Patient Assessment Drives Treatment Advances in Multiple Myeloma

Natalie S. Callander, MD.

Although the field of multiple myeloma treatment is expanding across the first-line and relapsed/refractory settings, further research and regulatory decisions are necessary to provide patients with accessible and tolerable treatments optimized to their disease risk levels, according to Natalie S. Callander, MD.

“Try different classes of therapy, thoroughly reevaluate patients, and think about BCMA-targeted therapy,” Callander said in an interview with OncLive® following an OncLive^® Institutional Perspectives in Cancer (IPC) webinar on multiple myeloma, which she chaired. “We are expecting many new drugs in the future.”

In the interview, Callander emphasized the importance of carefully evaluating a patient’s disease status when determining post-relapse treatments in multiple myeloma, noted how issues with access to CAR T-cell therapy have shaped the treatment landscape, and highlighted several ongoing clinical trials investigating CAR T-cell therapies and combination approaches.

Callander also explained the potential role of belantamab mafodotin-blmf (Blenrep) in relapsed/refractory multiple myeloma. This drug was withdrawn from US marketing in 2022, but remains under evaluation in studies such as the phase 3 DREAMM-7 trial (NCT04246047), which is investigating belantamab mafodotin plus bortezomib (Velcade) and dexamethasone vs daratumumab (Darzalex) plus bortezomib and dexamethasone in patients with relapsed/refractory disease.¹

Additionally, interim findings from the phase 3 ATLAS trial (NCT02659293) showed that carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) maintenance led to a median progression-free survival (PFS) of 59.1 months vs 41.4 months with lenalidomide alone in patients with newly diagnosed multiple myeloma who received induction therapy and autologous stem cell transplant (ASCT).² Callander contextualized the implications of these findings alongside other trials investigating maintenance regimens with triplet therapies.

Callander is an associate professor in the Division of Hematology, Medical Oncology, and Palliative Care in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health, as well as the director of the University of Wisconsin Carbone Cancer Center Myeloma Clinical Program in Madison.

OncLive^®: What are some important considerations when deciding future treatment options for patients with relapsed/refractory multiple myeloma?

Callander: We started [the IPC by discussing] the management of relapsed and refractory myeloma and reviewing some important workup elements. One [aspect] that sometimes gets lost is reevaluating patients before starting another line of therapy. That helps us figure out exactly how much myeloma they have or how difficult they will be to treat.

Matthew Brunner, MD, [of the University of Wisconsin Carbone Cancer Center], gave a nice overview of some of the testing, specifically the imaging, that can be quite helpful, particularly when patients are relapsed and refractory. Those include tests like PET scans and whole-body low-dose CT. We discussed bone marrow biopsies, which we favor for restaging patients because they can give us helpful information, particularly when patients have low blood counts, [which may be] because of a high burden of disease.

We also talked about the phenomenon where some patients, after multiple relapses, or sometimes early [in their disease], start losing the protein production we see at their initial diagnosis. [That can be] light chain escape, where the M protein is no longer made, and all we see are elevations of light chains. Or [it can be] a much harder situation that we are seeing more of, when patients make little protein of any kind, and then [we struggle] to figure out how much disease they have.

How does the array of available treatment options across multiple myeloma settings contribute to increasingly individualized patient care?

Zhubin Gahvari, MD, [of the University of Wisconsin Carbone Cancer], discussed [the therapies that are] commercially available right now for relapsed and refractory disease. He [divided these into categories that] many clinicians are used to looking at, [including] the management of early relapse vs late-line relapse. In early-line relapse, we advocate that patients who have not had an anti-CD38 antibody consider [receiving this therapy].

We reviewed some of the antibody combinations with the highest response rates, including a carfilzomib-containing regimen with either isatuximab-irfc [Sarclisa] or daratumumab, or pomalidomide [Pomalyst]-containing combinations. Then, we talked a bit about later lines of therapy, [including using] different classes if [they are accessible and] relevant, as well as trying to reassess patients. We discussed adapting therapy for [patients’] risk levels. If patients have high-risk disease and are relapsing, they’re typically going to need more therapy vs patients who might have more indolent myeloma and could have a single drug or maybe active observation before we start treating them.

I talked about currently available BCMA-targeted therapies. We reviewed belantamab mafodotin, the antibody-drug conjugate targeting BCMA. This drug had [an overall response rate of 41% in the phase 3 DREAMM-3 trial (NCT04162210)]. It is currently being studied in combinations but at this point is not available until more data are obtained [because of] a voluntary withdrawal by GlaxoSmithKline.

