Navigating Newfound Options, MRD Assessment, and Emerging Approaches in Multiple Myeloma

Partner | Cancer Centers | <b>Dana Farber</b>

The expanding therapeutic landscape in multiple myeloma is poised to integrate daratumumab-based quadruplet therapies and novel cellular therapies as standard options for patients with newly diagnosed and relapsed/refractory disease.

The expanding therapeutic landscape in multiple myeloma is poised to integrate daratumumab (Darzalex)-based quadruplet therapies and novel cellular therapies as standard options for patients with newly diagnosed and relapsed/refractory disease, said Omar Nadeem, MD, who added that although it is not fully realized, minimal residual disease (MRD) assessment could provide a tool to navigate the brimming armamentarium. 

“We have a plethora of options [for patients with multiple myeloma] and all of them have unique properties,” said Nadeem, clinical director of the Myeloma Cellular Therapies Program and a physician at Dana-Farber Cancer Institute, and an instructor in medicine at Harvard Medical School. “There is a lot of excitement in myeloma therapy across the board in the newly diagnosed setting, as well as in the relapsed/refractory setting. [This is] mainly because so many new drugs are now approved for these indications that weren’t [available] even just a few years ago.”

The Institutional Perspectives in Cancer webinar on multiple myeloma covered CAR T-cell therapy advances, treatment updates in frontline and relapsed/refractory populations, and the latest recommendations in amyloid light chain (AL) amyloidosis.

In an interview with OncLive®, Nadeem, who also chaired the webinar, narrowed in on these new additions to the newly diagnosed and relapsed/refractory armamentariums in multiple myeloma and AL amyloidosis, the current role of MRD negativity, and directions in which the field is headed.

OncLive®: How do you envision quadruplet regimens coming into standard practice for patients with transplant-eligible multiple myeloma?

Nadeem: By far the biggest trend that we have seen is the use of monoclonal antibodies in the frontline setting. We have historically used triplet-based therapy [in the frontline setting for patients with multiple myeloma] because they were shown to be superior to 2 drugs. Now, we are entering the next phase [of frontline treatment] where 4 drugs seem to be better than 3 drugs. [Quadruplet regimens] are being studied in transplant-eligible and transplant-ineligible populations. Some studies that we have seen presented and updated in recent years have been the CASSIOPEIA study [NCT02541383], which [evaluated] daratumumab, bortezomib [Velcade], thalidomide [Thalomid], and dexamethasone in the context of transplant [compared with bortezomib, thalidomide, and dexamethasone alone], as well as the GRIFFIN trial [NCT02874742], which [evaluated] daratumumab, lenalidomide [Revlimid], bortezomib, and dexamethasone [RVd] with transplant compared with RVd alone.

With the updates of these trials, we are seeing that the 4 drugs seem to be more efficacious [compared with 3 drugs] in terms of how well patients respond. In particular, we are seeing very high rates of stringent complete responses [sCR] and MRD negativity. Hopefully, this will translate into a significant improvement in outcomes, including progression-free survival [PFS] and, importantly, overall survival [OS]. However, a lot of the data are not yet mature.

The field is shifting toward [quadruplet regimens] gradually, particularly in the transplant-eligible population. In terms of the transplant-ineligible population, we are still using mostly triplet-based therapies, whether that is RVd, dose-modified RVd-lite, or daratumumab, lenalidomide, and dexamethasone. [The latter regimen] is based on the MAIA study [NCT02252172], which showed significant improvement [with the triplet] compared with the doublet [of lenalidomide plus dexamethasone].

A question moving forward as we are using these 4-drug regimens and achieving MRD-negative responses is: Do we need to consolidate these patients in the newly diagnosed setting with additional therapies, such as stem cell transplant? That question is going to be pertinent over the next few years as the data mature. This is something that we’ve seen in the 3-drug era where transplant certainly adds to how long patients will stay in their first remission, but [the use of transplant] hasn’t translated to an OS advantage with longer follow up. What does that mean for [quadruplet regimens]? We will have to see because there is clearly a subset of patients who will benefit from an intensification approach, such as patients with high-risk [multiple myeloma]. It’s an area where we still have to wait and see how the field evolves.

What are the clinical implications of the GRIFFIN trial in the transplant-eligible population?

[The GRIFFIN trial evaluated] a transplant-eligible population. Broadly speaking, these patients were more fit and were given the 4-drug regimen of daratumumab plus RVd.

There were no real safety signals seen that would preclude [the regimen’s] use [in this population]. We saw a higher rate of infections, which is not atypical in this patient population or with the use of monoclonal antibodies. Nothing else, such as severe hematologic toxicities, was seen that would [limit] our use [of the quadruplet] going forward.

