Subgroup Analysis of MASTER Trial for Newly Diagnosed MM


Insights on how the subgroup analysis of the MASTER trial informs the role of autologous stem cell transplantation and the use of quadruplet therapy for elderly patients.

Case: A 61-Year-Old Woman with Transplant-Preferred Newly Diagnosed Multiple Myeloma (NDMM)

  • Patient ML is a 61 y/o woman.
    • PMH: Hypertension (well controlled on medication)
    • SMH: Does not smoke; drinks occasional glass of wine in social setting; Walks with friends 2-3 times weekly.

Clinical Presentation:

  • In October 2022, ML visited her PCP for her annual checkup. She reported having persistent pain in her shoulders.

Clinical Workup and Diagnosis:

  • Calcium 13.2 mg/dL
  • LDH 600 U/L (> ULN)
  • CrCl, 45 mL/min
  • Hgb, 7.0 g/dL
  • Beta-2-microglobulin, 6 mg/dL
  • Bone marrow biopsy showed 24% monoclonal plasma cells.
  • Serum monoclonal protein, 5 g/dL
  • Serum kappa FLC, 200 mg/dL
  • Del(17p) cytogenetic abnormalities were detected by FISH.
  • PET-CT showed osteolytic lesions in the shoulders; no EMD.
  • ECOG PS 1
  • ML was diagnosed with ISS stage II/R-ISS stage III IgG-kappa myeloma; determined to be transplant-preferred.

Current Treatment:

  • After discussions with her family and clinical team, ML was initiated on Daratumumab/bortezomib/lenalidomide/dexamethasone induction therapy (D-RVd).
  • Post-induction therapy, ML achieve very good partial response (VGPR).
  • Patient underwent stem cell mobilization and 3 months later underwent ASCT.
    • Post-ASCT response: VGPR


Natalie Callander, MD: I was very fortunate to be part of the MASTER trial [NCT03224507] led by Luciano Costa, MD, PhD, of the University of Alabama in Birmingham. And in this trial, what we were trying to do is do a proof of principle, to basically find out if we got patients to a very deep response with a cutoff of 10-5, based on next-generation sequencing with treatment, would we be able to successfully discontinue treatment altogether. So, in this trial, we used a combination of carfilzomib [Kyprolis], lenalidomide [Revlimid], and dexamethasone with daratumumab [Darzalex] for 4 cycles. And then patients had an MRD [minimal residual disease] assessment and they went on to autologous stem cell transplant. But then they had additional blocks of KRd-D [carfilzomib, lenalidomide, dexamethasone plus daratumumab], if I can abbreviate it that way, based on their MRD testing. And once patients reached 2 consecutive MRD negative tests, they stopped therapy.

For patients who never reached that benchmark, they went on ultimately to lenalidomide maintenance. And one of the things that we learned is that in both standard and high-risk patients, we had a very high ability to get patients to MRD negativity. But one of the things that we did see, particularly in the patients who had 2 or more high-risk cytogenetic abnormalities, was that after prolonged follow-up, a median of about a little bit less than 3 years, that we started to see a decline in those particular patients in terms of their MRD positivity and their PFS [progression-free survival].

And interestingly, looking at the GRIFFIN trial [NCT02874742], using the same analysis, looking at those patients who had 2 or more high-risk cytogenetic abnormalities, if you saw the same general pattern, which is those patients who have only 0 or 1 cytogenic abnormality, do quite well for a prolonged period of time vs those patients who have 2 or more and had very similar PFS outcomes at several years of follow-up, very close to those that were seen in the MASTER trial. So what that means is that those patients absolutely benefit from a quadruplet therapy, but we do need to do something else probably in the maintenance sphere, or potentially introducing other drugs upfront as part of their induction.

One of the nice things that came out at ASH [American Society of Hematology Annual Meeting] is one of our coinvestigators, Smith Giri, MD, MHS, did a subanalysis in the MASTER trial, specifically looking at patients who were older than 70. And we had quite a few patients—I believe it was around 24—and he showed that they benefited just as much as those patients [younger] than 70 with the quadruplet and the MRD-based treatment strategy. That was very reassuring to us to know that, particularly since more and more patients are getting transplanted who are above 70, particularly in the US [United States], we can transplant them safely, but also transplant them with this pretty intensive regimen. Particularly if it’s MRD directed and has a stop to it. That was very reassuring data.

Transcript edited for clarity.

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