Meta-Analysis of Maintenance Therapy in Multiple Myeloma: Time to Rethink Immunomodulatory-Based Maintenance Therapy?

Maintenance therapy with immunomodulatory drugs (IMiDs; including thalidomide, lenalidomide, and pomalidomide) and the proteasome inhibitors bortezomib and carfilzomib has been shown to increase event-free and progression-free survival (PFS) in patients with multiple myeloma (MM), but questions about their efficacy in extending overall survival and the safety of long-term use remain.

In a recent meta-analysis published in the Journal of the National Cancer Institute, Yucai Wang and colleagues from the Department of Medicine at Rutgers New Jersey Medical School in Newark, New Jersey, examined randomized controlled trials (RCTs) that studied the safety and efficacy of thalidomide and lenalidomide as maintenance therapy for patients with MM, with the goal of establishing the best algorithms for MM management.

Dr. Wang and co-authors searched PubMed and abstract databases for major hematology/oncology meetings to identify 18 phase III RCTs, enrolling a total of 7,730 patients. Among these trials, IMiDs used in the maintenance therapy regimen included thalidomide (12 trials) and lenalidomide (6 trials). IMiD-based maintenance therapy was used after patients received autologous hematopoietic cell transplantation (AutoHCT) in seven trials, and nine trials evaluated the safety and efficacy of maintenance therapy in the non-transplant setting.

Two trials had enrolled both transplant-eligible and -ineligible patients.

Overall, IMiD-based maintenance therapy statistically significantly improved the PFS (hazard ratio [HR] = 0.62; 95% CI 0.57-0.67; p<0.001) in patients with MM (TABLE 1). In subgroup analyses, both thalidomide- and lenalidomide-containing regimens improved PFS. “[For thalidomide] the PFS prolongation was observed in all six studies (HR=0.56-0.73), demonstrating an unequivocal benefit of thalidomide maintenance therapy after AutoHCT in delaying disease progression,” Dr. Wang and colleagues noted.

This improvement was also seen in both transplant and non-transplant settings: HR=0.61 (95% CI 0.54-0.68; p<0.001) and HR=0.63 (95% CI 0.55-0.71; p<0.001), respectively.

Conversely, IMiD-based maintenance therapy was not associated with a statistically significant improvement in overall survival (OS), though there was a trend for longer OS: HR=0.93 (95% CI 0.85-1.01; p=0.082). This was true regardless of the type of IMiD used or transplant eligibility:

  • Thalidomide: HR=0.94 (95% CI 0.85-1.05; p=0.278)
  • Lenalidomide: HR=0.87 (95% CI 0.73-1.04; p=0.135)
  • Transplantation: HR=0.89 (95% CI 0.73-1.07; p=0.214)
  • Non-transplantation: HR=0.95 (95% CI 0.88-1.04; p=0.273)

Compared with control arms in the included RCTs, patients in the IMiD-containing arms had statistically significantly increased risks for developing grade 3/4 vascular events, including deep-vein thrombosis and pulmonary embolism and peripheral neuropathy (TABLE 2).

“Notably, an increased risk of grade 3/4 peripheral neuropathy was found with thalidomide (risk ratio [RR] = 2.83; 95% CI 1.26-6.35; p=0.012) but not lenalidomide (RR=1.94; 95% CI 0.66-5.77; p=0.231) maintenance therapy,” the authors reported. “In contrast, an increased risk of myelosuppression was only prominent with lenalidomide but not thalidomide.”

There was no observed increased risk for developing second primary malignancies in patients receiving either IMiD-containing maintenance regimen; however, the researchers did find that lenalidomide was associated with a higher risk of developing secondary primary hematologic malignancies (RR=2.10; 95% CI 1.08-4.09; p=0.029) but not solid tumors (RR=1.23; 95% CI 0.54-2.80; p=0.628).

“Although largely safe, prolonged use of IMiDs for maintenance therapy of MM can lead to increased risks of several adverse events,” Dr. Wang and colleagues reported. “While measures can be taken to prevent thromboembolism and other common adverse events that are largely manageable, increased risk of peripheral neuropathy with thalidomide, and more importantly increased risk for developing second primary malignancies with lenalidomide, warrant serious consideration when starting maintenance therapy with these agents.”

There was a high degree of variation among the included RCTs, which may limit the generalizability of the meta-analysis results, the authors noted, including differences in trial design, induction and consolidation therapies, patient characteristics, and definition of survival outcomes. There was also the possibility of publication bias in selecting trials for inclusion, as only published trials were included and some studies without sufficient data were excluded.

“Our meta-analysis clearly showed that IMiD-based maintenance therapy can statistically significantly improve PFS but not OS in MM regardless of AutoHCT status,” Dr. Wang and authors concluded. However, “another important question that cannot be answered by our study because of the lack of necessary data is which patient population will benefit the most from IMiD maintenance therapy.”


Reference

Wang Y, Yang F, Shen Y, et al. Maintenance therapy with immunomodulatory drugs in multiple myeloma: a meta-analysis and systematic review. J Natl Cancer Inst. 2015;108:342.

TABLE 1. Effects of IMiD-Based Maintenance Therapy on Progression-Free and Overall Survival
IMiD AutoHCT status Number of trials Progression-free survival Overall survival
HR (95% CI) p Value HR (95% CI) p Value
Thalidomide/lenalidomide Combined 18 0.62 (0.57-0.67) <0.001 0.93 (0.85-1.01) 0.082
With AutoHCT 9 0.61 (0.54-0.68) <0.001 0.89 (0.73-1.07) 0.214
Without AutoHCT 11 0.63 (0.55-0.71) <0.001 0.95 (0.88-1.04) 0.273
Thalidomide Combined 12 0.66 (0.61-0.72) <0.001 0.94 (0.85-1.05) 0.278
With AutoHCT 6 0.67 (0.61-0.74) <0.001 0.90 (0.73-1.11) 0.343
Without AutoHCT 7 0.66 (0.57-0.76) <0.001 0.97 (0.85-1.11) 0.627
Lenalidomide Combined 6 0.52 (0.44-0.62) <0.001 0.87 (0.73-1.04) 0.135
With AutoHCT 3 0.49 (0.41-0.57) <0.001 0.82 (0.48-1.41) 0.477
Without AutoHCT 4 0.55 (0.43-0.72) <0.001 0.95 (0.85-1.05) 0.308

TABLE 2. Grade 3 or 4 Adverse Events
Adverse event Number of trials Events in IMiD arm Risk ratio (95% CI) p Value
Vascular events 10 123/1,958 2.52 (1.41-4.52) 0.002
Peripheral neuropathy 6 53/1,419 2.27 (1.35-3.84) 0.002
Neutropenia 9 484/1,894 2.73 (1.63-4.55) <0.001
Thrombocytopenia 10 159/1,886 2.14 (1.34-3.40) 0.001
Anemia 10 149/1,955 1.43 (1.13-1.80) 0.003
Infection 9 297/1,654 1.64 (1.40-1.92) <0.001
Fatigue 10 130/1,969 1.48 (1.08-2.03) 0.016
Constipation 7 36/1,502 1.82 (1.03-3.21) 0.039
Second primary malignancies 7 93/1,593 1.33 (0.81-2.19) 0.257

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