New myeloma drugs improve response and extend survival
In this interview, Dr David Henry, the Editor-in-Chief of The Journal of Community and Supportive Oncology, and Dr Ken Anderson, the Kraft Family Professor of Medicine at Harvard Medical School and an international thought leader and investigator in myeloma, discuss three cases of patients with myeloma that are indicative of the remarkable therapeutic advances in oncology in general, and in myeloma in particular. In the last 10-15 years, numerous approvals by the US Food and Drug Administration have transformed the treatment landscape for multiple myeloma by providing patients and oncologists with many new options and combination possibilities for treating the disease. And since many of the agents have been tested in advanced myeloma, their use has edged the disease toward initial management. The encouraging news is that in the new classes of drugs, and especially the second-generation drugs, response rates, progression-free disease, and overall survival are significantly better, with some combinations yielding response rates of up to 70%-80%, and overall and progression-free survival of up to 10 years.
Listen to the interview here
Received for publication November 2017
Published online first December 8, 2017
Correspondence David.Henry@uphs.upenn.edu
Disclosures The authors report no disclosures/conflicts of interest.
Citation JCSO 2018;16(1):e53-e58
©2018 Frontline Medical Communications
doi https://doi.org/10.12788/jcso.0376
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DR HENRY Before we close, I have a couple practical questions with these antibodies. Daratumumab has the track record of first-treatment severe reactions and long infusion times. How long are you anticipating the first daratumumab treatment takes? There has been some talk that maybe splitting it in half and going over 2 days is easier on the patient and the infusion center. Have you done that?
DR ANDERSON Yes, I think that’s a very important point. We need to be thinking – first and foremost – about efficacy of our therapy. Equally important, however, are the safety profile and the user-friendliness for the patient. Daratumumab infusions are quite long – on the order of 8 hours or longer on day 1 of infusion. And to date, all the clinical trials have used daratumumab infusions weekly for 8 treatments, followed by 8 treatments given every 2 weeks. Then monthly daratumumab is given as a maintenance therapy. Thus, there is a requirement for multiple outpatient clinic visits that can be prolonged.
One of the opportunities that’s being tested is to give daratumumab subcutaneously. While this is being evaluated in protocols now, the results that have been reported at our national meetings look to be quite promising in terms of efficacy, similar to results with the intravenous administration. Obviously, this would allow for a much more convenient clinic visit and shorter time for the patients being treated.
I should mention that the other antibody, elotuzumab, has been approved in combination with lenalidomide and dexamethasone.15 The infusions with lenalidomide, dexamethasone, and the antibody elotuzumab are much shorter, on the order of 2- or 3-hour visits. The place for elotuzumab in the management of relapsed myeloma is yet to be totally defined. We tend to use it now in the setting of more indolent relapses, where patients might have a slowly rising monoclonal protein. Elotuzumab-lenalidomide-dexamethasone has maintained an overall survival advantage at 4 years compared with lenalidomide-dexamethasone when used in relapsed myeloma.
We are quite excited about both antibodies. Daratumumab tends to get most of the activity, as it achieves responses as a single agent,16 and the depth of the responses are markedly increased when it’s combined with lenalidomide-dexamethasone or bortezomib-dexamethasone.17,18 However, one shouldn’t forget elotuzumab15 based on its tolerability and the survival advantage I mentioned at 4 years.
The final point is that we think about myeloma genetically at the time of diagnosis and relapse in terms of standard or high-risk disease. One of the hallmarks of high-risk disease has been 17P deletion or P53 dysfunction. One of the most exciting outcomes of the development of monoclonal antibodies has been the responses observed even in the context of P53 deletion. Clearly, antibody-mediated cellular cytotoxicity, complement-mediated cytotoxicity, and other mechanisms of action of these antibodies do not require normal P53 function. The important point, therefore, is that what has previously been thought of as high-risk disease can nowadays be effectively treated with these new immune treatments, correlating with the marked improvement in survival and overall outcome.
DR HENRY We have outlined 3 kinds of myeloma patients we see, and especially interesting is the last patient, who has relapsed and then progressed, and in whom newer drugs have a role. Thank you for such a complete and thorough discussion, Dr Anderson.
