Salvage therapy for multiple myeloma patients should be tailored to molecular and clinical risk criteria, and tailored to individual disease characteristics when possible, according to two myeloma experts who debated at the 2017 Great Debates & Updates in Hematologic Malignancies meeting, held April 7-8.
Myeloma is a translational success story, said Robert Orlowski, MD, PhD, Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston. Data from the NCI Surveillance, Epidemiology, and End Results program show a decline in mortality for myeloma, with a median survival of 7-10 years, especially in good risk patients.
“The impact of many new drugs is not yet seen. The many novel agents recently approved include HDAC inhibitors, immunomodulatory drugs (IMiDs), monoclonal antibodies, and proteasome inhibitors (PIs),” Orlowski noted.
Challenges still remain. “Unmet medical needs include high-risk myeloma and relapsed/refractory disease. Myeloma incidence is rising, and the cost of care is among the highest for any malignancy.”
Treatment algorithms are exclusively driven by clinical factors and focus on previous therapy, not molecular factors. “Molecular targeting maximizes the likelihood of patient benefit, reduces exposure to unnecessary toxicity, minimizes delay to receiving definitive therapy, and produces substantially enhanced cost-effectiveness. Together, this leads to better outcomes for less money,” stated Orlowski.
He provided case studies on precision medicine with IMiDs, monoclonal antibodies, and PIs.
Cereblon, an IMiD binding partner, is a protein that in humans is encoded by the CRBN gene. “CRBN depletion is cytotoxic to myeloma. Surviving cells are highly resistant to lenalidomide and pomalidomide. Patients exposed to lenalidomide have lower CRBN levels,” Orlowski said.
Emerging data show CRBN can be used to predict outcome. In the upfront setting, CRBN expression by gene expression profiling (GEP) influences thalidomide maintenance efficacy. Patients with higher CRBN expression had better progression-free survival (PFS) and overall survival (OS) than those with lower expression. “There is a strong relationship of CRBN to response depth and quality in newly diagnosed patients treated with lenalidomide and dexamethasone.”
In the lenalidomide/dexamethasone relapsed/refractory setting, CRBN expression is related to response in pomalidomide-treated patients.
“Can CRBN help in treatment decision-making upfront?” asked Orlowski. If CRBN expression by GEP is high, then the best treatment may be thalidomide plus dexamethasone. If there is medium expression, then IMiD-based combinations may be better, or low expression, then choose a strategy to increase CRBN. If there is no CRBN expression, avoid IMiDs altogether.
Daratumumab has been shown to be effective in myeloma patients. Susceptibility of primary cells to daratumumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) does not depend on disease status. Higher CD38 levels correlate with greater daratumumab sensitivity through ADCC in combination with lenalidomide or bortezoimib, Orlowski explained. ATRA also increases CD38 expression levels and enhances ADCC against primary cells.
Orlowski outlined a potential strategy using evaluation of plasma cell surface CD38 and signaling lymphocytic activation molecule 37 (SLAM 37) density. If CD38 is high and SLAM 37 low, use a daratumumab-based regimen. If SLAM 37 is high and CD38 is low, use an elotuzumab-based regimen. If CD38 is high and SLAM 37 is high, use either daratumumab or elotuzumab. If CD38 is low and SLAM 37 is low, use ATRA/daratumumab or another therapy.
Tight junction protein 1 (TJP1) is a gene of interest because its expression predicts response and durability to the PI bortezomib. TJP1 expression also predicts time to progression.
Orlowski suggested a strategy to evaluate plasma cell TJP1 expression to choose therapy. If TJP1 expression is high, use PIs; if medium expression, a PI-based regimen; if low expression, increase TJP1 expression; and if zero expression, avoid PIs.
In summary, Orlowski noted, “Myeloma patients are doing better than ever and this will likely continue as the full effect of our current drugs is not yet being seen. Many challenges remain, including areas of unmet need and the rising clinical and financial toxicity of multi-novel agent regimens. Molecularly adapted therapy using biomarker-driven approaches is one vital key to improving outcomes of patients while managing costs.
“We have a better understanding of how our current novel agents work. Data are emerging about the utility of myeloma cell and patient-specific factors that are attractive as biomarkers. This must be valid in the context of combinations. An even stronger collaborative effort is needed between academia, industry, patients and regulators to support validation studies. More new drugs cannot be our only answer.”
Salvage therapy should be the same for everyone, but since each patient is different, treatment has to be personalized, said Ruben Niesvizky, MD, Director of the Multiple Myeloma Center at New York Presbyterian Hospital-Cornell Medical Center. “Consideration needs to be made for disease characteristics and prior therapy, including line of therapy, plateau phase, aggressiveness of relapse, relapsed or refractory disease, and high-risk disease.”
Niesvizky noted that response duration decreases with successive therapies, and time to progression after stem cell transplant correlates with OS after initial relapse.
The nature of relapse is particularly important. “How did the patient present? Some 80 percent of patients share clinical features with presentation. Has there been a shift on presentation? Is there intact immunoglobulin to light chain only, non-secretory relapse, or extramedullary disease?” he asked.
“We cannot target one patient over another, and cannot target one single abnormality. We need a more global approach,” stressed Niesvizky. Multiple myeloma has more than 5,000 mutations. “In relapse, it is even more difficult to target a single molecular abnormality. We have metabolically active targets. It is best to combine to capitalize on synergy among agents.”
Carfilzomib, pomalidomide, and dexamethasone is a highly active combination in relapsed/refractory multiple myeloma using a once-weekly dosing schedule. In a phase I and II study, “compared to historical data, response rates are better than single-agent pomalidomide or carfilzomib and similar to carfilzomib/pomalidomide/dexamethasone using a twice-weekly dosing schedule,” Niesvizky said.
Adverse event rates are similar between once- and twice-weekly dosing. More patients reduced dose or discontinued in the twice-weekly arm. With monitoring used to optimize blood pressure, there was a lower incidence of all-grade and grade 3 or 4 cardiovascular events.
The ORR was 64 percent, and PFS was extended to 9.2 months. “This is a potential new paradigm, with reduced toxicity,” he stated.
Niesvizsky has led a single-center, phase II study of clarithromycin combined with pomalidomide and low-dose dexamethasone in relapsed/refractory multiple myeloma. A group of 114 patients had a median of five prior therapies, including 60 percent with high-risk cytogenetics. ORR was 70 percent and PFS was 8.67 months with a median survival of 19 months.
Another phase II study of pembrolizumab plus pomalidomide and dexamethasone led to a 60 percent ORR, PFS of 17.4 months and was well-tolerated.
“There are pitfalls of precision medicine. In the era of novel therapies, we need to consider the relapsed patient is of higher risk. Genomic instability precludes rational actionable molecular treatment. Individualized treatment is always preferred,” concluded Niesvizky.