How does the accessibility of teclistamab-cqyv (Tecvayli) compare with that of CAR T-cell therapy in later-line treatment?

We talked about CAR T-cell transplants, which offer a high rate of response to patients, from 75% to as high as 95%. These are fantastic in late-line therapy. The biggest problem right now is access. Patients have asked: Is there a difference between 1 commercially available CAR T-cell product or another? We usually tell patients to try to get what they can get.

We also discussed the recently approved bispecific antibody teclistamab, some of its indications, and some of its pros and cons. Timothy Schmidt, MD, [of the University of Wisconsin Carbone Cancer], talked about the advantages of an off-the-shelf product like teclistamab, particularly for unstable patients. [With teclistamab], we can treat patients more effectively and quickly [than with] CAR T-cell therapy, which requires more planning and access. However, both are great choices for patients. Dr Schmidt also discussed the mechanisms [by which] patients don’t respond to these therapies, such as T-cell exhaustion.

How do the findings from ATLAS intersect with additional research investigating carfilzomib- and lenalidomide-based regimens in multiple myeloma? 

That’s an interesting trial. [The University of Wisconsin Carbone Cancer Center] was involved in the [phase 2] MASTER trial [NCT03224507], which evaluated minimal residual disease–directed [induction and] post-transplant consolidation using carfilzomib, lenalidomide, dexamethasone, and daratumumab. [Additionally], the [phase 2] FORTE trial [(NCT02203643) indicates that KRd] is a superior [induction strategy].

We still need to see more data [from ATLAS]. The proof of principle there was that we can administer a triplet combination as maintenance. [Many physicians] are interested in that strategy for high-risk patients.

The phase 3 CARTITUDE-4 trial (NCT04181827) met its PFS end point with ciltacabtagene autoleucel (Carvykti). Given the existing issues with access to CAR T-cell therapy, where do you see these data influencing the field, and how can community cancer centers better improve access?

We all assume that in the future, there may be a relabeling [of CAR T-cell therapy] by the FDA. Both CAR T-cell products [currently approved for multiple myeloma] are labeled for [patients who have received] 4 or more [prior] lines of therapy. That means that by the time we see some patients, they aren’t fit for CAR T-cell therapy.

The message from both CARTITUDE-4 and the [phase 3] KarMMa-3 trial [NCT03651128], which also met its [primary] end point, is that we should refer patients [to CAR T-cell therapy] earlier, because then patients may get the advantage that they would like to get, [which is] a long period off therapy, before needing to consider another treatment. What we have seen in real-world [data] of late-line use is that sometimes patients don’t get this advantage. Refer patients sooner for a discussion [about CAR T-cell therapy]. We may also see a change in the FDA labeling soon.

What ongoing research at The University of Wisconsin Carbone Cancer Center would you like to feature?

We are excited to be 1 of the sites involved in the [phase 2] BMTCTN1902 trial [(NCT05032820), which is] targeting patients who have a suboptimal response to ASCT and lenalidomide, defined as less than a complete response after 3 months of lenalidomide maintenance. This is an exciting trial where patients will be offered CAR T-cell therapy to improve their response followed by a year of lenalidomide maintenance. We have currently enrolled 3 patients. 

We are also happy to have recently opened the [phase 2 iMMagine-1 trial (NCT05396885)] investigating a different CAR T receptor approach with a synthetic, animal [variant region] instead of a single-chain variant region, which may be less immunogenic. This is another trial we’re excited about.

In later-line therapy, we are hoping to soon launch a trial investigating a combination of carfilzomib, isatuximab, selinexor [Xpovio], and dexamethasone for relapsed and refractory patients. We’re waiting to have the final pieces of that.

We also have [phase 2] MASTER-2 trial [NCT05231629] coming, which is being led by Luciano Costa, MD from the University of Alabama at Birmingham. Another trial we’re hoping to open soon is also looking to improve response rates after ASCT, but with a consolidation maintenance [therapy] containing iberdomide.

References

1. Evaluation of efficacy and safety of belantamab mafodotin, bortezomib and dexamethasone versus daratumumab, bortezomib and dexamethasone in participants with relapsed/refractory multiple myeloma (DREAMM 7). ClinicalTrials.gov. Updated December 12, 2022. Accessed January 31, 2023. https://clinicaltrials.gov/ct2/show/NCT04246047
2. Dytfeld D, Wrobel T, Jamroziak K, et al. Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomized, open-label, phase 3 trial. Lancet Oncol. 2023;S1470-2045(22)00738-0. doi:10.1016/S1470-2045(22)00738-0