Quadruplet regimens, such as those with daratumumab, are on the rise in the frontline treatment of patients with multiple myeloma, and the FDA approval of the first BCMA-targeted CAR T-cell therapy idecabtagene vicleucel represents the monumental advance made in the relapsed/refractory setting.
Quadruplet regimens, such as those with daratumumab (Darzalex), are on the rise in the frontline treatment of patients with multiple myeloma, and the FDA approval of the first BCMA-targeted CAR T-cell therapy idecabtagene vicleucel (ide-cel; Abecma) represents the monumental advance made in the relapsed/refractory setting, according to James E. Hoffman, MD.
The phase 2 GRIFFIN trial (NCT02874742) examined the addition of the CD38-targeted monoclonal antibody daratumumab to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) in patients with newly diagnosed multiple myeloma. Results indicated that by the end of post–autologous stem cell transplantation consolidation, the stringent complete response (sCR) rate achieved with the daratumumab quadruplet was 42.4% vs 32.0% with RVd alone (odds ratio, 1.57; 95% CI, 0.87-2.82; P = .068).1 Responses deepened over time.
“When you look at the GRIFFIN trial, it is very clear that adding daratumumab is safe up front, and as part of a quadruplet therapy, patients tolerate it well,” Hoffman said. “The responses are very deep, and deep responses are generally durable, at least statistically speaking. [The trial] is a proof of principle that it is reasonable to give quadruplet therapy [in this setting].”
In the relapsed/refractory setting, in March 2021, the FDA approved ide-cel for patients with multiple myeloma who had received 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. The decision was based on data from the phase 2 KarMMA trial (NCT03361748), in which the CAR T-cell product elicited an overall response rate of 72% (95% CI, 62%-81%), with a sCR of 28% (95% CI, 19%-38%) among 100 evaluable patients.2
“We have been waiting for this for a long time. We have been talking about CAR T-cell therapy forever and the fact that we finally got an approval for the first commercial [product], with many centers about to be able to start [administering it], is hugely exciting,” Hoffman explained. “It is going to be looked back on a real milestone in the treatment of this disease. I hope that it sets the stage for many new CAR T-cell therapies, bispecific T-cell engagers, and other related drugs that might even be better.”
The OncLive® Institutional Perspectives in Cancer webinar on multiple myeloma spotlighted advances made in frontline treatment, exciting data reported with combination regimens in the relapsed/refractory setting, progress made with immunotherapy, as well insight into the utilization of genomic signatures to define stable vs progressive precursor conditions and the evolving role of minimal residual disease (MRD).
In an interview with OncLive®, Hoffman, an assistant professor of the Department of Medicine at Sylvester Comprehensive Cancer Center, discussed key developments made across the frontline and relapsed/refractory treatment settings and their clinical significance in the treatment of patients with multiple myeloma.
Hoffman: [In the] up-front [setting], the primary [focus is] quadruplet or triplet [regimens]. There has been a lot of back and forth [regarding] the appropriate triplets. Bortezomib plus lenalidomide and dexamethasone and carfilzomib plus lenalidomide and dexamethasone are both reasonable options. The relative benefits between them [are often discussed] and data continue to evolve. [However], the addition of daratumumab to triplet therapy is [going to be] a very relevant hot topic moving forward.
It is pretty clear that the addition of daratumumab [to the triplet backbone] results in deeper responses. The challenge in myeloma, [and this is] a good [thing], is that because patients do so well for so long you do not really get overall survival data early on. As such, you end up relying on surrogate markers, such as depth of response. Even progression-free survival can take a long time [to see] in an up-front trial.
GRIFFIN provided the proof of principle that administering a quadruplet therapy is reasonable. The question now is: Is a triplet with daratumumab [that is] reserved [for] first relapse ultimately just as good from a survival perspective as using the daratumumab up front? That remains unknown. Unfortunately, we will not have absolute proof [to support] either direction for a very long time.
Daratumumab is a very safe drug. [However, we know that] it results in hypogammaglobulinemia with low antibody levels and a high risk of infection, [as well as] blunted responses to vaccines. These are [factors] that are relevant—especially in the current era of COVID-19. [We are aware of the] potential poor responses to the COVID-19 vaccine in patients with multiple myeloma, or at least less than ideal responses.
Some of these [considerations] are theoretical; we do not have perfect evidence [detailing the] long-term negative impact of incorporating daratumumab up front. In general, the data are supportive that [this approach] is safe. However, as I tell my patients, often nothing in medicine is a free ride; there are always downsides. [For one, we know that there] are cost-related issues. Quadruplet therapy is very expensive.
It is commonly spoken of within the field how exciting it is that we have all these novel options for [when patients] relapse; this is great for patients. Belantamab mafodotin-blmf [Blenrep], selinexor [Xpovio], CAR T-cell therapy, and melphalan flufenamide [Melflufen] are the kind of [approaches] that exist for when patients have progressed through the classic lines of therapy. In myeloma, when we talk about the anchor classes, we are talking about the proteasome inhibitors, such as bortezomib and carfilzomib; the immunomodulators, like lenalidomide and pomalidomide; and the monoclonal antibodies, like daratumumab.
