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CD38 Quadruplets for TE NDMM
FAQs: Individualizing Anti-CD38–Based Quadruplet Therapy in Transplant-Eligible NDMM

Released: May 19, 2026

Meletios-Athanasios C. Dimopoulos
Meletios-Athanasios C. Dimopoulos, MD
María-Victoria Mateos
María-Victoria Mateos, MD, PhD
Philippe Moreau
Philippe Moreau, MD
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Key Takeaways
  • Anti-CD38–based quadruplet regimens are now considered a standard of care for fit patients with transplant-eligible newly diagnosed multiple myeloma, demonstrating improved MRD negativity rates and progression-free survival compared with triplet therapy.
  • Although MRD is increasingly influencing clinical discussions and may help guide future treatment adaptation strategies, ASCT remains recommended for all transplant-eligible patients in current routine clinical practice.
  • Supportive care remains essential for patients receiving frontline anti-CD38–based therapy, including proactive management of infections, VTE risk, steroid-related toxicities, peripheral neuropathy, and bone health to help patients remain on effective treatment.

In this commentary, María-Victoria Mateos, MD, PhD; Philippe Moreau, MD; and Meletios-Athanasios C. Dimopoulos, MD, address key questions raised during a recent live webinar titled, “From Evidence to Action: Expert Strategies for Individualizing CD38-Based Quadruplet Therapy in Transplant-Eligible NDMM.” During this webinar, the expert faculty reviewed the evolving role of anti-CD38–based quadruplet regimens in newly diagnosed multiple myeloma (NDMM), discussed the clinical relevance of measurable residual disease (MRD)–guided treatment strategies and transplant decision-making and shared practical approaches to supportive care and toxicity management in patients receiving frontline anti-CD38–based therapy.

Are Anti-CD38–based quadruplets now the standard of care for fit patients with NDMM?

María-Victoria Mateos, MD, PhD:
The recently updated European Hematology Association and European Myeloma Network guidelines now clearly incorporate anti-CD38 monoclonal antibodies into the frontline treatment of patients with NDMM regardless of transplant eligibility. The synergistic effect observed when anti-CD38 monoclonal antibodies are combined with immunomodulatory drugs and/or proteasome inhibitors has translated into clinical practice, with an increasing use of anti-CD38–based quadruplet regimens, particularly in fit patients. Personally, I consider that incorporation of anti-CD38 monoclonal antibodies into first-line therapy significantly increases MRD negativity rates, and this translates into better outcomes. Ultimately, this contributes to achieving what may become the key surrogate marker for cure: sustained MRD negativity.

Philippe Moreau, MD:
We now have several phase III trials comparing triplet vs quadruplet therapy in transplant-eligible patients, including CASSIOPEIA, PERSEUS, IsKia, and GMMG-HD7. Across all these studies, quadruplet combinations are associated with higher response rates, higher MRD negativity rates, and significant improvements in progression-free survival (PFS). Therefore, if possible, we should try to use quadruplet combinations, where feasible, in fit patients. The PERSEUS study evaluated bortezomib/lenalidomide/dexamethasone (VRd) vs daratumumab (Dara)-VRd, both before and after autologous stem cell transplantation (ASCT), and demonstrated a very strong PFS benefit with the addition of  daratumumab, with an HR of 0.42 and a 4-year PFS rate of 84%, representing one of the best outcomes reported in a phase III study in transplant-eligible MM. MRD negativity rates at both 10-5 and 10-6 were also significantly increased with Dara-VRd. Of importance, there were no major additional safety concerns associated with adding a CD38 antibody to triplet therapy. Quadruplet combinations are now considered a standard of care.

Can fit older patients still benefit from quadruplet therapy?

Philippe Moreau, MD:
Of importance, the PERSEUS study enrolled patients up to the age of 70 years. This is highly relevant for routine clinical practice because it demonstrates that fit older patients can still benefit from anti-CD38–based quadruplet therapy in the transplant-eligible setting.

Similarly, the GMMG-HD7 study evaluated VRd vs isatuximab (Isa)-VRd in transplant-eligible NDMM and also enrolled patients up to 70 years of age. Both studies demonstrated significant improvements in MRD negativity and PFS with quadruplet therapy compared with triplet therapy. Overall, these data support the use of anti-CD38–based quadruplet regimens in fit older transplant-eligible patients, particularly when biological fitness is considered alongside chronologic age.

How should healthcare professionals use MRD in routine clinical practice, and should MRD status influence transplant decisions?

Philippe Moreau, MD:
This is a very important question. The French Intergroupe Francophone du Myélome evaluated an MRD-driven strategy in the MIDAS study using 6 cycles of Isa-carfilzomib/lenalidomide/dexamethasone (KRd) induction followed by systematic MRD assessment. Patients with standard-risk disease who achieved MRD negativity after induction were randomized to receive either ASCT or no upfront transplant. By contrast, patients with high-risk disease, that is, patients who remained MRD positive after 6 cycles of Isa-KRd, were randomized to single vs tandem ASCT. Of interest, approximately two thirds of patients achieved MRD negativity after induction and were randomized to receive either upfront ASCT or no transplant. The remaining one third of patients, who remained MRD positive after induction, were randomized to receive either single or tandem ASCT.

The primary endpoint of the MIDAS study was MRD negativity at 10-6 prior to maintenance therapy. At this stage, there was no significant difference in MRD negativity rates between patients who received upfront ASCT and those who did not. Similarly, among patients who remained MRD positive after induction, there was no difference in MRD negativity rates between single and tandem ASCT. These findings suggest that longer follow-up, particularly PFS analysis, will be important to better understand the impact of MRD-adapted strategies. However, the MIDAS study already supports the concept that, in the future, treatment decisions may be increasingly adapted according to MRD status.

