1. Fuerst, Mark L.

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NEW YORK CITY-A combination of the monoclonal antibody daratumumab plus lenalidomide and dexamethasone is the best available treatment for relapsed/refractory multiple myeloma patients, according to a myeloma expert who presented a case for this triple therapy at Lymphoma & Myeloma 2017: An International Congress on Hematologic Malignancies.


"The ideal therapy for relapsed multiple myeloma patients is cyclical from induction through potential transplantation and maintenance. This cycle repeats as patients relapse again," said Tomer M. Mark, MD, MSc, Associate Professor of Medicine? at the University of Colorado in Denver.


Survival worsens as patients become more refractory to therapy. Survival after frontline treatment is 20-50 months. Relapsed patients survive 14-16 months, and relapsed/refractory patients survive only 6-10 months. Treatment limitations and comorbidities also vary as the disease progresses. Some 15 percent of frontline patients have peripheral neuropathy on diagnosis. In relapsed patients, the incidence of peripheral neuropathy is more than 80 percent. They also often have compromised bone marrow reserve and cytopenia. Relapsed/refractory patients are generally intolerant or ineligible for available therapy, Mark noted.


Several new drugs have been approved in the past 5 years. "There are many choices for your relapsed patient," he said, including carfilzomib, pomalidomide, and daratumumab.


In 2015, daratumumab was approved as monotherapy for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug (IMiD) or are double-refractory to a proteasome inhibitor or IMiD. In 2016, the daratumumab label was updated to include combinations with lenalidomide and dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy.


In 2017, the daratumumab label was updated again to include a combination of pomalidomide and dexamethasone for the treatment of multiple myeloma patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.


"What defines the optimal next regimen in relapsed multiple myeloma?" Mark asked. Best response can be measured by overall response rate (ORR) or minimal residual disease (MRD) and survival by progression-free survival (PFS) or overall survival (OS). Safety factors, in particular for elderly patients and those with renal failure, need to be considered. Timing is also important. "Do we miss out on maximum benefit if a treatment is used in later lines of therapy?" he asked.


MRD defines the ideal treatment as a surrogate for PFS and OS. New studies provide more validation that MRD is a valid endpoint, he said. "The benefit of complete response or better is mostly due to achievement of MRD-negative status, especially in the case of high-risk cytogenetics," said Mark.


Elotuzumab Combination

Another monoclonal antibody, elotuzumab, combined with lenalidomide and dexamethasone for relapsed or refractory multiple myeloma also has shown promising results. The randomized phase III ELOQUENT-2 study evaluated the efficacy and safety of the triple combination versus lenalidomide plus dexamethasone. Elotuzumab plus lenalidomide/dexamethasone reduced the risk of disease progression or death by 30 percent versus lenalidomide/dexamethasone.


In an extended 3-year follow-up, the ORR increased to 79 percent with the addition of elotuzumab from 66 percent without elotuzumab (Br J Haematol 2017;178(6):896-905). The triple combination reduced the risk of disease progression/death by 27 percent versus the doublet therapy. Interim OS demonstrated a trend in favor of elotuzumab plus lenalidomide/dexamethasone. In patients with more median time from diagnosis and one prior therapy, the triple combination resulted in a 53 percent reduction in the risk of progression/death versus the doublet.


"Response rates increased modestly with elotuzumab, with a nice improvement in PFS, with 12-15 percent who did not progress at 1-3 years," Mark explained.


Daratumumab Update

Recently updated efficacy data on daratumumab show "responses continue to deepen in those patients who receive daratumumab plus lenalidomide plus dexamethasone with longer follow-up," Mark stated. "MRD-negativity rates were more than three-fold higher at all thresholds. And MRD-negativity is associated with better outcomes." Even among patients who were refractory to their last line of therapy, daratumumab still showed activity, he noted.


A combination of daratumumab plus lenalidomide may be more effective in patients with a short response or no response to first-line therapy. "A daratumumab/lenalidomide combination may synergize to enhance T-cell anti-tumor immunity," said Mark. T-cell receptor sequencing to assess clonality shows increased clonality of T cells with a combination of daratumumab plus lenalidomide and dexamethasone, but not in those who receive lenalidomide and dexamethasone. "The fraction of T cells in circulation increase with the daratumumab combination," he stated.


With so many combinations available, how does a clinician choose the optimal therapy for relapsed patients? A recent meta-analysis of 17 clinical trials of 18 treatment options for relapsed/refractory multiple myeloma provides some answers. This systematic literature review synthesized all efficacy evidence, enabling a comparison of all current treatments.


The combination of daratumumab, lenalidomide, and dexamethasone was identified as the best treatment. It was most favorable in terms of PFS and probability of being best. This treatment combination reduced the risk of progression or death by 87 percent versus dexamethasone, 81 percent versus bortezomib plus dexamethasone, and 63 percent versus lenalidomide plus dexamethasone.


The researchers concluded "until additional data from randomized studies are available, on the basis of this analysis, the combination of daratumumab, lenalidomide, and dexamethasone seems to be the best treatment option."


The combination of carfilzomib, lenalidomide, and dexamethasone has also shown to be effective as upfront therapy for multiple myeloma. Mark suggested that adding daratumumab to this combination may provide additional benefits for relapsed patients, and this is being explored in clinical trials now.


Mark L. Fuerst is a contributing writer.