Role of ASCT, Transplant, and MRD Are Examined in NDMM

Because of the rapid evolution of new standard of care for newly diagnosed multiple myeloma (NDMM), several key aspects of treatment remain unresolved in the context of current standard of care. In a Case-Based Roundtable event in Garden City, New York, moderator Marc J. Braunstein, MD, PhD, associate professor in the department of medicine at NYU Grossman Long Island School of Medicine, and participants discussed issues such as the continued role of autologous stem cell transplant (ASCT) and the clinical use of minimal residual diseases (MRD). Distinguishing the benefit of quadruplet regimens and transplant and using depth of response to guide treatment are challenges due to limited data, requiring physician judgment in these cases.

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CASE SUMMARY

• A 54-year-old woman presented with elevated fatigue, back pain, and occasional, but recurring dizziness, nausea, and constipation​.
• Past medical history: hypertension, well controlled with medication​
• Clinical workup​
  • Bone marrow: 22% monoclonal plasma cells​
• Laboratory results:
  • Hemoglobin 7 g/dL, albumin 3.2 g/dL, calcium 11.3 mg/dL, lactate dehydrogenase within normal limits, and creatinine 1.5 mg/dL​
  • Serum free light chains: κ 240 mg/L, λ 2 mg/L; κ/λ ratio 120​
  • Serum monoclonal protein: 5 g/dL; serum immunofixation electrophoresis: IgG-kappa present​
• Cytogenetics (fluorescence in situ hybridization/karyotype): hyperdiploidy (gain 9 and 11)​
• PET-CT: Multiple bone lesions in vertebrae without extramedullary disease.​
• ECOG performance status: 1​
• Revised International Staging System stage 3 IgG-κ myeloma​
• Patient was referred for autologous stem cell transplant (ASCT) evaluation.​
• She was determined to be a transplant candidate.​
• Daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) induction therapy was initiated.​
• She achieved very good partial response (VGPR) post-induction therapy.​
• She underwent stem cell mobilization and 2 months later underwent ASCT.​
• Post-ASCT response: VGPR

DISCUSSION QUESTIONS

• Based on the results of DETERMINATION (NCT01208662) what are your perspectives on the role of ASCT? Is there a continued role?​
• Do you consider transplantation in your practice? If not, what is your rationale?

Marc J. Braunstein, MD, PhD: How do you approach that conversation with patients? Even if you refer out of your practice, there has got to be some opinions here.

Abdul Mundia, MD: It’s a discussion.I think I tell patients that transplant is not going to cure you. There is a good chance that it will kick the can down the road even further, which is of benefit to you. I’ve also found that it’s very helpful now because the transplanters that I send them to are also the people doing chimeric antigen receptor (CAR) T-cell therapy, so it’s a great chance for them to get into the system, to meet the people that they need to meet. It’s something that I would still encourage, unless somebody is really hesitant. That’s maybe where I would send the ClonoSeq. I don’t regularly do MRD [minimal residual disease] on these patients, but that’s my gestalt on transplant. I think it’s still valuable.

Braunstein: I agree. It always comes down to conversation with the patient. Having a patient at least meet with the transplanter saves the time in clinic going through all the details and it gives them an opportunity to see that their oncologist cares about having all the options laid out for them. I think it’s always good to have that conversation.

Jaime Suarez-Londono, MD: Transplant for myeloma is very easy to give. On day 12 they engraft and they go home. Adverse events are not that [severe], and they get this progression-free survival [PFS] that is significant. Whether adding daratumumab changes that—at least, what I can see is that patients get a prolonged time after that.

Braunstein: It’s very safe, and I agree. The data driving the quadruplet with daratumumab is for transplant-eligible patients. It’s based on including transplant.

Robert Weiner, MD: I think you’re obligated to get a consult. We’re not in love with giving lenalidomide until progression.

Braunstein: Like everything in myeloma too, there’s some debate about how long we should be continuing maintenance. Some say until progression, some say until MRD negativity. Some do it for 2 years or 4 years; there is still some debate. But if you cross compare—and I know we’re not supposed to do that—but if you cross compare the PFS of Dara-VRd in the PERSEUS study [NCT03710603] with transplant to the CEPHEUS study [NCT03652064] for transplant ineligible patients, the PFS is longer with transplant.^1,2 [However], those populations are totally different, so it’s not fair to compare.

