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CD38 and BCMA as Targets in Myeloma
Key Insights on CD38 and BCMA as Targets for Therapy in Multiple Myeloma

Released: August 28, 2024

Expiration: August 27, 2025

Craig Emmitt Cole
Craig Emmitt Cole, MD
Thomas G. Martin
Thomas G. Martin, MD
Noopur Raje
Noopur Raje, MD
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Key Takeaways
  • Both transplant-eligible and transplant-ineligible patients with multiple myeloma should receive upfront quadruplet therapy that includes an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory drug, and dexamethasone.
  • HCPs should prescribe IVIG for patients receiving either BCMA-directed or CD38-targeted therapy if IgG levels are less than 400 mg/dL.
  • Belantamab mafodotin may be a more accessible treatment option for patients unable to get to treatment centers for CAR T-cell therapies and bispecific antibody therapies.

In this commentary, expert faculty respond to questions and share their perspectives on the current use of CD38-targeted and BCMA-targeted treatment for patients with multiple myeloma (MM).

Should healthcare professionals initiate quadruplet therapy for all patients (both transplant eligible and transplant ineligible) with MM?

Noopur Raje, MD:
From my perspective, all patients with MM—whether transplant eligible or transplant ineligible—should receive quadruplet therapy that includes an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory drug, and dexamethasone as we have seen positive clinical trials in both these settings.

For transplant-ineligible patients with newly diagnosed MM aged 18-80 years, we recently saw reports from the IMROZ trial, where isatuximab combined with bortezomib/lenalidomide/dexamethasone (VRd) was shown to significantly improve progression-free survival (PFS) when compared with VRd alone (median PFS: not reached vs 54.34 months, respectively; HR: 0.60; 95% CI: 0.41-0.88; log-rank P <.001). Isatuximab plus VRd also significantly improved 12-month and 18- month measurable residual disease (MRD) when compared with isatuximab plus Rd in the BENEFIT trial, which enrolled older patients with newly diagnosed MM (aged 65-79 years). Twelve-month MRD negativity at 10-5 and 10-6 by next-generation sequencing (NGS) was 51% vs 21% (P <.0001) and 32% vs 13% (P = .0005), respectively. Eighteen-month MRD negativity at 10-5 and 10-6 by NGS was 53% vs 26% (P <.0001) and 36% vs 17% (P = .0006), respectively. Together, these 2 trials support the use of a quadruplet regimen in patients not eligible for autologous stem cell transplant (ASCT), highlighting the efficacy of quadruplet therapy vs either a triplet combination with VRd or an anti-CD38 monoclonal antibody plus Rd.

When looking at transplant-eligible patients with newly diagnosed MM, we have seen results from the PERSEUS trial that compared the combination of daratumumab plus VRd vs VRd alone. In PERSEUS, daratumumab plus VRd significantly improved 48-month PFS (84.3% vs 67.7%; P <.0001) and sustained MRD negativity rate (65.1% vs 32.2% at 10-6 by NGS; P <.0001) when compared with VRd. Results of this trial led to the approval of daratumumab plus VRd in this patient population. The IsKia EMN24 trial also evaluated MRD negativity, this time for isatuximab plus carfilzomib/lenalidomide/dexamethasone (KRd) compared with KRd alone. The isatuximab-based quadruplet significantly improved MRD negativity measured at 10-6 by NGS compared with KRd (67% vs 48%, respectively; P <.001). In the phase III GMMG-HD7, isatuximab plus VRd also improved rates of MRD negativity at 10-5 by next-generation flow when compared with VRd (50% vs 36%, respectively) in transplant-eligible patients with newly diagnosed MM. These trials also highlight the advantage of a quadruplet regimen over triplets in newly diagnosed MM.

Craig Emmit Cole, MD:
I agree. These data support the use of quadruplet therapy for all patients with newly diagnosed MM regardless of transplant eligibility.

For a patient with high-risk MM who was negative for MRD after induction therapy, would you still recommend ASCT as part of first-line therapy? 

Noopur Raje, MD:
For eligible patients, ASCT is recommended regardless of disease risk, so yes, I would recommend transplantation for a patient with high-risk MM. Management of high-risk disease is an area of unmet medical need. Right now, transplant-eligible patients with high-risk disease are experiencing better outcomes with quadruplet therapies followed by ASCT and maintenance therapy. As we investigate the possibility of using immunotherapies earlier in the disease course and possibly in the frontline setting, I would also consider the use of CAR T-cell therapy followed by a bispecific antibody therapy for patients with high-risk MM.

Craig Emmit Cole, MD:
Ongoing clinical trials are evaluating the efficacy of ASCT vs CAR T-cell therapy for patients with newly diagnosed MM. In CARTITUDE-6 (NCT05257083), patients will receive daratumumab plus VRd followed by either ASCT, consolidation, and lenalidomide maintenance or ciltacabtagene autoleucel and lenalidomide maintenance. I eagerly await the results because I also ask myself whether patients with MRD negativity after induction therapy should receive ASCT.

