It was a pleasure to be attending the satellite symposium in which we were discussing about the role of monoclonal antibodies for patients with multiple myeloma. First we did a general introduction about what is the role, what is the mechanism of action of monoclonal antibodies - is there any rationale to be used in the treatment of patients with myeloma? The answer in general is yes because cancer cells in general, and myeloma cells in general, try to avoid the immune control. So there is a good rationale to use immunotherapy strategies for the treatment of patients with myeloma and monoclonal antibodies are included within these immunotherapy strategies.
We can use monoclonal antibodies as part of the passive immunotherapy when these monoclonal antibodies target antigens present on the surface of the plasma cells and directly act on the tumour. These monoclonal antibodies are called naked monoclonal antibodies and we can target CD38 but also we can target other different antigens like CD40, CD56 or even molecules present in the bone marrow microenvironment like BAFF, APRIL or interleukin-6.
The mechanism of action of these monoclonal antibodies includes some activities like complement-dependent cytotoxicity, antibody-dependent cell phagocytosis, antibody-dependent cell cytotoxicity and also these monoclonal antibodies are able to induce direct apoptosis of the plasma cells. In addition, with this passive immunotherapy we have also monoclonal antibodies included within what we call active immunotherapy because these monoclonal antibodies target the immune cells and they try to enhance and to stimulate the cells of the immune system. Within this active immunotherapy we have basically the checkpoint inhibitors, monoclonal antibodies targeting the PD-1 PD-L1 pathway often exploited by many solid tumours but also in myeloma, the result of overexpression of PD-1 and PD-L1 in T lymphocytes and also in the myeloma cells. So there is a good rationale to use all these monoclonal antibodies in myeloma.
In fact, if we move to the clinical we have already preliminary but also consolidated results about the use of monoclonal antibodies in myeloma. We can use elotuzumab, a monoclonal antibody targeting SLAMF7, that has showed no activity as single agent. However, there is a good rationale to be combined with immunomodulatory drugs and, in fact, elotuzumab was combined with len-dex in a phase III randomised trial, the ELOQUENT trial, and elo plus RD resulted significantly superior in terms of progression free survival and this combination is already approved for the treatment of relapsed and refractory myeloma patients.
Another monoclonal antibody is daratumumab targeting CD38. Daratumumab is already approved as a single agent in the US and also in Europe according to the results of the SIRIUS trial in which daratumumab was shown to be effective as single agent in heavily pre-treated myeloma patients. The main benefit these patients get from daratumumab single agent was a benefit in terms of overall survival because the overall survival was of twenty months when for this patient population the median expected overall survival would be only eight or nine months.
We have also results coming from other CD38 monoclonal antibodies like isatuximab or MOR202, evaluated also as single agent in heavily pre-treated myeloma patients with a similar efficacy, approximately 30% of overall response rate. But these new CD38 monoclonal antibodies have not been approved yet. The future, of course, of these CD38 monoclonal antibodies effective as single agents is to use them in combination and, in fact, we have already consolidated results coming from daratumumab in combination with two backbones in relapsed and refractory myeloma patients. Daratumumab plus lenalidomide and dexamethasone evaluated in the POLLUX trial with a significant benefit in terms of progression free survival, complete response rate and even minimal residual disease negative status. So daratumumab plus lenalidomide and dexamethasone is another new standard of care for the treatment of relapsed and refractory myeloma patients already approved in the United States and it will be very soon approved here in Europe because the CHMP gave a positive report just one week ago. Not only for dara in combination with dex but also for dara in combination with bortezomib and dexamethasone, another backbone regimen for the treatment of relapsed and refractory myeloma patients. Dara plus VD was significantly superior to VD and, again, it will be a new standard of care for patients with myeloma after at least one prior line of therapy.
The other CD38 monoclonal antibodies like isatuximab and MOR202 have been also evaluated in combination with the backbone regimens, mainly IMiD based combinations – lenalidomide-dexamethasone, pomalidomide-dexamethasone – with encouraging results but we don’t have any result available yet at the present time coming from phase III randomised trials.
Concerning the other monoclonal antibodies like the checkpoint inhibitors, we have also promising efficacy results when these checkpoint inhibitors have been evaluated in relapsed and refractory myeloma patients but in combination with immunomodulatory drugs because, again, one important concept is that these PD-1 or PD-L1 monoclonal antibodies showed no activity or just a very modest activity when they were evaluated as single agent. In combination with IMiDs the results are encouraging, especially because this combination showed to be active even in patients refractory to lenalidomide or refractory to pomalidomide. But, again, we have to wait to have results coming from phase III randomised trials.
In summary, what is the future of monoclonal antibodies? I think that probably the results coming from CD38 monoclonal antibodies, and specifically daratumumab because the development is much more wide than for the other monoclonal antibodies, that is to be a backbone to which the backbone regimens are going to be added. In the future we will use daratumumab in the upfront setting and, in fact, in the symposium Dr Moreau presented the trials that are being conducted in the upfront setting combining daratumumab with VTD, one of the standards of care for young, newly diagnosed myeloma patients, or in combination with lenalidomide and dexamethasone in the MAIA study for non-transplant eligible myeloma patients or with bortezomib melphalan and prednisone, another standard of care, for non-transplant eligible myeloma patients. So at the end the monoclonal antibodies are going to be the backbone and, of course, we have to select what is the optimal sequencing of treatment in the near future for our patients with myeloma but also this is an important question. I would like to summarise the symposium saying the best first so if we start in the near future to use triplet combinations plus monoclonal antibodies, and Dr San Miguel was talking about the possibility of curing myeloma, with these attractive options of therapy, with this very effective combination coming from monoclonal antibodies plus proteasome inhibitors, IMiDs and corticosteroids we will be probably able to cure some patients with myeloma.