Let me ask my colleagues, are you, in your routine practice, using MRD to select or adapt treatment for patients? For example, are you deferring ASCT in transplant-eligible patients who are already MRD negative after induction?

Meletios-Athanasios C. Dimopoulos, MD:
No, we still advocate high-dose therapy for all transplant-eligible patients. However, we do use MRD to support discussions with patients, particularly those who may be hesitant about transplant. If a patient remains MRD positive after induction, either at the molecular level or measurable level, that becomes an even stronger argument in favor of high-dose therapy.

María-Victoria Mateos, MD, PhD:
I completely agree. We continue offering ASCT to all transplant-eligible patients regardless of MRD status. Of course, studies such as MIDAS suggest that in the future, risk and response may guide transplant decisions, but we are not there yet in routine practice. MRD can already influence some practical decisions. For example, if a patient is MRD negative after induction and remains MRD negative after transplant, we may occasionally skip consolidation and move directly to maintenance. I also think MRD will increasingly be used to guide the duration of maintenance therapy moving forward.

Is there still a role for transplant in the era of anti-CD38–based quadruplet therapy?

María-Victoria Mateos, MD, PhD:
Transplant remains particularly important for patients with high-risk cytogenetic abnormalities. In the phase III PERSEUS study evaluating Dara-VRd, we have seen across different patient subgroups, including high-risk disease, that transplant continues to provide benefit. I would still recommend ASCT for patients with high-risk biology who are eligible for transplant to try to overcome the poorer prognosis associated with high-risk disease. There are also other patient populations in whom transplant remains very relevant. Patients with suboptimal depth of response after induction quadruplet therapy, particularly those who fail to achieve at least a very good partial response or who remain MRD positive, may benefit from transplant to improve the quality of response. Similarly, patients with extramedullary disease or bulky disease at diagnosis remain high risk, and high-dose melphalan followed by ASCT may help induce deeper responses in these patients.

What supportive care measures are essential for patients receiving anti-CD38–based therapy?

Meletios-Athanasios C. Dimopoulos, MD:
Despite the tremendous improvements in outcomes for patients with MM, supportive care remains critically important because many of the therapies we use are associated with toxicities. Appropriate supportive care allows patients to remain on effective therapy, avoid unnecessary dose reductions, and maintain quality of life.

Steroid-related toxicity also requires careful management. Although dexamethasone remains an important component of therapy, we increasingly reduce steroid exposure in older patients and often reduce the dose after the initial cycles of treatment to mitigate long-term toxicities.

Peripheral neuropathy remains an important toxicity, particularly with bortezomib-based therapy. We now administer bortezomib subcutaneously and most often weekly outside of clinical trials, and we reduce the dose as soon as there is evidence of neuropathy rather than waiting for higher-grade toxicity.

Venous thromboembolism (VTE) prophylaxis is another important component of supportive care. Patients with MM are at increased risk for thrombosis, particularly at the start of treatment. Infections remain a major concern in patients with MM because these patients frequently have impaired humoral immunity. We routinely administer antiherpes prophylaxis in the majority of patients receiving treatment, and we also use trimethoprim-sulfamethoxazole prophylaxis to prevent Pneumocystis jirovecii infection. Increasingly, intravenous or subcutaneous immunoglobulin replacement is also being used, particularly in patients receiving bispecific antibodies, but also in selected patients receiving anti-CD38 or anti-BCMA therapies who develop low IgG levels.

Vaccination is also important. We advocate inactivated influenza vaccination, pneumococcal vaccination, respiratory syncytial virus vaccination, and herpes zoster vaccination. Following high-dose therapy, vaccinations should be repeated. Bone protection should also be considered routinely in patients initiating anti-MM therapy. Even in the absence of obvious bone lesions, we generally recommend zoledronic acid or denosumab to help protect bone health.

How should VTE prophylaxis be approached in NDMM?

Meletios-Athanasios C. Dimopoulos, MD:
Risk-adapted prophylaxis is important, with aspirin generally used for lower-risk patients and anticoagulants, including direct oral anticoagulants (DOACs), considered for patients at intermediate or higher risk. In clinical practice, do healthcare professionals prefer DOACs vs low-molecular-weight heparin for VTE prophylaxis, and should patients begin with heparin before transitioning therapy?

María-Victoria Mateos, MD, PhD:
In clinical practice and based on current approvals in Spain, we are comfortable starting with low-molecular-weight heparin during the first cycles of therapy. Once the patient has responded, unless ongoing high-risk factors are present, we often transition to aspirin.

Should IVIG replacement be routinely used in patients receiving anti-CD38 therapy?

Meletios-Athanasios C. Dimopoulos, MD:
We are using IVIG replacement more liberally than in the past, particularly with BCMA-directed bispecific antibodies. Dr. Moreau, what is your current practice outside the bispecific setting, for example, in patients receiving anti-CD38–based therapy?

Philippe Moreau, MD:
When we use BCMA-targeted bispecific antibodies, we systematically use IVIG replacement from the beginning to reduce grade 3/4 infections. Outside the bispecific setting, however, I use IVIG much more selectively. Primarily, I use it in older patients in the relapsed setting who are experiencing recurrent severe infections, usually at least 1 or 2 significant infections per year. I monitor IgG levels, but overall this remains a relatively small subgroup of patients.

Your Thoughts
What questions do you have regarding the use of anti-CD38–based quadruplet therapy for transplant-eligible patients with NDMM? How are you currently incorporating MRD assessment, transplant decision-making, and supportive care strategies into routine clinical practice? Please answer the polling question and join the conversation by submitting your questions and comments in the discussion box below.

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How frequently are you currently using anti-CD38–based quadruplet therapy as frontline treatment for fit patients with transplant-eligible NDMM?

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