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Newly Diagnosed Myeloma
Key Questions in the Management of Newly Diagnosed Multiple Myeloma

Released: August 14, 2024

Expiration: August 13, 2025

Michele Cavo
Michele Cavo, MD
Francesca Gay
Francesca Gay, MD, PhD
Paul G. Richardson
Paul G. Richardson, MD
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Key Takeaways
  • In ASCT-eligible patients with newly diagnosed multiple myeloma, quadruplet therapy incorporating a CD38 monoclonal antibody has become the new standard of care.
  • For patients with ASCT-ineligible newly diagnosed multiple myeloma, incorporating a CD38 monoclonal antibody with both VRd or Rd has shown an improvement in efficacy compared to VRd or Rd alone, respectively.

In this commentary, expert faculty respond to questions and share their perspectives on incorporating CD38 monoclonal antibodies (mAbs) into the treatment of patients with newly diagnosed multiple myeloma (NDMM).

The phase III IsKia trial was a landmark study evaluating the addition of isatuximab to KRd induction and consolidation in autologous stem cell transplant (ASCT)-eligible patients with NDMM. What is your impression of this study, particularly in patients with high-risk disease?

Francesca Gay, MD, PhD:
At present, we only have data on minimal residual disease (MRD) negativity rate and not yet on duration of MRD negativity from the IsKia trial. The data we do have are exciting because the rate of MRD negativity was high in all risk groups. To me, it’s of particular importance that the rates of 10‑6 MRD negativity were also high, which is felt to be a more powerful prognostic factor compared to 10‑5 MRD negativity. The combination of isatuximab plus KRd works well in all patients, but of particular interest are the results on the subset of patients with high-risk disease. However, it is important not to come to conclusions too soon, because we have unfortunately seen many trials where the duration of MRD negativity in high risk is not so high. Hopefully, the data on the duration of MRD negativity will continue to show a benefit with the addition of isatuximab to KRd in patients with high-risk MM.

Michele Cavo, MD:
We have data from the GRIFFIN and MASTER trials, evaluating the addition of daratumumab to RVd and KRd induction/consolidation, respectively, in patients with ASCT-eligible NDMM. In both studies, patients with 2 or more high‑risk cytogenetic abnormalities (HRCAs), referred to as ultrahigh-risk MM, had the smallest progression-free survival (PFS) benefit with the addition of daratumumab, with estimated 4-year PFS rates of approximately 50%, compared to approximately 90% for those with 1 or no HRCA. The 1-year MRD negativity rate for these patients with 2 or more HRCAs ranged between 31% and 50%. Standard quadruplet regimens plus transplant therapy are likely to not be enough for ultrahigh-risk MM patients, and there is the need to explore more active treatment strategies in order to improve their outcomes.

Paul G. Richardson, MD:
I do agree with the very thoughtful comments above. I am struck that both carfilzomib-based therapy and the use of isatuximab may have particular importance in high-risk disease. In some respects, it may also be, given the results seen with the IMROZ and BENEFIT trials, that isatuximab can abrogate higher risk when using it as part of bortezomib-based combination therapy, which is an important consideration in those patients where carfilzomib use can prove challenging.

Given the importance of durability of MRD negativity, how do you see maintenance therapy evolving for patients with ASCT-eligible NDMM based on the current data from IsKia and other studies?

Michele Cavo, MD:
I think that we need to have more robust data with the use of doublet maintenance therapies, since we are still at the beginning of the story and several studies aimed at comparing lenalidomide alone with lenalidomide combined with a proteasome inhibitor (FORTE study) or a CD38 mAb (PERSEUS study) are ongoing. However, preliminary data with the combination of carfilzomib and lenalidomide do support the possibility that doublet maintenance therapy is superior in comparison with lenalidomide alone (FORTE).


In addition, the PERSEUS study was aimed at prospectively evaluating an MRD-guided maintenance therapy approach with daratumumab plus lenalidomide for at least 2 years and subsequent daratumumab discontinuation in patients who were in at least complete response (CR) and had sustained MRD negativity for at least 1 year. Preliminary data suggest that more than 60% of patients receiving daratumumab-lenalidomide maintenance subsequently discontinued daratumumab, but a longer follow-up is needed to more carefully evaluate their outcome. I do think that maintenance therapy driven by sequential MRD assessments leading to treatment de-intensification or intensification according to sustained MRD-negative or positive results, respectively, is a potential new paradigm for personalized therapy in MM.

In terms of toxicity, what are your main considerations with quadruplet therapy regimens?