I was happy to see that recent subgroup analyses of CARTITUDE-4 with ciltacabtagene autoleucel and KarMMA-2 with idecabtagene vicleucel that suggest that patients with functional high-risk MM do well with having CAR T-cell therapy after 1 previous line of therapy. Although there has been a lot of progress for the management of patients with high-risk disease, these patients still progress and require additional therapy.

What specific patient population might be eligible for belantamab mafodotin if it becomes available?

Noopur Raje, MD:
Belantamab mafodotin, a BCMA x CD3-targeted ADC, was originally approved in 2020 as the first BCMA-targeted agent but was withdrawn in 2023 because of lack of efficacy as a single agent in the DREAMM-3 trial. Other BCMA-targeted agents, including 2 CAR T-cell therapies and 2 bispecific antibodies, have since been approved for relapsed/refractory MM. However, we recently saw exciting data with belantamab mafodotin–based triplet therapies at ASCO 2024 and EHA 2024. In DREAMM-7, belantamab mafodotin in combination with bortezomib/dexamethasone (Vd) was compared with daratumumab plus Vd for management of relapsed/refractory MM. In this trial, belantamab mafodotin plus Vd significantly improved median PFS when compared with daratumumab plus Vd (36.6 vs 13.4 months, respectively; HR: 0.41; 95% CI: 0.31-0.53; P <.00001). Similarly, in DREAMM-8 belantamab mafodotin was combined with pomalidomide/dexamethasone (BPd) and compared with pomalidomide/bortezomib/dexamethasone (PVd) for patients with relapsed/refractory MM. In this trial, the median PFS was not reached for BPd compared with median PFS of 12.7 months with PVd (HR: 0.52; 95% CI: 0.30-0.73; P <.001).

Belantamab mafodotin can be administered outside of the hospital or designated treatment centers, so I think it will be beneficial for patients with relapsed/refractory MM who have logistic issues that may prevent them from being able to receive either CAR T-cell therapy or bispecific antibodies. CAR T-cell therapy requires infusion at an academic center, and patients should stay within close proximity of a certified healthcare facility for at least 4 weeks for monitoring for cytokine-release syndrome and neurotoxicity. Step-up dosing of bispecific antibody therapy is also done at an academic medical center and requires hospitalization. The community setting is not yet equipped to do step-up dosing with bispecific antibodies. As more bispecific antibodies become available, including 1 now approved in solid tumors and multiple approvals for hematologic malignancies, oncologists in the community setting will become more comfortable administering these agents in their clinical practice. But if combination therapy with belantamab mafodotin becomes available to the US market, this could be an alternative, more convenient BCMA-targeted therapy.

One key consideration when deciding on the appropriate sequencing of belantamab mafodotin is the potential for ocular toxicity. Vision disturbances can significantly affect patients’ lifestyle (eg, ability to drive and read). In DREAMM-7 and DREAMM-8, ocular toxicities were managed with dose delays and dose reductions. I think the dosing frequency may need to be adjusted. In DREAMM-7 and DREAMM-8, the dosing was every 3 weeks, but dosing belantamab mafodotin less frequently at every 8-12 weeks would be very convenient. In DREAMM-7, dose delays because of ocular toxicities did not significantly affect PFS. In the 126 patients who had dose delays ≥12 weeks, the median PFS was 36.6 months.

Craig Emmit Cole, MD
Belantamab mafodotin has the potential to help a lot of patients. As Dr Raje said, many patients including those in rural areas, those with lower income, and those with poor access to resources may have difficulty getting to the academic centers or certified treatment centers to receive CAR T-cell therapy or bispecific antibodies. Both require that patients be closely monitored for cytokine-release syndrome and immune effector cell–associated neurotoxicity within the weeks following administration. With belantamab mafodotin, administration does not require hospital admission or specialized treatment centers. As Dr Raje mentioned, ocular toxicities are the main concern, so eye exams are required at baseline and frequently during treatment. With appropriate planning, eye doctors can be more easily accessible in community practice, and community oncologists can work alongside patients’ eye doctor to clear them to receive belantamab mafodotin and to monitor their eye health during treatment.

Thomas G. Martin, MD 
I completely agree with my colleagues. Another advantage of belantamab mafodotin is that it is associated with lower incidence of infections than anti-CD38 monoclonal antibodies and other BCMA-directed therapies.

Should intravenous immunoglobulin (IVIG) therapy be prescribed as infection prophylaxis for all patients receiving bispecific antibody therapy? What about with CD38-targeted therapy?

Noopur Raje, MD:
The NCCN guideline recommendation is to administer IVIG to all patients with IgG <400 mg/dL before administration of bispecific antibodies and CAR T-cell therapies. In my experience, almost all patients receiving BCMA-directed bispecific antibodies are going to be immunoglobulin deficient, so I give IVIG to all my patients receiving BCMA-directed bispecific antibodies. I think that is the right thing to do. For my patients receiving anti-CD38 monoclonal antibodies, I would certainly give IVIG if their IgG levels are <400 mg/dL.

Craig Emmit Cole, MD:
I check IgG levels every time I see my patients who are being treated with CD38-targeted therapy, and I have been giving more IVIG because it mitigates a lot of those infectious risks.

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