion that we have with all of our patients when we put them on maintenance therapy: all good things come with some downsides.”
Given the long life expectancy for patients with multiple myeloma, overall survival can be challenging to demonstrate, said Dr. Shah, but analysis across numerous studies—whether maintenance with thalidomide, lenalidomide, or bortezomib—suggests that continuous therapy offers the best overall survival advantage. “Ultimately, we have to reconcile any gains in survival with quality of life, which is so important,” she concluded. “The burden is on us to design interesting and innovative ways of approaching this problem so we can optimize therapy for patients with myeloma.”
DISCLOSURE: Dr. Efebera has received honoraria from Janssen Pharmaceutica Products, LP, Pharmaceuticals North America, Inc, and Takeda and is a scientific advisor for Akcea. Dr. Shah reported no conflicts of interest.
REFERENCES
1. Efebera YA, Shah N: Debate: Fixed duration versus until progression: How long should the initial treatment of myeloma last? 2019 NCCN Annual Congress: Hematologic Malignancies. Presented September 28, 2019.
2. Palumbo A, Hajek R, Delforge M, et al: Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366:1759-1769, 2012.
3. Attal M, Lauwers-Cances V, Hulin C, et al: Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 376:1311-1320, 2017.
4. Attal M, Lauwers-Cances V, Marit G, et al: Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1782-1791, 2012.
5. McCarthy PL, Holstein SA, Petrucci MT, et al: Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: A meta-analysis. J Clin Oncol 35:3279-3289, 2017.
6. Holstein SA, Jung SH, Richardson PG, et al: Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: A randomised, double-blind, phase 3 trial. Lancet Haematol 4:e431-e442, 2017.
