ASCO 2024: The More the Better in Newly Diagnosed Multiple Myeloma

Several studies presented at the 2024 ASCO meeting showed that using four-drug combination therapies helped newly diagnosed myeloma patients achieve lower disease burden as measured by minimal residual disease (MRD) and longer remissions (progression-free survival). Additionally, the CD38 monoclonal antibodies are helping to close the gap between fit and unfit patients.

Three studies were presented that used MRD negativity as key measurement points because achieving MRD negative status after the first line of therapy is one indicator of better outcomes:

IMROZ Study

The IMROZ study compared the use of a four-drug combination followed by three-drug maintenance therapy with a three-drug regimen followed by maintenance with a doublet (4-3 vs. 3-2): Isatuximab/lenalidomide/bortezomib/dex (IsaRVd) with Isa-Rd maintenance vs. lenalidomide/bortezomib/dex (RVd) with lenalidomide/dexamethasone maintenance (Rd).

The results showed improved MRD status with the quad therapy compared to the triplet therapy. This was the only study to include dexamethasone as maintenance therapy. 

Conclusions presented by Thierry Facon, MD, University of Lille, were that this combination could be considered a new standard of care in newly diagnosed patients under the age of 80 and who are not eligible for transplant. The FDA is currently reviewing these results to potentially approve this new use for isatuximab. Learn more about this study here.

BENEFIT Study

In this study, the combination of isatuximab/lenalidomide/bortezomib/dexamethasone (IsaRVd) was compared to isatuximab/lenalidomide/dexamethasone (IsaRd, NCT04751877). Again, a quad-therapy vs a triplet therapy in newly diagnosed patients for who a transplant is not an option. The goal was to study if the quadruple combination could improve MRD and survival for these patients, but also to see if it was possible to optimize the administration schedule of bortezomib (Velcade) to improve safety without risking the efficacy of the regimen.

The study was presented by Xavier P. Leleu, MD, PhD, Université de Poitiers et Centre Hospitalier Universitaire de Poitiers. The investigators reported that the IsaRVd combination provided better MRD negativity rates than the triple combination, and noted that IsaRVd could be used as a new standard of care for newly diagnosed transplant-ineligible patients under the age of 80.

We had the chance to catch up with Dr. Leleu at the conference. Take a look below for his top insights from this study.

PERSEUS Study

A similar study design was used in the Perseus study, but with daratumumab as the anti-CD38 antibody (instead of isatuximab), and for newly diagnosed patients who are eligible for transplant (NCT03710603).

In this clinical trial, they compared daratumumab/lenalidomide/bortezomib/dex (DaraRVd) + transplant + daratumumab/lenalidomide maintenance (DR) against lenalidomide/bortezomib/dex (RVd) + transplant + lenalidomide maintenance (4-3 vs 3-2).

Paula Rodríguez-Otero, MD, PhD, from the Universidad de Navarra, shared that about 64% of patients stopped daratumumab as part of their maintenance therapy within a two-year period because they had achieved MRD negativity status. The MRD negativity rates were better in the DaraRVd combination, and the presenter suggested that this four-drug combination would become a standard of care for transplant-eligible newly diagnosed patients.

Dr. Pieter Sonneveld, one of the lead investigators of the Perseus trials, shared his main takeaways with us. Watch below:

Conclusions

Ola Landgren, MD, PhD, University of Miami, summarized that all three studies show that using a four-drug therapy combination provided better MRD negativity rates and longer progression-free survival than the triple combinations for newly diagnosed myeloma patients, regardless of transplant eligibility.

While these studies included bortezomib, which is known to cause neuropathy, additional studies show a similar four-drug impact when replacing bortezomib with carfilzomib.

The reviewers recommended making other modifications in clinical practice, such as discontinuing dexamethasone or reducing the dose and frequency of bortezomib to minimize potential side effects.

Further work is still necessary to move beyond categorizing patients as "transplant-eligible" or "transplant-ineligible" and towards the development of personalized medicine, as some patients can achieve MRD-negative status with less therapy.

Overall, the conclusion is that using four-drug combinations is superior to three-drug combinations for newly diagnosed patients, regardless of whether they are headed to transplant or not. This "best foot forward" approach for patients with newly diagnosed multiple myeloma will help extend remissions and hopefully provide time for patients until better therapies can be developed. 

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Sources: 

• Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ).
• Phase 3 randomized study of isatuximab (Isa) plus lenalidomide and dexamethasone (Rd) with bortezomib versus isard in patients with newly diagnosed transplant ineligible multiple myeloma (NDMM TI).
• Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): Analysis of minimal residual disease (MRD) in the PERSEUS trial.