What are the future perspectives for anti-CD38 mAbs in the treatment of MM?

The Multiple Myeloma Hub was pleased to speak with Hermann Einsele, Julius-Maximilians-Universität Würzburg, Würzburg, DE. We asked about the future perspectives for anti-CD38 monoclonal antibodies in the treatment of multiple myeloma (MM).

In this interview, Hermann Einsele discusses the future perspectives of anti-CD38 antibodies, highlighting their role in first-line treatment for both transplant-eligible and -ineligible patients as well as applications in the second line and smoldering MM. Einsele also discusses outcomes from key trials and outlines potential combinations of anti-CD38s with emerging therapies, including cereblon E3 ligase modulators (CELMoDs), bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies.

Key learnings

• Anti-CD38 antibodies are now a key part of first-line treatment for both transplant-eligible and -ineligible patients with MM.

Transplant-ineligible NDMM

IMROZ¹

• IMROZ (NCT03319667) is a phase III trial which evaluated the addition of isatuximab (Isa) to the standard of care bortezomib, lenalidomide, and dexamethasone (VRd) regimen.
• The Isa-VRd quadruplet regimen resulted in an increased rate of complete response, measurable residual disease (MRD) negativity and sustained MRD negativity vs VRd alone.
• There was also a significantly improved 60-month progression-free survival (PFS) rate with Isa-VRd at 63.2% compared with 45.2% with VRd.
• Median PFS was not reached with Isa-VRd and is estimated to be between 7 and 8 years.
• These data led to the FDA and EU approval of the Isa-VRd regimen for the treatment of transplant-ineligible newly diagnosed multiple myeloma (NDMM).^2,3

CEPHEUS⁴

• CEPHEUS (NCT03652064) is a phase III trial that evaluated the addition of subcutaneous daratumumab (D) to the standard of care VRd regimen.
• At a median follow-up of 58.7 months, the MRD-negativity rate was improved at 60.9% in patients treated with D-VRd, compared with 39.4% in those treated with VRd alone.
• The risk of disease progression or death was reduced by 43% in the D-VRd group, with a hazard ratio of 0.57 (95% CI: 0.41–0.79; p = 0.0005).
• These data provide further evidence to support the addition of an anti-CD38 antibody to the standard VRd treatment regimen for transplant-ineligible NDMM.

Transplant-eligible NDMM

PERSEUS⁵

• PERSEUS (NCT03710603) is a phase III trial that evaluated the D-VRd regimen as induction and consolidation followed by daratumumab plus lenalidomide (D-R) maintenance in transplant-eligible NDMM.
• MRD negativity was improved in the D-VRd arm compared with the VRd arm at the end of consolidation, up to 12 months, 24 months, and 36 months.
• Sustained MRD-negativity was observed in 64.8% of patients in the D-VRd group and 29.7% in the VRd group. 

GMMG-HD7⁶

• GMMG-HD7 (NCT03617731) is a phase III trial that evaluated the addition of isatuximab to VRd as induction therapy for transplant-eligible NDMM.
• In Part 1 of the trial, the addition of isatuximab to VRd significantly improved MRD negativity rates (50% vs 36%; p = 0.00017). Grade 3 or 4 adverse events were similar between groups, though neutropenia was more frequent with isatuximab (23% vs 7%).
• In the trial, patients were re-randomized after transplantation to receive either isatuximab maintenance or no further treatment, with the aim to determine whether the continued use of isatuximab in maintenance therapy further improves patient outcomes.
• Results from Part 2 of the trial are pending.

Second-line therapy

• Anti-CD38 antibodies, including isatuximab and daratumumab, are commonly used in second-line therapy, often combined with dexamethasone and either carfilzomib or pomalidomide.
• The use of anti-CD38 containing regimens have been particularly effective for patients who are refractory to lenalidomide.
• In cases where CAR T-cell therapies or bispecific antibody therapies are unavailable, anti-CD38-based regimens are considered the preferred treatment options.

Retreatment with CD38

• Retreatment with the same anti-CD38 antibody may be possible if there is a sufficient treatment-free interval.
• An interval of approximately 6 months is recommended to allow for the regeneration of natural killer cells and the restoration of CD38 expression.⁷
• In rare cases, patients may develop genetic alterations that lead to a loss of CD38 expression. In these cases, retreatment with an anti-CD38 antibody is not effective.

Smoldering MM⁸

• The phase III AQUILA (NCT03301220) study evaluated the use of daratumumab for the treatment of patients with high-risk smoldering MM.
• With a median follow-up of 65.2 months, daratumumab was observed to reduce the risk of progression to MM or death by 51% compared with active monitoring alone.
• These results suggest that, in the future, anti-CD38 antibodies may be approved for early intervention in patients with high-risk smoldering MM.

Future perspectives

• Ongoing research is currently exploring combination regimens containing anti-CD38 antibodies with emerging therapies, including CELMoDs, bispecific antibodies, and CAR T-cell therapies.

• Anti-CD38 antibodies may enhance the effectiveness of T cell-based therapies by depleting regulatory T cells, which could improve the response of the immune system to treatment.

This educational resource is independently supported by Sanofi. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.