OncoAlert

In newly diagnosed multiple myeloma (NDMM), recent studies highlight the critical role of minimal residual disease (MRD) in guiding treatment decisions and improving outcomes. A significant trial showed that adding isatuximab (Isa) to lenalidomide, bortezomib, and dexamethasone (RVd) increased MRD negativity rates after induction therapy compared to RVd alone. MRD negativity was achieved in 50% of patients receiving Isa-RVd versus 36% in those receiving RVd. Additionally, Isa-RVd provided longer progression-free survival (PFS) in MRD-positive patients, though PFS was similar between Isa-RVd and RVd in MRD-negative patients. This suggests Isa offers a significant advantage for MRD-positive patients.

After a median follow-up of 48 months, patients achieving MRD negativity after induction or transplant had significantly better PFS compared to those who remained MRD-positive. The GMMG-HD7 trial, the first phase 3 study to confirm the long-term benefits of achieving MRD negativity with an 18-week induction regimen, demonstrated that deep MRD responses can result in lasting benefits, even without post-transplant consolidation therapy. Future analyses will assess the role of maintenance therapy with or without isatuximab.

Another study examined MRD progression (MRD-P) in NDMM patients treated with quadruplet therapy and autologous stem cell transplantation (ASCT). Though rare, MRD-P predicted imminent progression to full disease. Patients with MRD-P had shorter time to progression and poor survival free from failure of second-line therapy. MRD-P was driven by a plasma cell population resistant to existing therapies, including monoclonal antibodies, highlighting the need for new markers and treatment strategies for high-risk patients.

The CEPHEUS phase 3 trial evaluated the addition of daratumumab (DARA) to the standard VRd regimen in NDMM patients who were transplant-ineligible or deferred transplant. The D-VRd combination significantly increased MRD negativity rates at both the 10^-5 and 10^-6 sensitivity thresholds and led to sustained MRD negativity in more patients than VRd alone. This deeper response resulted in superior PFS, with over 80% of MRD-negative patients remaining progression-free at 54 months. D-VRd improved outcomes in both MRD-positive and MRD-negative patients, positioning it as a new standard of care for transplant-ineligible or deferred patients.

A final study explored whether sustained MRD negativity could allow for discontinuation of lenalidomide maintenance after ASCT. Patients who achieved sustained MRD negativity after three years of lenalidomide maintenance discontinued therapy, with MRD testing every six months. Of the 194 patients, 26.3% achieved sustained MRD negativity, with most remaining MRD-negative for up to 30 months post-therapy. Only 23% became MRD-positive, and a small number progressed to active disease. Among those who restarted lenalidomide, the median time to progression was 9.5 months. This suggests sustained MRD negativity may serve as a marker for safely discontinuing lenalidomide, though further trials are needed to confirm these findings.

In conclusion, MRD status plays a vital role in optimizing treatment and improving outcomes in NDMM. From the benefits of isatuximab and daratumumab in enhancing MRD negativity to the possibility of safely discontinuing maintenance therapy, MRD testing is proving essential in multiple myeloma management.

Disclosure: Supported by Sanofi.