The treatment of patients with multiple myeloma is poised to undergo a dramatic transformation, as novel monoclonal antibodies and combination strategies race toward approval.
Kenneth C. Anderson, MD
The treatment of patients with multiple myeloma is poised to undergo a dramatic transformation, as novel monoclonal antibodies and combination strategies race toward approval. To gain insight into this rapidly changing treatment environment, OncLive interviewed multiple myeloma expert Kenneth C. Anderson, MD, from the Dana-Farber Cancer Institute and a Giant of Cancer Care in Multiple Myeloma, on the new agents currently in development.
OncLive: What are some of the most promising agents currently being explored in the field of multiple myeloma?
Anderson: Monoclonal antibodies, or in particular immunotherapies, have been an area of research in myeloma for many decades. There are two main targets for monoclonal antibodies that look very promising at the present time. The first one is elotuzumab, which is directed at an antigen called SLAMF7. We and others have found this antigen in patient tumor cells and we have studied the function of SLAMF7 on multiple myeloma cells and found that a humanized antibody directed against that target mediated antibody-dependent cellular cytotoxicity.
This and much other experimental data, contributed to the rationale to go quickly to the clinic. As a single agent, elotuzumab achieved stable disease in patients whose myeloma was progressing.
Excitingly, because of Dr Tai’s work showing that lenalidomide, the immunomodulatory drug, added to elotuzumab upregulated its activity in our preclinical models, this was quickly translated and 80% to 90% of people responded, with responses lasting up to 33 months including relapsed/refractory and high-risk myeloma patients.
Phase III trials have already been completed and this particular antibody will probably be approved sometime in 2015.
The target called CD38 is a little different from SLAMF7 because it’s expressed surely on myeloma cells but on many other cells too. These cells include immune-effector cells or endothelial cells. So we were fearful that there might not be a therapeutic index or a therapeutic window if we were to target this antigen, the adverse effects might be prohibitive.
Suffice it to say that there are antibodies, humanized antibodies, against CD38. One is called daratumumab and a second one is called SAR (SAR650984). Both of these CD38 antibodies have single agent activity but both are now going forward combined with lenalidomide, because this can markedly increase the antibody-dependent cellular cytotoxicity and the frequency of response.
Can you discuss the biology behind these combinations?
The basis for combining monoclonal antibodies and lenalidomide has been worked out quite precisely. Immunomodulatory drugs, such as lenalidomide, increase the activity of T lymphocytes, natural killer cells, and also NK T cells, the hybrid cell. They increase the number and function of these immune-effector cells. Conversely, they also downregulate the function of what are called T regulatory cells. These T regulatory cells are at least in part responsible for inhibiting the immune response in patients with myeloma.
Lenalidomide by upregulating the effector cells and relieving the repression on the immune system, results in an overall upregulation of the immune response.
Now, if you give these agents in combination with an antibody, you’re not only upregulating the immune response, but you’re doing it in a way that you will selectively augment immunity against that antibody targeted, in this case, at the myeloma tumor cell.
What research is going on involving PD-1 inhibitors for the treatment of hematologic malignancies?
Many of us, myself included, have been excited about immune therapies for many decades and are very excited that the promise seems to be coming. Monoclonal antibodies and immunomodulatory drugs are both arms of immune therapies but there are two other areas that are most exciting.
Vaccines against entire tumor cells or vaccines against peptides that are directed against particular cancers have not been very effective in the past. They have been explored extensively at the Dana-Farber Cancer Institute and elsewhere but what’s exciting now is that the new excitement is predicated upon the so-called checkpoint inhibitor.
Tumor cells pretty universally express either PD-L1 or PD-L2. Effector cells, including mostly T cells, express PD-1. The ligand receptor interaction between either PD-L1/2 and PD-1 is a down regulatory circuit; conversely, antibodies to either PD-1 or PD-L1/2 to block that circuit upregulate the host immune response.
There are now responses to these checkpoint inhibitors, either to PD-L1 antibody or PD-1 antibody, even in advanced solid tumors where patients have no other option. To me, the most exciting thing, and we’re doing this in the hematologic malignancies, is to use these various arms of the immune response, the antibodies, immunomodulatory drugs, and vaccines, not alone but in combination.
So we’ve combined lenalidomide with CD38 antibodies, we’ve combined lenalidomide with vaccines because once you get an immune response with a vaccine; you can upregulate it with lenalidomide. We are combining checkpoint inhibitors, the PD-1 antibody, with vaccines for the same reason. And finally we have monoclonal antibodies plus checkpoint inhibitors, because antibodies target particular cells and the checkpoint inhibitors upregulate the immune response.
So the excitement is really palpable. Even high-risk tumors can respond to this immune approach. Tumors that don’t have the mechanisms for death are responding to the immune approaches, such as those with p53 deletions.
Since the side effects are mild with vaccines, is there any talk about combining three of these agents?
I do think that’s the future. Early experiences, now over 60 years ago, of using a single agent and then combining drugs resulted in a cure rate in childhood acute lymphoblastic leukemia of 85%, and combination therapies have also cured Hodgkin’s disease and many other cancers. In this sense, immunotherapies of various kinds are going to be combined and I do think it’s only in combinations that we’re really going to see huge paradigm shifts and hopefully cures.