In 2021, Susan Bobulsky sat down with Dr. Luciano Costa to learn about the initial results from the phase 2 MRD response-Adapted Sequential ThERapy (MASTER) trial. The trial evaluated daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Dara-KRd) as induction therapy in patients with newly diagnosed multiple myeloma (MM), followed by autologous stem cell transplant (ASCT) and up to 8 cycles of Dara-KRd consolidation. Measurable residual disease (MRD) status measured by clonoSEQ® was used to modulate treatment duration and cessation.
The findings represented a huge step forward for understanding how we should be personalizing treatment decisions based on MRD-negative status. Specifically, it examined the cessation of therapy in newly diagnosed multiple myeloma patients who showed deep MRD-negative responses to treatment. Data from the final analysis of MASTER with extended follow-up time were published earlier this fall, so we checked back in with Dr. Costa to discuss what else we’ve learned and hear his perspective on how the findings might be implemented into practice.
1. Can you speak to the additional findings from the MASTER final analysis vs. the initial publication? What else have we learned?
With the extended follow-up (median 42.2 months vs. 23.8 months in the initial publication) we learned a few important things. Perhaps the most important is that most patients with standard risk multiple myeloma (MM) will achieve and sustain MRD-negative response without ongoing therapy. A longer follow-up gives us more confidence in this approach. We could also demonstrate that the use of MRD-adapted treatment modulation appears to negate the prognostic impact of MRD after transplant. This is a very important step to demonstrate the utility of adjusting therapy to depth of response.
2. Can you share your insights on the subset of patients whose outcomes were better with sustained MRD negativity at 10-6?
With longer follow-up we could also examine the impact of sustained (12 months) MRD negativity. We demonstrated that among patients with sustained MRD<10-5, those with sustained MRD<10-6 have better progression free survival (PFS) than those with sustained MRD between 10-5 and 10-6. This further supports the notion that the lower the threshold for “positivity,” the better the assay will be able to identify patients with exquisitely good prognosis.
3. How have you implemented the findings from this study into clinical practice and how do you feel others can implement findings?
That has been an important practical lesson from this study, that sequential MRD assessment can be incorporated in the management of patients with NDMM and can be employed to inform depth of response. In an era where most patients will achieve responses deep enough to render serum and urine paraprotein unquantifiable, MRD becomes the only way to quantitatively track disease burden. We have fully incorporated this tool in our patient management, and we routinely use this information to decide on post-transplant consolidation and to defer subsequent therapy in patients without ultra-high-risk MM who have sustained MRD negativity.
4. We at Adaptive have been so thrilled to see the first published results from a trial in MM where MRD is used not only as a correlative but as an actionable parameter. In what other ways do you think we should be studying MRD to continue to generate actionable insights?
Absolutely. Like others, we have an ongoing trial employing experimental, enhanced consolidation for patients with MRD>=10-5 after ASCT. We also have the ongoing MASTER-2 trial, asking different questions for patients who are MRD-positive and MRD-negative after completion of induction. If successful, this can solidify MRD assessment post induction as a parameter to decide on subsequent therapy. Other trials are underway on the same premise. MRD is not a perfect biomarker, and we don’t have a perfect biomarker in any cancer. But I have no doubt it is the best indicator of treatment success and the strongest prognostic factor. The notion of asking different treatment questions to populations with different prognoses and/or achieving different levels of response was always a natural element of developing therapies for malignancies we now consider curable. We should do the same for MM.
5. What are you most looking forward to seeing at the upcoming ASH meeting?
For MM, I think this will be an ASH about better understanding MM and our treatments rather than an ASH about new treatments. There is an explosion of good work geared towards understanding mechanisms of resistance to immunotherapy, both intrinsic to the clonal cells and related to the immune environment. This will be crucial as we learn how to best choose and sequence the many available new therapies.
clonoSEQ® is available as an FDA-cleared in vitro diagnostic (IVD) test service provided by Adaptive Biotechnologies to detect minimal residual disease (MRD) in bone marrow from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL) and blood or bone marrow from patients with chronic lymphocytic leukemia (CLL). clonoSEQ is also available for use in other lymphoid cancers and specimen types as a CLIA-validated laboratory developed test (LDT). For important information about the FDA-cleared uses of clonoSEQ including test limitations, please visit clonoSEQ.com/technical-summary