COMMENTARY

Myeloma Data at ASH 2016 Focus on Novel Combinations

Saad Z. Usmani, MD

Disclosures

December 12, 2016

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Welcome to Medscape Oncology Insights. I am Saad Usmani, director of the Plasma Cell Disorders Program and director of Clinical Research and Hematologic Malignancies at the Levine Cancer Institute, Carolinas Healthcare System, in Charlotte, North Carolina. I am at the American Society of Hematology (ASH) 2016 Annual Meeting in San Diego, where there have been a number of important studies that I would like to highlight for you. I would like to focus on the novel combinations in several settings that have been presented at ASH this year, including smoldering myeloma, newly diagnosed multiple myeloma, early-relapse myeloma, and late-relapse/refractory disease.

Smoldering Myelomas

Within the early smoldering myelomas, Irene Ghobrial, MD, presented data combining elotuzumab with lenalidomide and dexamethasone in high-risk smoldering-myeloma patients.[1] The objective of her study was to see the time to active myeloma development in this patient population. She reported efficacy data on the first 39 patients. The response rates within that population were somewhere around the 70% mark, with some patients seeing better than very good partial responses (VGPR) rates. The data are early but are a testament to the type of evaluations being done for this subset of patients who are at high risk for progression to active myeloma. Although the debate is still going on about whether to treat or observe these patients, it is clear that a subset of smoldering-myeloma patients are at high risk of developing myeloma. We will get more data from the ECOG trial of lenalidomide versus observation, hopefully within the next year and a half, to resolve that debate. Investigations in this area are still needed, and it is encouraging to see this clinical trial showing safety and efficacy for the patients.

Newly Diagnosed Myeloma

In the newly diagnosed myeloma setting, there were two presentations on the use of carfilzomib, lenalidomide, and dexamethasone (KRD) as induction and consolidation in transplant eligible patients followed by maintenance therapy. One presentation[2] was from Todd Zimmerman, MD, and Andrzej Jakubowiak, MD, PhD, from the University of Chicago. This was an update of their data. The second study[3] was from the French myeloma group, with the same concept: utilization of the KRD regimen as induction and consolidation in the transplant-eligible setting.

The difference between the two studies was not in the robustness of response but the appearance of some cardiac events that occurred in the French study. It is important to distinguish the patient populations and the safety profile across these two studies without trying to do too much of a cross-comparison. These are early data, and we need to really tease into why there appear to be some cardiac signals with this combination. There are thoughts around vascular endothelial damage in preclinical models, but we do not have a clear answer to this. Nevertheless, the combination of KRD is very robust, and it does have the advantage of not causing neuropathy side effects, which can be seen with the predecessor regimen, RVD, where bortezomib has been utilized as the proteasome inhibitor of choice and is currently the standard of care in the United States.

Early Relapse

The other combinations of interest are in the early-relapse phase. There was a lot of excitement about daratumumab combinations, with lenalidomide-dexamethasone (len-dex) and bortezomib-dexamethasone being approved by the US Food and Drug Administration (FDA) this year after the release of the POLLUX[4] and CASTOR[5] trial data, respectively. These were large, randomized phase 3 studies comparing the combination of daratumumab and bortezomib-dexamethasone with bortezomib-dexamethasone as the standard-of-care arm in the CASTOR study, and the combination of daratumumab and lenalidomide-dexamethasone compared with the lenalidomide-dexamethasone regimen in the POLLUX trial. In both studies, the three-drug combination trumped the two-drug combination with exceptional depth of response, most impressively in the POLLUX trial. The DRD regimen of daratumumab, lenalidomide, and dexamethasone showed very impressive results of about 93% overall response rate, and the median progression-free survival has not been reached.

When looking at patients from a perspective of prior lines of therapy, whether it was one, two, three, or more, or cytogenetics, regardless of those particular features, it appears that the DRD regimen is robust across all subgroup analyses.[6] This is very encouraging, and we are going to continue to see daratumumab get engaged with other platforms within myeloma therapy in early lines of treatment.

Relapsed/Refractory Disease

The other combination of note is the checkpoint inhibitor pembrolizumab combined with lenalidomide-dexamethasone and pomalidomide-dexamethasone.[7] The settings are obviously different, but there appears to be good synergy. The objective of this type of regimen is more immunologic in nature rather than cytotoxic. These two clinical trials, particularly the pomalidomide-dexamethasone combination, presented by Ashraf Badros, MD, showed that there is very good rationale and activity for a checkpoint inhibitor and immunomodulatory drug combination with myeloma. The pomalidomide combination also included patients who were pomalidomide-refractory, showing a robust response.

These are the novel agents that are now being combined with available platforms and showing promise to be more clinically relevant in the next couple of years.

Thank you for joining me for this edition of Medscape Oncology Insights. This is Saad Usmani, reporting from ASH 2016.

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