Myeloma Data Presented at ASCO Highlight Continued Evolution of Treatment Paradigm

Noa Biran, MD

Data from multiple myeloma clinical trials presented at the 2024 ASCO Annual Meeting—including findings from the phase 3 DREAMM-7 (NCT04246047), CARTITUDE-4 (NCT04181827), and IMROZ (NCT03319667) trials—underscore the continued evolution of this treatment paradigm, according to Noa Biran, MD.^1-3 She added that as the multiple myeloma field continues to evolve, new unmet needs have arisen, such as managing infection rates in patients treated with bispecific antibodies in later lines of therapy.

“[It is important to] continue to use our therapies, learn how to sequence them [more effectively], and learn how to dose them in a much safer way to prevent infections in our patients,” Biran said in an interview with OncLive^®.

In the interview, Biran outlined key clinical trial data in multiple myeloma presented at the 2024 ASCO Annual Meeting, expanded on the challenges currently faced by patients with this malignancy, and detailed potential future directions in multiple myeloma research.

Biran is an associate professor of medicine at Hackensack Meridian School of Medicine and a medical oncologist/hematologist in the Multiple Myeloma Division at John Theurer Cancer Center in New Jersey.

OncLive: What are some of the most prevalent unmet needs for patients with multiple myeloma?

Biran: Multiple myeloma is a chronic disease, and thankfully, we've had a lot of new treatments approved in the last [several] years. We've come a very long way for patients with multiple myeloma; however, [patients] ultimately relapse, and most of them die of their disease.

A year or two ago, a [major] unmet need was [treatment for] patients who were triple-class refractory, [meaning they were] refractory to the most common agents: proteasome inhibitors, Immunomodulatory drugs, and anti-CD38 monoclonal antibodies. At this time, [an unmet need] we're looking at is [treatment for] patients who have progressed after BCMA-directed therapy. For these patients, we still struggle to come up with novel therapies. I would say BCMA-exposed or -refractory patients now represent a population for which treatments need to rapidly advance.

What are the implications of findings from the DREAMM-7 trial presented at the 2024 ASCO Annual Meeting?

DREAMM-7 evaluated the combination of daratumumab [Darzalex], bortezomib [Velcade], and dexamethasone [DVd], which is a standard-of-care regimen for patients with early relapsed myeloma, compared with belantamab mafodotin-blmf [Blenrep]—a BCMA-directed antibody-drug conjugate—in combination with bortezomib and dexamethasone for patients with early relapsed myeloma.

What's important about [DREAMM-7] is that it was a triplet-to-triplet, head-to-head comparison of belantamab mafodotin vs daratumumab with bortezomib and dexamethasone, and it showed a significant improvement in duration of response. The median progression-free survival [PFS] was 36.6 months [95% CI, 28.4–not reached] with belantamab mafodotin plus bortezomib and dexamethasone compared with 13.4 months [95% CI, 11.1-17.5] with DVd. [Belantamab mafodotin] is an important treatment that was previously approved by the FDA and then taken off the market because of a potential lack of efficacy and toxicity. [Findings from DREAMM-7] may change the FDA's opinion [on belantamab mafodotin] and provide [support] for the approval of this regimen in the early relapse setting.

What were the key takeaways from long-term follow-up data presented from the CARTITUDE-4 trial?

There was long-term follow-up of CARTITUDE-4 that focused on the high-risk subset. The functionally high-risk subset of patients who relapse early after transplant [represent] a very difficult-to-treat population. The CARTITUDE-4 study evaluated ciltacabtagene autoleucel (cilta-cel; Carvykti), which is a BCMA-directed CAR T-cell therapy, compared with standard-of-care regimens—such as daratumumab plus pomalidomide (Pomalyst) and dexamethasone or daratumumab plus carfilzomib (Kyprolis) and dexamethasone—in these functionally high-risk patients. There was a significant improvement in median PFS and overall response rate with the use of cilta-cel compared with standard-of-care regimens. In fact, we saw almost equal PFS in high-risk patients compared with standard-risk patients among those who received cilta-cel, which means that cilta-cel may abrogate high-risk features in the early relapse setting. This may solidify the use of CAR T-cell therapy early in relapse, especially for high-risk patients.

How could the IMROZ trial affect the treatment approach for patients with newly diagnosed, transplant-ineligible multiple myeloma?

The IMROZ study may change how we treat transplant-ineligible patients in the newly diagnosed setting. The standard of care up until now was the combination of daratumumab, lenalidomide [Revlimid], and dexamethasone for patients who were transplant-ineligible. The IMROZ study compared isatuximab-irfc [Sarclisa] plus bortezomib, lenalidomide, and dexamethasone [VRd] vs VRd alone in patients with transplant-ineligible, newly diagnosed [disease]. This is the first time that a proteasome inhibitor is incorporated into the [frontline] treatment regimen for patients with transplant-ineligible myeloma. [IMROZ] proved both the efficacy and feasibility of the delivery of a quadruplet regimen [for this patient population]. A proteasome inhibitor is important, especially in high-risk patients who are transplant ineligible.

What future research endeavors are needed to advance care for patients with multiple myeloma?

As we focus more on patients who are living a very long time, we're seeing more and more patients develop immune deficiency and chronic infections; [some patients require] repeated hospitalizations for upper respiratory infections, and [there have also been] opportunistic infections that we are not used to seeing in patients with multiple myeloma. [These infections are] due to chronic therapy, chronic steroid use, and more specifically, the use of bispecific T-cell engagers, which dampen T-cell response and immune response.

The field needs to move in a direction where we can use the bispecific T-cell engagers, which are very effective therapies, but in a much more safe and conservative way. That may [require] finding new antigen targets, such as FcRH5. [We could look at] using fixed-duration therapy [with bispecific T-cell engagers], perhaps 6 to 12 cycles and then stopping therapy, or we could convert to a monthly dosing regimen, which we're already evaluating in clinical trials.

References

1. Mateos MV, Robak P, Hus M, et al. DREAMM-7 update: subgroup analyses from a phase 3 trial of belantamab mafodotin (belamaf) + bortezomib and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2024;42(suppl 16):7503. doi:10.1200/JCO.2024.42.16_suppl.7503
2. Costa LJ, Weisel KC, van de Donk NWCJ, et al. Ciltacabtagene autoleucel vs standard of care in patients with functional high-risk multiple myeloma: CARTITUDE-4 subgroup analysis. J Clin Oncol. 2024;42(suppl 16):7504. doi:10.1200/JCO.2024.42.16_suppl.7504
3. Facon T, Leleu XP, Beksac M, et al. Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ). J Clin Oncol. 2024;42(suppl 16):7500. doi:10.1200/JCO.2024.42.16_suppl.7500