Role of Dual Maintenance Remains Uncertain in Multiple Myeloma

The introduction of quadruplet frontline regimens has redefined the expectations of a favorable response outcome in newly diagnosed multiple myeloma. 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 what level of response they look for now in transplant-eligible patients and how they consider use of maintenance after transplant, such as the addition of daratumumab (Darzalex) in high-risk cases, and what tools they can use to make these decisions easier such as minimal residual disease (MRD) testing.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

CASE SUMMARY

• A 54-year-old woman presented with elevated fatigue, back pain, and occasional, but recurring dizziness, nausea, and constipation​.
• 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, 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 QUESTOINS

• What do you consider an adequate/successful treatment response in your patients following induction therapy in the real-world setting?​

Marc Braunstein, MD: In the real-world setting, what is an adequate response after your initial 4 to 6 cycles of whatever you give? Is it a complete response or a VGPR?

Abdul Mundia, MD: Obviously you want to get as deep of a response [as possible]. I would counsel a patient against transplant despite what a transplanter says if they don’t have VGPR. I don’t think transplanters are transplanting patients who have less than VGPR.

Jaime Suarez-Londono, MD: Yes, if it’s less than VGPR, if you have nothing else to do, we transplant the patients, but otherwise, [we do not].

Braunstein: I agree. The depth of response to your first treatment, in a way even more so than cytogenetics, tells you about their biological behavior. If they haven’t achieved at least a partial response to high-dose chemotherapy, that’s worrisome. Those patients are moving to clinical trial or quickly moving on to a second line, either second-line quadruplet if insurance permits or [chimeric antigen receptor] T-cell therapy.

DISCUSSION QUESTIONS

• How do you manage adverse events for patients receiving induction therapy? ​
• Does it differ for quadruplet vs triplet therapy? Daratumumab vs isatuximab (Sarclisa) based?

Braunstein: What are your experiences like? What are the most common adverse events to deal with during induction?

Mundia: It’s generally [related to] the proteasome inhibitor or the immunomodulatory drug. It is not the anti-CD38; they are incredibly well tolerated.

Robert Weiner, MD: In those trials, they were using lenalidomide at 25 mg.^1,2 That’s challenging in a lot of patients.

Braunstein: I agree; sometimes we…reduce the lenalidomide dose instead of just continuing to try. We go down to 15 mg, go up to 20 mg again, play around with the dose.

Weiner: So what do you start at?

Braunstein: I start at 25 mg for transplant-eligible patients, unless they have some renal failure. Then you have to dose adjust it…. If they are aged 80 and transplant ineligible, I start at 15 mg, and for the maintenance, usually I go down to 15 mg.

Weiner: In lymphoma, nobody tolerates 25 mg. Sometimes, we don’t even start at that.

Braunstein: Speaking of lymphoma, I looked at the SEER database for the median 5-year survival for myeloma; it’s approaching what it is for non-Hodgkin lymphoma, it’s 64%, so it’s getting there.³ So we’re definitely doing better.

We rarely have patients having to be admitted for neutropenic fever, but every now and then it happens during induction. It’s usually pneumonia or something like that. I do use growth factors sometimes rather than delaying treatment. Neuropathy tends not to be a major issue; grade 3 or 4 neuropathy [is rare] with the dose of bortezomib they get.

DISCUSSION QUESTION

• Does your choice of induction therapy impact your choice of maintenance therapy in patients with transplant-eligible multiple myeloma?​
• In your practice, what choice of maintenance therapy do you utilize?

Braunstein: If everyone’s giving daratumumab, what are you doing for maintenance? What choice of maintenance do you utilize?

The AURIGA study [NCT03901963] didn’t include the patients we’re seeing [who received] quadruplet up front. Those were daratumumab-naive patients. But clearly it improves depth of response.⁴ For patients who are high risk, I might consider dual maintenance, or if they’re still MRD positive after transplant.

Mundia: How do you incorporate MRD positivity here? What I do is, if you’re MRD positive, I encourage you to go on dual maintenance, especially if you have high-risk cytogenetics. If not, just take the lenalidomide. My question is, is lenalidomide even in a low dose better or is single-agent daratumumab better, because single-agent daratumumab is easy to do, and with isatuximab coming out as an [on-body injector], is CD38 maintenance the way to go in the future? I don’t know if you have a trial that answers that.

Braunstein: There is a trial comparing single-agent daratumumab to lenalidomide,⁵ but the GRIFFIN [NCT02874742] or PERSEUS [NCT03710603] trials didn’t answer that dual vs single [maintenance question]. Lenalidomide was standard for many years, and there are potential secondary malignancies, but it’s generally relatively low. Adding daratumumab doesn’t increase the risk of secondary malignancies either, it just increases the risk for infections and myelosuppression.

I think it’s your choice, but I agree with you. For a higher-risk patient, someone who didn’t achieve a depth of response, like our patient, who went from VGPR to VGPR [after transplant], and didn’t change, I think maybe giving dual-agent maintenance would be reasonable in that setting. But you can discuss it with the patient, and you could always stop the daratumumab or lenalidomide down the line too. There is no one standard of care in this setting.

DISCUSSION QUESTION

• How will MRD testing change practice in the future?​

Braunstein: I’m sure not everybody is using it. It’s a little bit cumbersome in real-world practice. But how do you think you would in an ideal world if it’s easy to test, and you get it right away? How would you implement it to make practice decisions? Let’s say it’s like a mass spectrometry test on the blood and it comes back in a day. How would you use it after induction to decide on transplant? In an ideal world, how would you want to use MRD to guide the management?

Mundia: Post induction, if somebody’s really hesitant…if they’re afraid of the hospital or whatever it is, [if they’re] MRD negative, I don’t need to twist their arm. But if you’re MRD positive, you know you’re at risk. You know your risk that the disease activity is going to come back earlier. If you still want to take that risk, that’s fine, but I think these are probably the places that would help patients decide whether they want something more intense or less intense.

Braunstein: Right now, doing MRD testing on bone marrow is a big ask for patients. They talk about in clinical trials like it was just reflexively done, like a blood test. But not every patient, especially in real-world practice, wants to have a bone marrow biopsy, certainly not every month. But if we could have a blood test, or you could sample it every 3 months very easily, that might change how we use MRD down the road.

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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. 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

3. National Cancer Institute. Cancer stat facts: multiple myeloma. Surveillance, Epidemiology, and End Results Program. Accessed March 13, 2026. https://tinyurl.com/mvwp3xdt

4. Badros A, Foster L, Anderson LD Jr, et al. Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study. Blood. 2025;145(3):300-310. doi:10.1182/blood.2024025746

5. Rajeeve S, Derkach A, Devlin S, et al. Daratumumab versus lenalidomide as maintenance therapy in newly diagnosed multiple myeloma – final results from a randomized investigator-initiated trial. Blood. 2025;146(suppl 1):2273. doi:10.1182/blood-2025-2273