New drug data challenge the ways we treat myeloma

At the recent annual meetings of the American Society of Clinical Oncology (ASCO) and the European Hematology Association (EHA), important data were presented on the monoclonal antibodies elotuzumab and daratumumab. The first acts against SLAMF7 and the second against CD38. These new targets on the surface of myeloma cells provide ways to attack myeloma separate from traditional chemotherapy and the immunomodulatory drugs (IMiDs) or proteasome inhibitor “novel” agents. The conventional resistance mechanisms linked to high-risk features such as t (4; 14) and 17p- can be circumvented.

But the question is, how much extra benefit is achieved on top of the recently developed novel double and triple combinations plus autologous stem cell transplant? Are we now facing the prospect of not just three drugs, but maybe four or five drugs as recommended strategies?

In the case of elotuzumab, the combination with lenalidomide and dexamethasone (Revlimid/dexamethasone) is required to achieve the added benefit reported by Dr. Sagar Lonial at ASCO. For patients with 1-3 relapses, the progression-free survival (PFS) was 19.4 months with Elo/Rd versus 14.9 months with Rd alone. Additional PFS benefit was seen at 2 years (41% versus 27%), indicating more sustained remissions with elotuzumab. Clearly this is important as a new class of agent which recruits NK cells to help attack myeloma. But elotuzumab does not have single-agent activity, and recent data have indicated substantial activity of other Rd combinations in the 1-3 relapse setting, such as carfilzomib (Kyprolis [K])/ Rd reported in the ASPIRE trial results versus Rd alone.

The data raise immediate philosophic and logistic challenges. At first relapse, for example, should we be pushing for the maximum response and PFS by adding elotuzumab to KRd? This seems reasonable, but we have no data for that. Or maybe it is okay to use the Kyprolis and elotuzumab combinations sequentially to achieve maximum ongoing disease control? And what about the toxicities and quality of life—plus costs of 2-, 3-, 4-, or 5-agent combinations? There are many questions, but no immediate answers.

Turning to the daratumumab data—also presented by Dr. Lonial at ASCO—the key difference versus elotuzumab is the significant single agent activity (daratumumab alone), with an overall response rate of 29% (≥50% improvement) in the relapsed and refractory setting. In this case, 95% of treated patients were double (iMid and proteasome inhibitor) refractory. The PFS was 4.7 months and 65% of patients were alive at 1 year (28 out of 31 responding patients).

These data fulfill what is generally considered to be an unmet need: providing a valuable treatment option for such relapsed/refractory patients. In this case, it is easier to envisage added benefit in combination with current regimens and easier to expect added benefit—despite the challenges of costs, toxicities, and potential impacts on quality of life. But again, trials are needed to carefully asses the value of this new monoclonal antibody in various disease settings.

At the recent IMWG Summit in Vienna, several sessions touched on these topics and led to very lively discussions. Do we need more standardized templates to evaluate patients in these upcoming more complex trials? Do we need new response criteria tools to allow better comparisons of treatment regimens? And how do we figure in costs and ultimate global access to these exciting new drugs? Outside of the US, specific trials are required to receive regulatory approval for each new combination. This is certainly a challenge.

So in all, the exciting new developments presented at the meetings this year were tempered by the need to carefully assess added benefits of new therapies and come up with the trial designs and combinations which are realistic moving forward. These are good problems to have, and will certainly engage the members of the International Myeloma Working Group (IMWG) in many fruitful discussions in coming months!

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