The treatment of multiple myeloma (MM) in 2020 includes at least seven different therapeutic classes: corticosteroids, conventional chemotherapy, immunomodulatory agents, proteasome inhibitors, deacetylase inhibitors, XPO1 inhibitors, and now the growing immunotherapy class, which includes monoclonal and bispecific antibodies, antibody-drug conjugates, and T-cell therapies. At this year’s ASH Annual Meeting, Ajai Chari, MD, will chair a session in which myeloma experts discuss the growing number of immunotherapy options in this disease, as well as the unmet medical needs that persist despite so many available therapies.
What does the immunotherapy landscape in myeloma look like today?
At the moment, we have four FDA-approved antibodies for treatment of MM: daratumumab and isatuximab (anti-CD38 monoclonal antibodies); elotuzumab (an anti-CS1 [SLAMF7/CD319] monoclonal antibody); and belantamab mafodotin (a BCMA-targeting antibody drug conjugate). While other classes of drugs also harness the immune system, these four agents comprise our current arsenal of antibody-based immunotherapy.
What is nice about immunotherapeutic approaches is that we generally do not see cardiac, renal, pulmonary, or hepatic side effects, because antibodies are engineered to bind specifically to the target of interest, thereby minimizing off-target effects. That is not to say that they do not have their own side effects, though.
Before the “boom” in the newer approaches, what were the standard treatment options?
Patients typically receive triplet induction therapy with a lenalidomide backbone, followed by autologous transplant (if eligible), and then maintenance therapy until disease progression. In the relapsed setting, we use a variety of triplet combinations, which are guided by patient factors, disease factors, and responses or side effects to prior therapy. We continue to use multiple triplet regimens until we have exhausted them. These approaches have resulted in improvements in the overall survival of MM.
However, we have issues of attrition and diminishing returns: If we start with 100 patients with newly diagnosed MM, not everyone is able to get to the nth line of therapy because, unfortunately, we still don’t have a plateau in overall survival. Also, with each subsequent line of therapy, treatment efficacy diminishes because the disease becomes more genomically complex and the ability to deliver effective immunotherapy is progressively more compromised. So, despite all our progress, we still have unmet needs.
How do you see immunotherapeutic approaches helping patients with unmet medical needs?
We must ask ourselves, “Who are the people for whom the overall survival curves are least flat?” Those would be frail, elderly, and molecularly high-risk patients; people with renal failure that has not improved; patients with multi-drug refractory disease; or those with other high-risk features such as extramedullary disease. These are the patients who have the greatest need for new approaches.
T-cell redirection is one example of the exciting new immunotherapy approaches. These include bispecific antibodies, which are “off-the-shelf” therapies, and chimeric antigen receptor (CAR) T-cell therapies, which are manufactured for each patient. To put the efficacy results of these T-cell redirection approaches into context, the last few drugs approved for MM (carfilzomib, daratumumab, selinexor, and belantamab mafodotin) had response rates typically between 20 and 30%, with a progression-free survival (PFS) of approximately 3 to 3.5 months. The new T-cell redirection therapies are yielding response rates of 70 to 100%. The data are still immature, but some of the CAR T-cell therapies are already yielding a median PFS of 1 year. To be seeing these types of results in patients who have exhausted all prior approved agents is a game changer.
The unparalleled efficacy results in relapsed/refractory disease raise the question, “What outcomes will we see as these therapies move into earlier lines of therapy? Might we see some flattening of the overall survival curves for patient populations with unmet needs?” Those data still need to be generated.
Can you give us a preview of what you and the other presenters will be speaking about?
Niels van de Donk, MD, PhD, will discuss how to sequence all of these therapies. When you have seven classes of drugs with multiple agents in each class, the question becomes, “What is the right way to combine and sequence them?” In particular, “What are the pros and cons of moving monoclonal antibodies into frontline therapy?”
Eric Smith, MD, PhD, will talk about the future of CAR T cells in myeloma. As I mentioned, the response and PFS rates with CAR T cells have been impressive, but we are still seeing relapses, even in patients who achieve measurable residual disease negativity. What are the mechanisms of relapse? Are they tumor-specific or T-cell–specific?
I will be discussing novel antibodies and the different antigens under investigation for immunotherapeutic approaches and antibody drug conjugates. My talk will focus on the available data on BCMA-directed bispecifics, as well as the emerging bispecifics targeting CD38, FCHR5, and GPRC5D and investigational trispecifics.
Where do you think clinicians need more guidance regarding these therapies?
Historically, there have been concerns about using new drugs early and having no options for later in the disease course. Hopefully, this session will allay concerns about using novel therapies upfront, help clinicians figure out strategies for relapse, and familiarize them with the efficacy and safety data of novel agents that will likely be in the clinic very soon.