When [patients] have been through those 3 classes, that is when they [pivot to these novel] agents. Each of these drugs offers a response rate and can generally be given safely. Unfortunately, the response rates [achieved with] any one of [these approaches] are not sky high. [As such, we tend to] cycle patients through [these options], and hopefully, we will find the one that works for them.
Isatuximab is a little controversial; [it is] the newest CD38-targeted monoclonal antibody [and we have been] trying to find a place to use it. [The agent] adds to backbones with carfilzomib and pomalidomide in the same way that daratumumab did. The unknowns have really included where to fit [the agent] into an environment where we are already using a lot of daratumumab. [Isatuximab] has a slightly different target on the myeloma cell. There are [also] some differences in administration [compared with daratumumab]. However, the agent is safe and effective.
The question is, [is isatuximab] an alternative to daratumumab? Will there be a relative advantage [with isatuximab vs] daratumumab? How do we sequence the 2 drugs? These are some of the questions that [have been] brought up, but not answered. The synopsis is that isatuximab is safe and effective [agent]…that has a role in the treatment of [patients with] myeloma. It is just a little bit unclear what the defined role is.
We cannot be too precise [with] saying, 'Hey, look, we think isatuximab looks relatively better or relatively worse than daratumumab.' I try to avoid doing that. However, I would say they are on par with one another. The magnitude of benefit seems to be in the [same] ballpark. Maybe there are some subsets that will do better with one [agent] or the other.
Right now, isatuximab is intravenous and daratumumab can be given subcutaneously. Isatuximab is cheaper than daratumumab, [which is a] very important [consideration]. Isatuximab [is administered] every 2 weeks and daratumumab [can] eventually [be administered] monthly. Some of these nuanced differences exist between the drugs, but we cannot look at the efficacy [data from] these different trials and make any real clear statements.
I sometimes talk to my patients about how it might be that this is the dial up and we are going to get to the broadband later on. Treating patients earlier [with this approach] may result in more benefit; however, is clear is that for a one-time treatment, we see a dramatic benefit in some patients—very deep responses that are somewhat durable.
Unfortunately, patients do relapse with time. This might have been somewhat a function of the fact that these are very heavily pretreated patients, on average. [Regardless], this is a monumental advance for patients with limited options; deep remissions are actually possible. Many patients are going to benefit from [this agent], and that this is a building-off point for the next year or 2, where we really hope to see an explosion of this type of treatment. We hope to potentially be able to offer [this modality] earlier in the course of disease.
Smoldering myeloma has really been a complicated illness. The reason for that is, you have monoclonal gammopathy of undetermined significance [MGUS], which is very benign and certainly can be observed; you have myeloma, which hurts patients and definitely [requires treatment]; and then you have patients who numerically [have] myeloma but are not sick.
The reason why that has been so challenging is, we evaluate this middle group numerically. We look at how many plasma cells are in the bone marrow, how high the abnormal antibody is, [and] how high the M-spike is. However, those are just numbers. You can have someone with high numbers [whose disease] behaves in an indolent fashion, and you can have someone with low numbers [whose disease] acts more aggressively.
The most exciting area of advancement in smoldering myeloma is [focused on] how to get at the biological underpinnings of this kind of intermediate disease and really identify biologically, who has signatures that are progressive and who has signatures that are non-progressive. By doing that, we can avoid lumping all these patients into 1 category and treating them all in the same way.
That is not a great approach because you have this category where some are going to progress, and some are not. If you give them all the same medicine, you are overtreating some and you may be undertreating others who really have myeloma. However, this approach can help us identify the progressors. As such, we can treat them [as we would] myeloma and leave the other ones alone, like we do with MGUS. I am hoping in the next year or 2, we move away from these numerical assessments, which are plagued with difficulty, and move to biologic assessments.
MRD is an excellent end point. I mentioned earlier that we cannot wait around for survival data, so we look at depth of response. We have had partial responses [PRs], very good PRs, and complete responses [CRs], but by digging deep into this MRD assessment, you can find those patients who are in the deepest possible remission. It has been known for some time that the deeper the response, the better, and that MRD negativity is better than MRD positivity and MRD positivity is better than lack of CR.
The challenge, however, is [figuring out] where to incorporate that into current practice. If you have a patient who did really well, whether they are MRD positive or negative, are you going to change your approach for that patient? It is becoming clear that groups of patients who can achieve sustained MRD negativity are going to do very well. That is becoming a reasonable surrogate end point for some of these novel and aggressive therapies.
It is probably, true to a degree, that getting to sustained MRD negativity is far more important than how you got there. Whether you needed transplant to get there or whether you needed a quadruplet regimen, getting there is what really matters. Certainly, as it relates to clinical trials, MRD has become an acceptable end point. In terms of common practice, it is not there yet because we really do not know what to do with the information. However, all the forward-thinking approaches are utilizing MRD negativity, and I do not see that changing.