Paul G. Richardson, MD:
In terms of the tolerability of CD38 mAb-based quadruplet regimens, I am most struck that we are not seeing a meaningfully significant worsening in toxicity with the quadruplet regimens compared to triplet therapy, except for an increase in infections, which have proved generally manageable. The prophylactic use of IVIG when indicated is important to emphasize and in our experience is highly efficacious in both limiting and preventing serious infection.

Francesca Gay, MD, PhD:
In ASCT-eligible patients, toxicity was not a major issue and the quadruplet regimen did not cause an increase in significant drug‑related toxicity. There may be slightly more infections, but most of the time these are manageable. My advice is to be particularly observant during the induction phase, where we know that the risk of infection is higher due to the disease itself, and when initiating post‑transplant consolidation, where patients may have some resulting immune suppression.

Michele Cavo, MD:
In every study combining a CD38 mAb with other agents, both in the newly diagnosed and the relapsed/refractory setting, an increase in the rate of infection was observed, more frequently over the first treatment course. So it may be that an adequate prophylactic treatment may also mitigate the risk of infection for these patients, but we do not have data available at present.

Paul G. Richardson, MD:
One additional comment is that with the combination of isatuximab-KRd compared to KRd, the vascular signal was less for the quadruplet than the triplet regimen, and I think that’s very interesting. One argument is that because the disease is cytoreduced much quicker with quadruplet therapy, the intrinsic vascular stress of high disease burden may be less. I think that’s a potentially important observation for newly diagnosed patients where thromboembolic and other endothelial toxicities can be especially challenging early in their disease course.

What are your thoughts on the phase III IMROZ trial evaluating the addition of isatuximab to VRd in patients with ASCT-ineligible NDMM?

Paul G. Richardson, MD:
The data from the IMROZ trial are impressive. In this trial, the 60-month PFS rate with isatuximab-VRd was 63.2% vs 45.2% with VRd alone, with relatively mature follow-up (59.7 months). Although the VRd‑alone arm performed well, with a median PFS of 54.3 months, the median PFS for the quadruplet regimen has not yet been reached and may approach or even exceed 80 to 90 months, based on current estimates. This is remarkable and suggests we can anticipate clinical benefit for our patients as reflected by median PFS exceeding 6 to 7 years in an ASCT-ineligible population.

Michele Cavo, MD:
My personal view is that the IMROZ trial will change the treatment landscape. Historically, we had different treatment approaches for patients based on their ASCT eligibility or ineligibility, but the IMROZ data have suggested that most patients can receive similar treatment with the available quadruplet regimens. The IMROZ trial included patients up to 80 years of age and showed that while we should still evaluate patients’ fitness/frailty before recommending quadruplet therapy, a 4-drug treatment will prolong PFS even for those not eligible to receive ASCT.

What are your thoughts on the BENEFIT trial evaluating the combination of isatuximab and Rd with or without bortezomib in ASCT-ineligible patients with NDMM?

Francesca Gay, MD, PhD:
Like the IMROZ trial, the results of the BENEFIT trial are also striking. These data support the use of quad therapy and highlight the importance of the proteasome inhibitor in the combination. These data are also reassuring for the option of a less intensive bortezomib schedule, with the reduction in bortezomib dosing from twice weekly to the once weekly schedule in this setting, which may be more feasible in the clinic.

What are your thoughts on the use of a CD38 mAb in the setting of extramedullary disease (EMD)?

Francesca Gay, MD, PhD:
I think that definitely there is a rationale to use a CD38 mAb. We know the combinations with CD38 mAbs are more effective than those without, and if we look at the outcomes of patients with EMD treated without the CD38 mAb, they are particularly poor. So to me, we should use these agents. In the majority of trials, these patients unfortunately have a poor prognosis and an inferior outcome. I do feel that novel treatment strategies are needed for these patients.

Michele Cavo, MD:
This is a typically difficult-to-treat patient population. We do not have any established therapy, and also in this patient population, the outcomes with bispecifics or CAR T-cell therapy are inferior in comparison with the overall patient population. I anticipate that there is probably a sink effect related to high BCMA soluble levels that may impair the effect of newer immunotherapies.

Paul G. Richardson, MD:
I fully concur with the above comments. In the context of EMD, it’s important to note that we have exciting new data from both recently approved new agents as well as novel therapies still in clinical trials suggesting potential benefits for this important area of unmet clinical need. Melflufen is one example of an active drug with full approval in Europe where its potent activity against EMD is seen in the relapsed and refractory setting. Mezigdomide, the oral and highly potent CelMod, has also shown great promise in several studies for relapsed and refractory disease with extensive EMD.

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