Summary
Multiple myeloma is a heterogeneous malignancy, with individuals having disease that can display a wide array of genetic abnormalities. Depending on the specific abnormalities present, differing treatments may be available or clinical outcomes may be observed. Among the more frequently encountered anomalies in these patients are translocations involving the chromosome 14, trisomies and amplifications, or deletions involving chromosomes 1, 13, and 17.
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Original Article
Study Assesses Outcomes in Patients With t(11;14) Multiple Myeloma
Oncology Times
Richard Simoneaux
Multiple myeloma is a heterogeneous malignancy, with individuals having disease that can display a wide array of genetic abnormalities. Depending on the specific abnormalities present, differing treatments may be available or clinical outcomes may be observed. Among the more frequently encountered anomalies in these patients are translocations involving the chromosome 14, trisomies and amplifications, or deletions involving chromosomes 1, 13, and 17.
One translocation that is frequently encountered in plasma cell disorders is t(11;14). This abnormality, which can be found in diseases such as mantle cell lymphoma or chronic lymphocytic leukemia, is also found in approximately 15 percent of patients with multiple myeloma. This translocation had been previously considered a standard risk abnormality, however, recent clinical data suggest an association with less than expected outcomes.
Yet, this translocation also suggested a potential targeted therapy for these patients. Preclinical studies with human myeloma cell lines and primary multiple myeloma tissue samples that were positive for the (11;14) translocation showed a high susceptibility to venetoclax, a targeted small molecule inhibitor of Bcl-2 protein (Leukemia 2014;28(1):210-212).
A subsequent phase I/II clinical study (NCT01794520) evaluating venetoclax in patients with relapsed or refractory multiple myeloma showed particular efficacy for the Bcl-2 inhibitor in the subset of patients with t(11;14)-based disease (Blood 2017;30(22):2401-2409).
Recently, a retrospective study was performed by members of the International Myeloma Working Group to evaluate clinical outcomes in patients with t(11;14) multiple myeloma. One participating clinician in this study was Shaji Kumar, MD, Professor of Medicine, Division of Hematology, Department of Internal Medicine, Mayo Clinic. Findings from this study were recently presented by Kumar at the 2019 ASH Annual Meeting by (Abstract 3066).
Concerning their findings, Kumar noted, “In this patient population, two particular therapies proved particularly helpful for improving overall survival: autologous stem cell transplant and immunomodulatory agent plus proteasome inhibitor combination therapy.”
“This was a multicenter study with the aim of identifying clinical outcomes of patients with t(11;14)-based multiple myeloma, using a retrospectively assembled cohort,” he stated. The study included patients who were diagnosed with multiple myeloma from 2005 to 2015 who had confirmation of the t(11;14) translocation via fluorescence in situ hybridization (FISH) analysis performed within 6 months of diagnosis, and who had treatment details available; if patients were still alive, a minimum of 12 months of follow-up were required.
Study Results
“A total of 1,216 patients were included in the present analysis, with a median age of 62.6 years, and 58.7 percent of whom were male,” Kumar noted. For the entire cohort, the median follow-up time from diagnosis was 51.9 months; importantly, 69.1 percent of the patients were still alive as of the last follow up. The International Staging System stage distribution for the patients included was as follows: Stage I – 35.7 percent, Stage II – 34.0 percent, and Stage III – 15.1 percent. Staging data for the remaining patients were missing.
In addition to the aforementioned t(11;14) translocation, the following co-occurring anomalies were detected in patients using FISH: trisomies – 3.5 percent, del 13q – 13.3 percent, 1q amp – 8.8 percent, and del 17p or monosomy 17 – 5.8 percent.
The following distribution of initial therapies was noted in the study participants: immunomodulatory agent – 27.2 percent, proteasome inhibitor – 45.9 percent, immunomodulatory agent plus proteasome inhibitor combination – 17.7 percent, and a non-novel agent – 9.0 percent.
“Early stem cell transplant, which was defined as within 12 months of the start of first-line treatment, was employed in nearly half (49.4%) of the patients,” Kumar stated. A measure of therapeutic effectiveness, the median time to next treatment after starting initial treatment was 26.6 months (95% CI: 23.9-29.2 months). For the entire cohort, the median overall survival (OS) from diagnosis was 95.1 months (95% CI: 85.9-105.9 months). The 4-year survival estimates for patients were divided into two separate groups: those diagnosed from January 2005 to December 2009 (77.5%), and those from January 2010 to December 2014 (78.6%). For those patients having any one high risk FISH-confirmed abnormality (e.g., del 17p or 1q amp), the median OS was 67.5 months (range: 55.2-97.1 months), while the median OS for those lacking a high-risk feature was 101.7 months (range: 89.7-107.3 months).
“Those patients with early stem cell transplant, i.e., within 12 months of diagnosis, had better OS, with a median value of 108.3 months (range: 103.8-133.0 months), as compared to 69.8 months (range: 61.5-80.3 months) for those who did not receive that therapy,” Kumar noted.
Discussion
“As a general rule,” Kumar observed, “patients with t(11;14) without concurrent high-risk FISH abnormalities have an excellent survival. The best survival data were noted in two groups of patients: those received a proteasome inhibitor plus immunomodulatory agent combination, and those who received autologous stem cell transplant as part of their initial therapy.
“Although the patients in the later lines that received newer drugs such as venetoclax and daratumumab had high response rates and durable responses, their numbers were rather limited,” Kumar cautioned. “The identification of venetoclax as a potentially useful targeted therapy for this patient population was important, and with the groundwork we have done with this study, we can now track the effectiveness of this agent in real time,” Kumar concluded.
Richard Simoneaux is a contributing writer.