The use of immunomodulatory drugs was likely one of the most effective and earliest true treatment developments in multiple myeloma. It started with thalidomide, which, in many ways, was superior to the alkylators and/or to the corticosteroids when given separately. However, many would argue that allogeneic hematopoietic stem cell transplantation was the first major advancement. While it may be a valuable option for some patients, I would not count that in the same category as the immunomodulators in terms of treatment efficacy.

As second- and third-generation immunomodulator drugs (ie, lenalidomide and pomalidomide) have become available, and now with the cereblon E3 ligase modulators iberdomide and CC-9480 in development, we have come to understand that these agents not only influence multiple myeloma cell survival but also have a major effect on immune function. Part of the success of the CD38-directed monoclonal antibodies daratumumab or isatuximab is that they synergize so nicely with immunomodulatory agents, beyond what a doublet in 2 different classes would generally add.

And I am optimistic, as we look to the data on the persistence of response with immune-based therapies such as bispecific antibodies and even chimeric antigen receptor (CAR) T-cell therapy, that immunomodulatory drugs may be good partners with those strategies and may enhance their efficacy as well. The idea is to use immunomodulatory drugs throughout the disease course as a way to kill multiple myeloma cells and to set up other agents for success. Given that we have drugs such as iberdomide or CC-9480 in development that are more potent immune simulators than either pomalidomide or lenalidomide, this field will become even more exciting.

The immunomodulatory drugs are appropriately named because they upregulate T cell, natural killer (NK) cell, and NKT cell responses. They also downregulate regulatory T cells, which are at least in part responsible for the immune compromise in patients with multiple myeloma. These treatments are wonderful partners with proteasome inhibitors and with monoclonal antibodies, as they upregulate antibody-dependent cellular cytotoxicity, among other activities.

We are in the midst of an extremely exciting time with novel immune therapies emerging, such as the bispecific T-cell engagers (BiTEs) and the CAR T-cell therapies. To focus on the utility of immunomodulatory drugs in this setting, we conducted a preclinical study of one of the BiTEs directed against B-cell maturation antigen, specifically looking at the effect of a combination with lenalidomide or pomalidomide. The results showed the synergistic killing of multiple myeloma cells at low doses of the BiTEs combined with low doses of either lenalidomide or pomalidomide, as well as at lower effector cell to target cell ratios (ie, lower ratios of immune cells to multiple myeloma cells). In other words, the ability to add immunomodulatory drugs to novel immune therapies may not only enhance efficacy but also may allow for the use of lower doses of each, thereby improving the therapeutic index.

Along with enhancing response and achieving an improved side-effect profile, we need to determine whether immunomodulatory drugs can prolong the responses to novel immune agents, just as they have prolonged responses when used as maintenance therapy. Although CAR T-cell therapies have achieved a remarkable depth of response even in advanced multiple myeloma, the durability of these responses has been 8 to 12 months, and clinical trials will determine whether immunomodulatory drugs can prolong responses.   

Empirical evidence is what we are ultimately going to rely on. It is almost expected that new drugs will be tested with an immunomodulatory drug, given the potency of these agents, to see whether the partnership will be a good one. We know that immunomodulatory drugs work in multiple myeloma, but we do not know exactly what will happen when these pairings are tested in the clinic. I suspect that we will someday have that empirical evidence on the feasibility, safety, and efficacy of combining new drugs with immunomodulatory agents. My hypothesis is that we will see an augmentation of the activity of these immune-targeted therapies, but, since much of this is currently unknown, we need empirical evidence.

There are a number of immune-based strategies now, and we tend to classify them as monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, or cellular therapies such as CAR T cells. However, in the long run, I believe that it is more important to look at the targets and determine whether resistance has developed. Whether the target is CD38 or BCMA, or like we saw at the American Society of Hematology Annual Meeting & Exposition last year, GPRC5D, which is an orphan receptor, or FCRH5, and so on.

Thus, you pick the antigen and then consider the circumstances to target it, and this is a way of looking at it that makes it easier to consider combinations. For instance, suppose the combination of an anti-CD38 therapy with BCMA-directed therapy is of interest. Then you would look at the available BCMA-directed options and decide which one would be best combined with an anti-CD38 monoclonal antibody.