Selecting Optimal Treatments for Patients With Relapsed Multiple Myeloma

At the 2023 Great Debates & Updates in Hematologic Malignancies meeting in Boston, Massachusetts, Andrew Yee, MD, Massachusetts General Hospital, Boston, Massachusetts, explores optimal treatment options for patients with relapsed multiple myeloma (MM) after 1 to 3 prior lines of therapy, including, but not limited to, anti-CD38 antibodies, cyclophosphamide-based combinations, and BCL-2 inhibitors.

Transcript: 

Hi. My name's Andrew Yee and I'm the Clinical Director [of] the Center for Multiple Myeloma at Massachusetts General Hospital. At the Great Debates [and Updates in Hematologic Malignancies] session in Boston, I talked about the management of patients with 1 to 3 prior lines of therapy [for multiple myeloma]. 

As you may have heard from the other Great Debates sessions, the multiple myeloma field is changing rapidly. We have all these great, excellent treatment options for newly diagnosed patients, but the challenges remain for patients who do have relapsed disease. My focus was to talk about what options are available that are accessible right now for practitioners in the community [and] for patients with 1 to 3 prior lines of therapy.

I think about how we have, as you may have heard from the Great Debates session, really amazing cellular therapies, [chimeric antigen receptor] (CAR) T-cell therapies, and bispecific antibody therapies, which have been transformative for multiple myeloma. However, the main limitation [of] those therapies is that access to them can be challenging. 

One of the things I wanted to bring across in my session was to talk about therapies that people can have access to right where they're being treated right now, without necessarily having to go to a major medical center for these more advanced therapies. 

When we think about relapsed disease, the same principles apply in terms of choice of therapy as they do for newly diagnosed therapy. So, we think about patient characteristics, the nature of the disease, and maybe some of the molecular underpinnings of the disease. In terms of the clinical characteristics, we think about, is it a symptomatic relapse where patients have symptoms of the relapse? It could be related to a bone lesion, or it could be related to anemia and worsening fatigue. We also think about biochemical relapse, where the patients themselves may not have symptoms of it, but you can see [a] rise in monoclonal protein or free light chain. Increasingly, for relapsed diseases, these patients are being monitored more often.

Biochemical relapse is the more common way of presentation where patients have, again, a laboratory value indicating relapse. One of the points that we discussed at this Great Debates session is how it's important to not necessarily wait for symptomatic relapse but to think about treatment at [the] time of biochemical relapse. 

Its outcomes tend to be better for patients treated at [the] time of biochemical relapse than at [the] time of symptomatic relapse. Some of this is based on a retrospective study done out of the Mayo Clinic that looked at outcomes of patients who were treated [for] biochemical relapse.

We also talked about how it's important to use your best therapies earlier rather than waiting for later. You don't want to wait necessarily for a later line of therapy because sometimes patients may not have the opportunity to get to that point, because, with myeloma therapy, there can be attrition over time. In terms of treatment in 1 to 3 prior lines, we have all these great options available. 

One of the things we discussed was that if a patient hasn't had a chance to have an anti-CD38 antibody, like daratumumab or isatuximab, this is the best opportunity to use it. We think about partners for these anti-CD38 antibodies, such as carfilzomib or pomalidomide, and these are both great choices. In terms of choosing one or the other, that can really be driven by patient characteristics. For patients who have more of a biochemical relapse, sometimes I think about pomalidomide since, again, it's effective in relapsed disease. But the treatment schedule, I think, is easier for using a pomalidomide-based combination combined with an anti-CD38 antibody.

That's because carfilzomib [is] given on a weekly basis for 3 out of 4 weeks, for example, and I think that does impose a burden on the patient so, for a biochemical relapse, I think a pomalidomide-based combination works great. For patients with more of a symptomatic relapse, I do think more about using a carfilzomib-based combination. Granted, there are no head-to-head trials comparing carfilzomib to pomalidomide in this specific setting but, based on the data that's been presented so far, I think that a carfilzomib-based combination probably would be a little bit more effective. But it does have a trade-off in terms of, for the patients, it is more of a burden and there can be some side effects to think about such as cardiac-related side effects.

In clinical practice where we're using it once a week, [with] attention to hydration, I just don't see that degree of shortness of breath as has been previously described. The other tools that can be really useful for relapse disease would be cyclophosphamide-based combinations. We don't usually hear a lot about cyclophosphamide but, for patients who have relapsed disease where you need to essentially try to get them some additional time until they can have access to some of the more advanced, like CAR T-cell therapies or bispecific therapies, carfilzomib-based combinations can be really effective and these can be combined with, say, carfilzomib or pomalidomide. 

Now, another great tool for relapsed disease would be selinexor, an oral XPO1 inhibitor. When I think about using selinexor, I think about using, again, in terms of these combinations. When used in combination with, say, carfilzomib or pomalidomide, the dosing of selinexor can be less. By using a lower dose, you can maintain efficacy and help minimize some of the [gastrointestinal] (GI) side effects that can be associated with selinexor. Again, when we're thinking about relapsed disease, we're thinking about the more tools you have the better. 

One of the final points in the discussion of relapsed disease was venetoclax, which is a BCL-2 inhibitor that many oncologists are already familiar with based on its established role in chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia. Venetoclax can be a really effective option, specifically for patients with translocation 11;14 disease (t 11;14). The role of venetoclax in myeloma is complicated because, in the BELLINI trial when you looked at the overall outcomes, the survival was worse overall, but when you looked at the translocation 11;14 subset, you can see some amazing responses.

For patients with translocation 11;14 disease, venetoclax can be a really effective drug, either with dexamethasone or in combination with a proteasome inhibitor or daratumumab. We are really awaiting the results of the CANOVA study, which is a randomized study that will hopefully establish, more definitively, its role in translocation 11;14 disease and potentially get an official FDA label for that. Those were some of the high points of the presentation. Thank you.

Source:

Yee, A. Making Sense of the Choices in Relapsed Myeloma. Presented at the Great Debates and Updates in Hematologic Malignancies Meeting; August 17-19, 2023; Boston, Massachusetts.