Modified Daratumumab-Based Quadruplet Shows Feasibility in Older Multiple Myeloma

As 4-drug regimens have become a staple in the standard management of newly diagnosed multiple myeloma, using a modified quadruplet such as daratumumab (Darzalex), lenalidomide (Revlimid), ixazomib (Ninlaro), and dexamethasone (D-Rid) could potentially aid in toxicity management and treatment adherence without affecting efficacy outcomes in patients who are older or frailer, according to Andrew Yee, MD.

Data from the phase 2 Alliance Foundation Trial 41 (NCT04009109), which were presented at the 22nd International Myeloma Society (IMS) Annual Meeting and Exposition, showed that patients with newly diagnosed multiple myeloma who were ineligible for or deferred autologous stem cell transplant (n = 79) treated with D-RId experienced an overall response rate (ORR) of 92.4% (95% CI, 84.2%-97.2%), including a very good partial response or better rate of 69.6% (95% CI, 58.3%-79.5%) and a complete response or better rate of 22.8% (95% CI, 14.1%-33.6%).1,2 The 12-month progression free survival (PFS) rate was 92% (95% CI, 86.1%-98.4%), and the 12-month overall survival rate was 93.6% (95% CI, 88.3%-99.2%).

In an interview with OncLiveâ, Yee discussed current challenges with utilizing 4-drug multiple myeloma regimens in older or frailer patient populations, detailed the rationale for exploring D-Rid in this study, and highlighted key efficacy data reported from the first year of treatment.

Yee is an associate professor of medicine at Harvard Medical School and clinical director of the Center for Multiple Myeloma at Massachusetts General Hospital in Boston.

OncLive: What was the rationale for evaluating a modified 4-drug regimen in patients with transplant-ineligible or -deferred, newly diagnosed multiple myeloma?

Yee: We know that 4-drug regimens are increasingly a standard for [patients with] newly diagnosed multiple myeloma, and that does not matter if you are a younger [patient who is] transplant-eligible or [a patient who is] transplant-ineligible. [This 4-drug approach] is based on randomized phase 3 studies that showed outstanding responses. However, with the regimens used for older [patients who are] transplant-ineligible, they took the same regimens that were meant for younger, fit [patients who were] transplant-eligible…without making any modifications. We know that older, more frail patients can be more sensitive to the [adverse] effects [AEs] of these regimens in general.

In our trial, we [asked] how we could optimize this 4-drug regimen. How could we make it more patient friendly, especially for older and frail patients? We [attempted to address this] through a couple [methods]. First, we reduced the dose of lenalidomide from 25 mg to 15 mg. Next, we replaced the proteasome inhibitor bortezomib [Velcade] with the oral proteasome inhibitor, ixazomib.

Bortezomib is a well-established drug, but it has a couple limitations, one [being] that it requires an injection in the stomach, which means you have to go the clinic to receive it. Additionally, [bortezomib] is associated with peripheral neuropathy, and peripheral neuropathy can be an issue, especially if [a patient is] older, less fit or robust, and prone to falls. [Peripheral] neuropathy can be a more significant AE for [older] patients.

Since ixazomib is an oral medication, it is much easier for [older] patients [to receive] because they do not have to go to clinic to receive it, and it is also not associated with peripheral neuropathy. The combination of [ixazomib] being an oral medication that lacks peripheral neuropathy means that [older] patients can stay on this medication for longer periods of time to potentially gain the benefit of having a proteasome inhibitor as part of their overall treatment regimen.

How was the phase 2 trial designed?

The trial accrued 79 patients; the intended [patient population] size was approximately 188 patients, but the COVID-19 pandemic did affect the [trial’s] accrual. In first year of treatment, [all patients] received the same regimen [of D-Rid]; after 1 year patients were assigned through randomization, either continuing maintenance lenalidomide as a standard treatment or the combination of daratumumab, lenalidomide, and ixazomib.

The primary end point is longer-term PFS [in order to] to see the effect of daratumumab, lenalidomide, and ixazomib as maintenance or extended therapy. [At IMS 2025], we showed results for the first year’s worth of treatment.

What data were presented from this study at IMS 2025?

After the first year of treatment, [we saw] a high ORR [at 92.4%], which translates to a 1-year PFS [rate of 92%]—similar to what we have seen reported with the traditional randomized phase 3 studies looking at older and frailer patients. Moreover, you can get similar efficacy but with significantly lower rates of neutropenia, no high-grade peripheral neuropathy, and a much lower rate of [any-grade] neuropathy. This was an important point to emphasize from the study. You can adapt a regimen meant for younger patients and apply it to older patients to make for a more pleasurable and positive patient experience.

What does this study underscore regarding personalized treatment approaches for patients with multiple myeloma?

[Patients who are] older and frailer need regimens that are adapted, customized, and tailored to them to make for an overall positive patient experience. When it comes to patient regimens and treatments, you have to tailor the regimen for the patient in front of you. Can we adjust and modify the dosing and schedule of a treatment? We were able to accomplish that [here] with the lower dose of lenalidomide and by using the oral proteasome inhibitor ixazomib. [These factors] help move the ball forward in terms of how we customize treatments to help ensure optimal patient outcomes.

References

1. Yee AJ, O’Donnell EK, Nadeem O, et al. A randomized phase 2 study of daratumumab, lenalidomide, ixazomib, and dexamethasone in transplant-ineligible/deferred patients with newly diagnosed multiple myeloma: Alliance Foundation Trial 41. Clin Lymphoma Myeloma Leuk. 2025;25(2):S362. doi:10.1016/S2152-2650(25)04004-2
2. Ryan C. Daratumumab/ixazomib quadruplet yields durable efficacy in transplant-ineligible or -deferred, newly diagnosed myeloma. OncLive.com. September 19, 2025. Accessed November 19, 2025. https://www.onclive.com/view/daratumumab-ixazomib-quadruplet-yields-durable-efficacy-in-transplant-ineligible-or-deferred-newly-diagnosed-myeloma