In terms of efficacy, that is really where the story is. The primary end point was sCR rate, and the study clearly met this end point. Roughly half of the patients were MRD negative, and that number improved over time, well into the maintenance setting.

The key is that [patients] are achieving almost twice as much MRD negativity with the 4-drug regimen [vs the 3-drug regimen]. Transplant was universal in both arms of the study, so we can’t necessarily say that transplant is what led to the higher rates of MRD negativity. [The benefit seems to be derived from] the up-front use of the quadruplet.

The take-home message is that we are getting an early signal of a highly efficacious regimen without a lot of additional safety concerns. We don’t know what this translates to and a lot of this goes into maintenance therapy. [Maintenance treatment] in the GRIFFIN study consisted of daratumumab for 2 years plus lenalidomide vs lenalidomide [alone]. We will get a lot more information over time as to that intensified maintenance approach.

What barriers have prevented MRD assessment from being utilized more widely in myeloma treatment selection?

We know that MRD is prognostic based on all the data that have been seen over many studies. Whether [MRD] is useful to guide treatment selection is a separate question that we [are trying to] answer with other clinical trials; it hasn’t been solidified yet. Although we can assess for [MRD negativity] now that we have an FDA-approved test, I don’t know [if we are able to] use that information to tailor therapy. That is not something we have proven yet.

Where can [MRD assessment] be useful? In terms of induction therapy with quadruplet-based regimens, if a patient is MRD negative, could we potentially defer transplant? That is [a clinical scenario] that comes up [commonly]. The other [potential use of MRD assessment] is for maintenance therapy when we are choosing between a more intensified maintenance approach vs single-agent maintenance therapy vs observation. We can potentially use MRD as a tool [in those situations] because if those patients achieved [MRD negativity], hopefully that will translate into better outcomes.

The problem with MRD to some extent is that the definition is quite broad depending on the study we are looking at; there are layers of MRD negativity that have to be universally defined. Also, the duration of time that we do MRD analysis [differs] because patients will frequently deepen their responses and become MRD negative into maintenance therapy. They may have been MRD positive after the initial portion of their therapy, so where we assess MRD is an important distinction.

The durability of MRD [remains a challenge]. We call it sustained MRD, which means that a patient is [MRD negative] at several time points of whatever the interval is, such as 6 months or 1 year. We hope to see durable, MRD-negative disease as a much more powerful prognostic tool vs just the one-time MRD assessment.

Shifting to the relapsed/refractory setting, how has the integration of isatuximab-irfc (Sarclisa) opened up another option beyond daratumumab in multiple myeloma?

It is great to have another CD38-directed antibody available in the clinic that we can use in these combinations. In terms of [isatuximab’s] use in the relapsed/refractory setting, we are using a lot of these antibody-based therapies earlier, including in the frontline setting. That is where the challenge lies because we have patients who are not uncommonly refractory to a CD38-directed antibody in their first or second relapse. We don’t know the efficacy of isotopes in that population, so that is really the barrier of [utilizing] these combinations more.

With that being said, the data [with isatuximab] in combination with pomalidomide [Pomalyst] and dexamethasone, as well as with carfilzomib [Kyprolis] and dexamethasone, are encouraging. We are seeing very high response rates, excellent tolerability, and fairly high levels of deep responses, particularly with the isatuximab/carfilzomib/dexamethasone combination.

How that translates into [isatuximab’s] comparator—which is always going to be daratumumab—we don’t know yet. However, [the integration of isatuximab] does give us an option in the clinic for patients who have had a CD38-directed antibody. There are some subtle differences between [isatuximab and daratumumab], but ultimately, even in patients who have had previous CD38-directed antibodies but have not been exposed [to them] in many lines [of treatment], we can think [of using] this type of strategy [again]. Although, [retreatment with CD38-directed antibodies] has not been proven yet as to whether patients will respond to the [isatuximab-based] combination in subsequent lines.

In the heavily pretreated setting, how are you navigating treatment selecting given the approvals of selinexor (Xpovio), melphalan flufenamide (melflufen; Pepaxto), and belantamab mafodotin-blmf (Blenrep)?

It’s great to have options for these patients with multiple relapses. We have a lot of patients living a long time with [multiple myeloma] now because up-front therapies have become so effective. However, this disease is still incurable. We have a lot more patients with triple-class refractory disease [who have progressed on] immunomodulatory drugs, proteasome inhibitors, and CD30-directed monoclonal antibodies. That is really the space where we need new drugs.

[All of the newer agents that have entered] the clinic have unique properties in terms of mechanism of action, mode of administration, and toxicity. That is where the differences come into play, particularly in patients who have had multiple relapses. Each patient is different; some patients are frailer, others prefer oral therapies, and some may have renal insufficiency, for example. These are all [factors] that we must take into consideration when choosing therapy that far out in a patient’s myeloma journey.