DISCUSSION QUESTION

• With the emergence of quadruplet induction regimens, is there a continued role for triplet regimens in patients with newly diagnosed multiple myeloma?​​

Braunstein: It is not surprising at this point that adding a monoclonal antibody improves outcomes, but [in the GRIFFIN trial (NCT02874742)], it’s certainly clear when you look at the patients who got the quadruplet vs the triplet pretty much at every time point, end of induction, before transplant, after transplant, and final analysis, there were deeper remissions with the quadruplet regimen plus transplant than without it, and higher rates of MRD negativity, which is as deep as we can get in terms of remission.³ It met its primary end point of stringent complete response. There are several studies that have examined quadruplet-based regimen, and if you look at the rates of MRD negativity, they are all very high.^1,4-6 It’s not meant to be a cross comparison between different trials, but all the studies have MRD negativity rates of greater than 50% which is remarkable, because that really translates to the highest PFS and overall survival.

Mundia: I’m struck by the fact that we have now MRD rate negativity rates that match just a decade ago, what we were striving for an overall response [ORR]. We had 80% ORR and we were so happy, and now we’re at MRD negativity of 80% We’ve done so well in this disease.

Braunstein: For some of these bispecific trials up front, are even having 100% MRD negativity. It’s early, but you’re right, the field has come a long way.

Weiner: Could you review the benefits of MRD [negativity]?

Braunstein: Mostly based on retrospective data, MRD negativity correlates with better OS and PFS than MRD positivity.⁷ This has been shown in almost every study, that if you’re randomly assigned to Dara-VRD vs VRd alone, regardless of what arm you are randomly assigned to, if you’re MRD negative, you do better than the patients who are MRD positive.

Weiner: There seems to be a subset of patients with myeloma out there who aren’t necessarily the most robust patient but just go on even for years with [residual disease]. There’s definitely disease present. You’re not even that anxious to keep [biopsying] them. PET scans are reasonable, but they just [last] long on treatment. Others, obviously, once they progress, they’re really in trouble with worsening bone disease. But there is that, and it’s not that rare.

Braunstein: It’s a good point. I think that MRD is not the only marker. How the patient is [functioning] is ultimately how you know their true risk status. I think for people who are MRD negative and convert to positive, that’s probably more of a harbinger of oncoming relapse. But I agree. I think the basic markers we use, looking at the M protein spike and the light chains, are just as relevant in long-term surveillance. MRD is not the only marker, but we know that the patients who are MRD negative at least tend to fare the best based on retrospective studies.

_{DISCLOSURES: Braunstein previously disclosed consulting or advisory role with Pfizer, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen Oncology, AbbVie, Guidepoint Global, Epizyme, Sanofi, Seagen, CTI BioPharma Corp, AstraZeneca, Lava Therapeutics, and Ipsen; speakers’ bureau for Janssen Oncology; travel and accommodations from Cardinal Health.}

REFERENCES

1. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

2. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. 2025;31(4):1195-1202. doi:10.1038/s41591-024-03485-7

3. Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837. doi:10.1016/S2352-3026(23)00217-X

4. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. 2022;40(25):2901-2912. doi:10.1200/JCO.21.01935

5. Gay F, Roeloffzen W, Dimopoulos MA, et al. Results of the phase III randomized Iskia trial: isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. Blood. 2023;142(suppl 1):LBA4. doi:10.1182/blood-2023-177546

6. Mai EK, Bertsch U, Pozek E, et al. Isatuximab, lenalidomide, bortezomib, and dexamethasone induction therapy for transplant-eligible newly diagnosed multiple myeloma: final part 1 analysis of the GMMG-HD7 trial. J Clin Oncol. 2025;43(11):1279-1288. doi:10.1200/JCO-24-02266

7. Shi Q, Paiva B, Pederson LD, et al. Minimal residual disease-based end point for accelerated assessment of clinical trials in multiple myeloma: a pooled analysis of individual patient data from multiple randomized trials. J Clin Oncol. 2025;43(11):1289-1301. doi:10.1200/JCO-24-02020