Effective Utilization of CD38+ Agents, IMiDs Spur Further Clinical Research in Relapsed/Refractory Myeloma

Amandeep Godara, MBBS

Recent advances in relapsed/refractory multiple myeloma treatment have not only led to a variety of effective anti-CD38 antibody combination regimens, but are also leading researchers to potentially expand the role of CAR T-cell therapy in earlier lines of therapy, according to Amandeep Godara, MBBS.

The CD38-directed monoclonal antibodies isatuximab-irfc (Sarclisa)¹ and daratumumab (Darzalex)², are currently approved for the treatment of patients with relapsed/refractory multiple myeloma. Clinical trials have demonstrated their efficacy and safety in combination with proteasome inhibitors, such as carfilzomib (Kyprolis) and bortezomib (Velcade), and immunomodulatory drugs (IMiDs), such as lenalidomide (Revlimid) and pomalidomide (Pomalyst), Godara explains.

“Trials that have combined daratumumab with lenalidomide [Revlimid], carfilzomib or pomalidomide [respectively] have changed our way of treating myeloma after the first or second relapse,” said Godara, a medical oncologist at Huntsman Cancer Institute and assistant professor in the Division of Hematology and Hematologic Malignancies at the University of Utah in Salt Lake City. “We are [also] moving the goalposts in terms of candidacy for CAR T-cell therapy in patients [with late relapsed myeloma].”

In the interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar, Godara discussed the evolving treatment landscape in both early and late relapsed multiple myeloma, updated clinical trial results with CAR T-cell therapy in this population, and key considerations when navigating treatment selection in this disease space.

OncLive: What do you consider to be the optimal sequence of therapies in early relapsed multiple myeloma?

Godara: We have several combinations of proteasome inhibitors, IMiDs, and anti-CD38 antibodies [for] patients who experience [their] first or second relapse after initial treatment. The first thing to determine is [whether] relapse occurred while a patient was taking lenalidomide. Lenalidomide is used as maintenance in both transplant-[ineligible] patients and in those who have undergone autologous stem cell transplant [ASCT].

Once we know if a patient is sensitive or refractory to lenalidomide, it is easier to decide what type of therapy to [select]. If we have a patient who is sensitive to lenalidomide and has not been exposed or refractory to an anti-CD38 antibody, we can consider treating them with a combination of daratumumab, [lenalidomide], and dexamethasone [DRd].

Patients who are sensitive to lenalidomide but are refractory to an anti-CD38 antibody might [benefit from] adding lenalidomide to another proteasome inhibitor, such as carfilzomib. If patients are refractory to lenalidomide when they are progressing, we might consider combining daratumumab with carfilzomib. If the patient is not refractory to bortezomib, we could also use it [in combination] with an anti-CD38 antibody.

What data do you find to be impactful regarding the addition of anti-CD38 monoclonal antibodies to standard doublet therapies in relapsed disease?

Over the last few years, several phase 3 trials [have supported the use of] anti-CD38 antibodies combined with other proteasome inhibitors and IMiDs in the relapsed/refractory setting.

We also have trials using combinations of the anti-CD38 antibody isatuximab and carfilzomib and pomalidomide. One thing that stands out across these trials is that progression-free survival [PFS] in these patients was better when we use that triplet regimen containing an anti-CD38 antibody. Updated [data from] the [phase 3] POLARIX trial [NCT03274492] further confirm the advantage of this [approach] in patients with relapsed/refractory multiple myeloma [by showing an] improvement [in] overall survival [OS]. This trial [showed] that OS was better with the triplet regimen containing an anti-CD38 antibody vs a doublet regimen [without one].

Another update on the [phase 3] IKEMA trial [NCT03275285] trial last year showed a significant improvement in PFS with isatuximab, carfilzomib and [dexamethasone.

How are CAR T-cell therapies being used in patients with late relapsed myeloma?

The current FDA approvals for CAR T-cell therapy are for patients who have had 4 or more prior lines of therapy, including a proteasome inhibitor, IMiD, and an anti-CD38 antibody. We have 2 CAR T-cell therapies that are approved in multiple myeloma: ide-cel and ciltacabtagene autoleucel [Carvykti; cilta-cel]. These therapies were approved based on results from the [phase 3] KarMMa [NCT03361748] and CARTITUDE-1 [NCT03548207] trials, respectively. These clinical trials included patients generally younger than the average patient with myeloma, and the median age was in the early 60s. In both trials, [patients] had around 5 to 6 prior lines of therapy.

Which patient populations might benefit most from CAR T-cell therapy in the late relapsed setting?

We now have some real-world experience with idecabtagene vicleucel [Abecma; ide-cel] which was presented at the 2022 ASH Annual Meeting. In the real world, [patients with myeloma] are much older than the patient population that was included in this trial. These patients could also have comorbidities, such as chronic kidney disease, that might make them ineligible for these clinical trials.

We do have some data indicating that CAR T-cell therapy can be safely [utilized] in patients who are older [or] have renal dysfunction. This means that currently available CAR T-cell therapies should be considered for the average patient who has had 4 or more prior lines of therapy and is considered fit.

What future avenues exist for continued CAR T-cell development in this space?

Now that we have a current indication for using CAR T-cell therapy in [patients with] myeloma, there are several [ongoing] clinical trials that [aim] to [utilize] CAR T-cell therapy earlier in a patient's disease course. We have several trials like [the phase 3] KarMMa-3 [NCT03651128] and CARTITUDE-4 [NCT04181827] studies, which look at the benefit of [CAR T-cell use after] either 2 to 4 prior lines of therapy, or 1 to 3 prior lines of therapy [respectively].

Results [from] these trials will hopefully be available this year and could help us understand whether earlier [use of] CAR T-cell therapy might improve outcomes, especially for triple-or penta-refractory patients.

Reference

1. FDA approves new therapy for patients with previously treated multiple myeloma. News release. FDA. March 2, 2020. Accessed February 24, 2023.https://www.fda.gov/drugs/isatuximab-irfc
2. Darzalex. Prescribing information. 2019. https://www.accessdata.fda.gov/drugsatfda_docs