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Longer lenalidomide maintenance after HSCT improves PFS, OS in multiple myeloma
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A prolonged course of lenalidomide maintenance following autologous hematopoietic stem cell transplantation improved survival outcomes without increasing the incidence of second primary malignancies in patients with multiple myeloma, according to retrospective study results.
“Nearly all patients with multiple myeloma who undergo autologous HSCT ultimately experience disease relapse,” Qaiser Bashir, MD, assistant professor in the department of stem cell transplantation at The University of Texas MD Anderson Cancer Center, and colleagues wrote. “It has been well established that posttransplant maintenance therapy can delay the relapse and potentially prolong survival. ... Despite promising survival data, many clinicians remain apprehensive about the long-term use of lenalidomide [Revlimid, Celgene] maintenance because of the unclear association between the duration of maintenance and survival, the increased risk for toxicity and the higher incidence of second primary malignancies.”
Bashir and colleagues identified all patients with multiple myeloma placed on lenalidomide maintenance from January 2007 to December 2013 after an autologous HSCT at MD Anderson Cancer Center.
The study excluded patients who received maintenance therapy with other agents. The majority of patients (85%) received conditioning with single-agent melphalan. Lenalidomide doses ranged from 5 mg to 15 mg per day.
The researchers evalauted response, disease progression and relapse based on International Myeloma Working Group criteria.
Median follow-up was 26.6 months (range, 4.3-78.7).
The study included data from 464 patients (median age, 60.1 years; range, 30.9-80.2; 56% men), with a median time to HSCT from diagnosis of 7.2 months (range, 1.7-170.2).
The cohort had a median time to lenalidomide maintenance initiation of 4.2 months (range, 0.9-61.7). Forty-six percent of patients (n = 213) initiated maintenance earlier than 4 months.
The overall response rate was 97%. A total of 158 patients (36%) experienced a response improvement during maintenance — including 86 patients who achieved a complete response — which increased the ORR to 98%.
Maintenance therapy increased the complete response rate from 40% (n = 175) to 59% (n = 261). Median time to complete response after initiation of maintenance therapy was 8.6 months (range, 0.9-46).
The entire population had a median PFS of 38 months and a median OS of 78 months. Patients with high-risk cytogenetic features (n = 83) had a median PFS of 24.6 months and a median OS of 67.7 months; for patients without high-risk cytogenetics, the median PFS was 39.6 months, and median OS had not been reached (P < .001).
Timing of maintenance therapy initiation (< 4 months vs. 4 months) did not influence PFS (31.9 months vs. 31.5 months) or OS (64 months vs. not reached). The researchers also did not observe any significant PFS and OS differences based on whether patients did or did not achieve complete response after HSCT (PFS, HR = 1.17; OS, HR = 1.28).
However, duration of maintenance therapy did affect outcomes. Survival improved among patients who remained on maintenance for more than 2 years (PFS, HR = 0.13; OS, HR = 0.09) or for more than 3 years (PFS, HR = 0.02; OS, HR = 0.05).
The researchers observed 12 cases of second primary malignancies in the cohort, including myelodysplastic syndrome (n = 4), melanoma (n = 2), sarcoma (n = 2), acute myeloid leukemia, lung cancer, Hodgkin lymphoma and squamous cell carcinoma of the skin (n = 1 for each).
The median time to development of a second primary malignancy was 2.2 years (range, 0.6-5.5).
Disease progression served as the most common reason for maintenance discontinuation (n = 143). Twenty percent of the cohort (n = 91) discontinued due to adverse events.
Study limitations included the retrospective design, lack of complete data from all patients and a lack of standardization for second malignancy screenings.
“However, we have conducted an exhaustive analysis of the impact of the duration of lenalidomide maintenance on survival and the incidence of second primary malignancies, and we conclude that conceivably the most practical approach is to continue maintenance lenalidomide until unacceptable toxicity or disease progression after autologous HSCT,” the researchers wrote.
The prolonged survival observed in this study, coupled with low rates of second malignancies, may assuage fears about the association of adverse outcomes and extended maintenance therapy, Saad Z. Usmani, MD, FACP, director of plasma cell disorders and director of clinical research in the department of hematologic malignancies at Levine Cancer Institute at Carolinas HealthCare System, as well as a HemOnc Today Editorial Board member, wrote in an accompanying editorial.
“Does this study answer any of the major questions posed here? It probably does not, but it may support the notion that lenalidomide maintenance does provide a survival benefit to real-world patients, and there is probably a group of patients who may even benefit from a longer duration of lenalidomide maintenance,” Usmani wrote. “These data will be important in answering most of the questions posed specifically about lenalidomide maintenance. In my practice, lenalidomide maintenance until relapse/progression is recommended to all upfront posttransplant patients, with high-risk patients also receiving bortezomib [Velcade, Millennium/Takeda].”
Available data support lenalidomide maintenance as standard of care; however, before personalized maintenance decisions can be made for multiple myeloma patients, knowledge gaps must be filled, Usmani wrote. – by Cameron Kelsall
Disclosure: Bashir reports research funding from, or advisory board positions with, Celgene, Millennium, Spectrum Pharmaceuticals and Takeda. Please see the full study for a list of all other researchers’ relevant financial disclosures. Usmani reports research funding and speakers fees from, as well as consultant roles with, Array Biopharma, Celgene, Janssen, Millennium, Onyx, Pharmacyclics, Sanofi and Takeda.
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