Selinexor has the advantage of being an oral agent. We are starting to see a lot of combination data now and it seems to be an effective drug. Starting low [with the dose of selinexor] and escalating depending on tolerance is [an approach] we routinely [adopt] in practice.

Melflufen is a novel alkylating agent that is targeted to the myeloma cell based on its mechanism of action. [Melflufen] has attractive features as well, such as its activity in the multiple relapse setting and in patients with extramedullary disease, which is an area where a lot of patients experience relapses. Melflufen is given intravenously once a month, and it is easy to administer to some patients even though it requires central access. A lot of my patients prefer that route vs a weekly treatment, so [melflufen] is a potential option in patients who have not had an alkylator or who have but are not refractory to an alkylator.

BCMA-directed therapy as a whole is an exploding area of research in myeloma. We recently had idecabtagene vicleucel [ide-cel; Abecma] approved, which is our first [approved] CAR T-cell therapy in myeloma.

Now, with belantamab mafodotin and ide-cel, we have competition with BCMA-directed therapies. In terms of which therapy is more efficacious or which [therapy] patients prefer, they are so different. We are seeing entirely different efficacy and toxicity profiles between [belantamab mafodotin and ide-cel]. Belantamab mafodotin has its advantages in that it is off-the-shelf, and it is given in a 3-week schedule. However, [belantamab mafodotin] has toxicity concerns with keratopathy and visual changes that [can be concerning] to patients or impair their quality of life. [Choosing between BCMA-directed therapies] is a real discussion that we have with patients.

Keeping with BCMA-directed therapies, how do you anticipate other CAR T-cell therapy options fitting into the landscape now that ide-cel is approved? What about other cellular therapies that are in the pipeline?

We are seeing very exciting results with CAR T-cell therapy, broadly speaking. Ide-cel was approved based on very impressive data from the KarMMa studies. The median PFS was approximately 1 year, which is unheard of in this patient population. Ciltacabtagene autoleucel [cilta-cel] has also shown very impressive response rates with not only deep responses but durable responses. The median PFS is approaching almost 2 years for some patients. The efficacy bar has been raised quite a bit in multiple myeloma, particularly with these compounds and CAR T-cell therapy in general.

We will see how the bispecific antibodies play out. They are very exciting because they are easy to give and convenient, and their efficacy seems to be very promising in this very refractory population. [The response rates] and depth of responses may not be quite as high as with CAR T-cell therapy, but [the efficacy with bispecific antibodies] is still good compared with some of the other agents in this space. Additionally, the toxicity profile appears manageable without high-grade cytokine release syndrome or neurologic toxicities that we see with CAR T-cell therapy.

Since there are so many options, the question of sequencing will always remain. How do we sequence BCMA-directed therapy? Is one [BCMA-directed approach] going to work after another? We don’t know that yet, but it is nice to have these options. Some patients will be ideal for CAR T-cell therapy. Some patients may prefer the one-and-done approach with CAR T-cell therapy and be able to handle the initial toxicity to reap the benefits for, hopefully, a long time.

As these therapies move into early lines of therapy, we will get a sense of the durability of these responses in [a less heavily refractory] population, so it is an area that is going to evolve over the next couple of years.

On the heels of that, we have new targets. Patients who have failed BCMA-directed therapies [can get] newer bispecific antibodies [directed toward] new targets, such as GPRC5D. That is really going to be the next wave of myeloma therapeutics.

Pivoting away from multiple myeloma, could you highlight some of the key updates in amyloidosis?

Amyloidosis is a disease that has been incredibly difficult to study, and then to have therapies approved for. It [affects] a relatively rare population of patients within these plasma cell disorders. Also, these patients are often quite ill with organ involvement, so we are unable to get them on some of the clinical trials and therapies that we can get patients with myeloma on.

The ANDROMEDA study [NCT03201965] was conducted and showed impressive results with the use of daratumumab in the context of the standard cyclophosphamide, bortezomib, and dexamethasone [VCd] backbone. That study really highlights the use of antibodies in the frontline setting to deepen those hematologic and organ-specific responses. The key is that patients come in with these impaired organs from amyloidosis, so if they are seeing improvement rapidly [that is relevant]. That regimen has taken over the field in terms of the standard of care and based on the [ANDROMEDA] trial data, [daratumumab plus VCd] is now FDA approved and routinely used in the clinic.

What is the significance of the IPC webinars for providers in the academic and community settings?

With the rapid pace of approvals in multiple myeloma and other diseases, a lot of data are generated routinely based on ongoing trials. With the ongoing [COVID-19] pandemic, a piece has been missing in terms of sharing that information with a lot of our colleagues. These types of meetings are good about succinctly summarizing the highlights of these data to update the general public and community. We also can have discussions about which therapies and trials may be practice changing, so it is something that will be welcomed going forward.