Quadruplet Regimens Revive Newly Diagnosed Multiple Myeloma Treatment

With the addition of antibodies, quadruplet regimens build on the established efficacy of triplets to safely and effectively deliver enhanced treatment outcomes for patients with newly diagnosed multiple myeloma, according to C. Ola Landgren, MD, PhD.

“Adding a fourth drug, an immunotherapy [agent], to the backbone [generates] improved outcomes both in older patients and younger patients who are transplant eligible and ineligible,” Landgren said in an interview with OncLive^® during the 2024 ASCO Annual Meeting.

In the interview, Landgren discussed standard quadruplet regimens for use in patients with newly diagnosed multiple myeloma, how these regimens deliver increased efficacy compared with regimens containing fewer agents, and ongoing research that aims to mitigate the adverse effects (AEs) associated with carfilzomib (Kyprolis) and other agents in these standard regimens.

One regimen Landgren highlighted was daratumumab (Darzalex) plus carfilzomib, lenalidomide (Revlimid), and dexamethasone (Dara-KRd), which was evaluated in the phase 2 MANHATTAN trial (NCT03500445) in patients with newly diagnosed multiple myeloma. In this trial, treatment with Dara-KRd yielded a minimal residual disease (MRD)–negativity rate of 71% (95% CI, 54%-83%) among 41 evaluable patients.¹

He also noted the clinical relevance of the phase 3 MAIA trial (NCT02252172) triplet regimen of daratumumab plus lenalidomide and dexamethasone for this patient population. In MAIA, at a median follow-up of 56.2 months (interquartile range, 52.7-59.9), the median progression-free survival (PFS) was not reached (NR; 95% CI, 54.8 months-NR) with daratumumab plus lenalidomide and dexamethasone vs 34.4 months (95% CI, 29.6-39.2) with lenalidomide and dexamethasone alone (HR, 0.53; 95% CI, 0.43-0.66; P < .0001).²

Landgren is a professor of medicine, chief of the Division of Myeloma in the Department of Medicine, director of the Sylvester Myeloma Institute, co-leader of the Translational and Clinical Oncology Program, and the Paul J. DiMare Endowed Chair in Immunotherapy at the University of Miami Miller School of Medicine and the Sylvester Comprehensive Cancer Center in Florida.

OncLive: What were the key points you raised in your presentation about quadruplets in newly diagnosed multiple myeloma at the 2024 ASCO Annual Meeting?

Landgren: I [discussed] 3 different studies [that were presented] at the 2024 ASCO Annual Meeting. They shed light on the use of 4 drugs, using an antibody in addition to established 3-drug combinations with proteasome inhibitors [PIs], immunomodulatory drugs, and steroids. The first 2 presentations focused on older patients, and the last presentation focused on patients who were slightly younger and underwent a bone marrow transplant.

Some of the summary points that were discussed at the session were how you can improve outcomes independent of transplant status by adding an antibody [to standard regimens]. The field is narrowing the gap between the older patients and the younger patients. Maybe the 2024 ASCO Annual Meeting was the turning point where it’s time to think about retiring this 40-year-old terminology of ‘transplant eligible’ and ‘transplant ineligible’ because now we have effective therapies for all patients in the newly diagnosed setting.

What regimens do you typically use in your practice for patients with newly diagnosed disease?

In my practice, we frequently use 4-drug combinations. Sometimes we use 3-drug combinations, too. We are restricted by what has been approved by the FDA and what’s in the National Comprehensive Cancer Network [NCCN] guidelines because that’s where the reimbursement mechanisms [kick in].

One 4-drug combination we commonly use is Dara-KRd, which is [listed as useful in certain circumstances in the NCCN Guidelines as primary therapy for patients with transplant-eligible disease]. [The team at Sylvester Comprehensive Cancer Center] developed this regimen [through] the MANHATTAN study, [results from which were] published in 2021. We also frequently use the MAIA study [regimen], which is daratumumab, lenalidomide, and dexamethasone, in newly diagnosed patients.

In some patients, we use daratumumab plus bortezomib [Velcade], lenalidomide, and dexamethasone. That could be [used in] situations where we choose to do variations of [it]. For example, in patients with renal failure, instead of using lenalidomide, we use cyclophosphamide.

What advantages do quadruplet regimens have over regimens containing fewer agents?

At the 2024 ASCO Annual Meeting, we [saw data] from multiple studies [showing] that adding a fourth drug to the backbone, you can improve the efficacy [of the regimen]. More patients reach MRD negativity and have deeper MRD negativity. They go from [an MRD negativity threshold of] 10^–5, which [meets] the current guidelines for MRD negativity, to 10 times deeper 10^–6 negativity. All these outcomes translate into longer PFS. There is no doubt that adding an antibody to the [3-drug] backbone will increase efficacy.

Are quadruplet regimens associated with more toxicities than regimens containing fewer agents?

When it comes to the safety signals, overall, it’s fair to say that there is not much going on. But when you start looking into the details, the addition of bortezomib—a PI—increases the rate of peripheral neuropathy quite a lot. There is an underappreciation of this dilemma in the literature because many of these patients have grade 2 peripheral neuropathy. However, grade 2 peripheral neuropathy has severe interference with the active daily living capacity for patients. When it comes to peripheral neuropathy, bortezomib is a drug that has a lot of problems.

Alternative strategies are being explored. They were presented at the 2023 ASH Annual Meeting, and [more might] be presented at the 2024 ASH Annual Meeting. For example, the second-generation PI carfilzomib [is not associated with] peripheral neuropathy. That drug is associated with other AEs for frailer patients. For patients with cardiovascular disease, that’s not an optimal drug because it could interfere with heart function in those patients. However, [using carfilzomib] could be one strategy [for avoiding peripheral neuropathy].

Other strategies include using bispecific antibodies. Those trials are ongoing, so we don’t have the data yet, but we will see many new combinations going forward. I envision that the field will probably see a lot of chemotherapy-free treatments going forward. Immunotherapies are coming in many combinations, and the data look promising.

References

1. Landgren O, Hultcrantz M, Diamond B, et al. Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma: the MANHATTAN nonrandomized clinical trial. JAMA Oncol. 2021;7(6):862-868. doi:10.1001/jamaoncol.2021.0611
2. Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6