A protein biomarker predicts response to immunomodulatory drug (IMiD) therapy for multiple myeloma (MM). At PMO Live 2015, A. Keith Stewart, MB, ChB, Consultant, Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, presented a case study illustrating the relative merits of an MM-specific gene panel to test for targetable mutations and the measurement of cereblon as a predictive biomarker of response or resistance to IMiDs.
Case: High-Risk MM
A 69-year-old retired nurse with IgGκ MM presents with a hemoglobin of 92 g/dL and lytic lesions; her creatinine and calcium levels are normal. With an albumin level of 3.8 and an elevated β2-microglobulin level of 5.8 µg/mL, she is considered a higher-risk patient (International Staging System III). Using fluorescence in situ hybridization to define genetic risk reveals trisomy 9, which is generally considered a good prognostic feature, with 1q+ amplification, an adverse risk feature.
Overall, this patient would be in the intermediate to higher risk because of her high β2-microglobulin and 1q+ amplification. Gene expression tests are not widely accepted over concerns about reproducibility.
The introduction of proteasome inhibitors and IMiDs into therapy for MM has resulted in dramatic increases in survival over the past 2 decades. However, 25% of patients are still dying within the first 3 years of diagnosis, and for most patients, MM remains a chronic relapsing disease.
From whole genome sequencing, “we’ve learned that there’s no smoking gun in myeloma,” said Stewart. “A random assortment of mutations is present with disappointingly little information with respect to targetable lesions.”
A limited set of genes is recurrently mutated in MM, and with that knowledge, sequencing a whole exome is considered to be of little value in MM. An MM-specific gene panel was developed that encompassed common mutations, including drug-resistance gene markers. Using the panel, mutations are found in 66% of the panel genes of untreated and double-refractory MM patients. The average number of mutations per patient was 3. The clonal diversity of the mutational spectrum is dramatic: 50% of the mutations are present in <25% of the tumor cells, and 25% of mutations are found in <10% of the tumor cells (Ann Hematol. 2015;94:1205-1211). Targetable mutations found include BRAF in 9%, of which 5% were the classic V600.
Stewart related the discovery of 5 unique clones identified in 1 particular high-risk MM patient (Blood. 2012;120:1067-1076). When sampled over the entire disease course from diagnosis to terminal plasma cell leukemia, the frequency of 2 competing subclones was found to ebb and flow over time with chemotherapy. Therefore, suppression of a sensitive clone could allow a refractory clone to become proportionally more dominant, even though stable. A minor drug-resistant clone eventually proved lethal in this particular patient. The finding suggests that combination therapy targeting coexisting disease subclones is important for high-risk MM.
The biology (multiple clones with variable drug sensitivity) supports the need for combination chemotherapy in the case patient, so she received cyclophosphamide, bortezomib, and dexamethasone therapy for 4 months. The minor drug-resistant clone supports deep remission, so autologous stem cell transplantation was performed to obtain the deepest remission possible. The biology also supports continuous suppressive therapy, so she received maintenance lenalidomide 10 mg for 17 months.
The patient is enrolled on a clinical trial of carfilzomib and pomalidomide with dexamethasone. She becomes febrile and dyspneic on day 2 of therapy, and her urine output drops. She is seen in the emergency department; her creatinine level is up to 274 µmol/L, and her blood pressure is 182/102 mm Hg. Carfilzomib is discontinued, and she remains on pomalidomide and dexamethasone but does not respond. A research bone marrow is obtained.
The protein cereblon on chromosome 3 is the molecular target of IMiDs. It is required for the antiproliferative activity of IMiDs in MM. Lenalidomide-resistant MM cells have been shown to lack cereblon (Blood. 2011;118:4771-4779), and gene expression levels of cereblon predict response rates to pomalidomide and overall survival (OS) of pomalidomide-treated patients (OS of 9.1 months vs 27 months with lowest vs highest quartile of cereblon levels) (Leuk Res. 2014;38:23-28). About one-fourth of patients with relapsed/refractory MM have mutations in the cereblon pathway.
Conclusion
An MM-specific gene mutation panel is clinically viable and usually informative. Cereblon has a central role as a target of lenalidomide and pomalidomide. It therefore serves as a predictive biomarker of response or resistance to IMiD therapy, and measuring it prior to institution of IMiD therapy is useful and cost-effective.