Fellow's Perspective: Patient Case of Newly Diagnosed Multiple Myeloma

Marc J. Braunstein, MD, PhD, FACP

Associate Professor of Medicine

Fellowship Program Director

NYU Grossman Long Island School of Medicine

NYU Perlmutter Cancer Center

New York, NY

Olivia Main, MD

PGY5 Fellow, Hematology/Oncology

NYU Grossman Long Island School of Medicine

NYU Perlmutter Cancer Center

New York, NY

PATIENT DISCUSSION

MAIN: There was a second revision of the R-ISS score that incorporated some further chromosomal abnormalities, most notably the 1q gain. In the second revision, all of these values were given a weighted score. Where this comes into play is it further delineates our patients in this intermediate categorization to help further prognosticate these patients in the intermediate risk score.

BRAUNSTEIN: For our first discussion, Dr Main, which treatment regimens would you consider for this patient?

MAIN: Our patient has a relatively good performance status, stage II disease, and transplant eligibility, so I would start her on an induction regimen with a quadruplet regimen. I would consider daratumumab [Darzalex] with lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone [D-RVd] for her. We can talk a bit further about those studies in a moment. Dr Braunstein, how would her cytogenetics and [disease] stage impact these treatment decisions for you?

BRAUNSTEIN: I agree that using a quadruplet regimen would be appropriate in this setting and in a fit, transplant-eligible patient. She appears to be high risk based on her 1q gain, although there are emerging data that when you have a 1q gain combined with hyperdiploidy cytogenetics, that might not be as high risk as someone who has only a 1q gain with or without additional high-risk cytogenetic lesions. That ultimately will contribute to her stage, but I would focus on the cytogenetics in terms of guiding the use of quadruplet induction regimens.

QUADRUPLET DATA

MAIN: To touch upon the NCCN guideline recommendations, we would choose a quadruplet regimen for this patient, which is now being recommended for upfront induction.¹ This is based on the results from 2 trials.

The first trial I wanted to discuss is the phase 2 GRIFFIN trial [NCT02874742]. This looked at patients with transplant-eligible newly diagnosed multiple myeloma, and randomly assigned the patients 1:1 to receive either the quadruplet regimen with D-RVd vs RVd alone. The patients received 4 cycles and then went on to transplant. They…then received consolidation therapy with either arm that they had received before transplantation, and then went on to maintenance therapy.

The primary end point they were looking for was stringent complete response [CR]. At the end of the treatment evaluation, they also looked at progression-free survival [PFS], as well as overall survival [OS]. Those who received the quadruplet regimen had statistically significant improvement in PFS with an 87.2% 4-year PFS rate compared with 70.0% [for D-RVd vs RVd].²

This was also seen both at the end of the induction therapy as well as at the end of final analysis. [The percentage of] those who achieved a CR or better after the end of induction was around 19% in the D-RVd group, but we saw this even further depth of response increase at the end of the final analysis to 83% in those who received the quadruplet regimen, compared with 60% of patients who received the triplet regimen alone. This led to another study that I’ll talk about, the PERSEUS trial [NCT03710603], which also demonstrated that the quadruplet regimen improved the depth of responses for these patients.

One final note on the GRIFFIN study: They also were looking at minimal residual disease [MRD] negativity at the end of the trial. The quadruplet regimen led to a greater depth of response by MRD negativity as compared to the triplet regimen [in this population].

To talk a little bit further about the phase 3 trial, which was PERSEUS, transplant-eligible patients were assigned to receive the quadruplet regimen vs a triplet regimen. They went on to transplant and then received consolidation therapy with the same regimen they had received before, whether that be quadruplet vs triplet, and then went on to maintenance therapy. The primary end point was PFS, with secondary end points including MRD negativity, overall response rate, and OS.

As I talked about in the GRIFFIN study, the [4-year] PFS in the quadruplet arm of PERSEUS was statistically significant and improved compared with the triplet: 84.3% vs 67.7%, respectively, of patients.³ Looking at the CR rates in both groups, the quadruplet regimen did demonstrate statistical significance, both in the stringent CR and CRs overall. Even looking at the subgroup analysis, most patients who were delineated into further subgroups also still fared better with the quadruplet regimen compared with the triplet arm.

The MRD negativity [rates at] 10^-5 as well as 10^-6 [sensitivity] were statistically significant, favoring the quadruplet regimen over the triplet regimen, demonstrating this prolonged depth of response in those who received the quadruplet regimen.

Adverse events were fairly well matched between both groups, the quadruplet and the triplet arms. There was slightly more neutropenia in the quadruplet regimen, a bit more cytopenias overall in the quadruplet regimen, but in terms of the grade 3 or 4 adverse events, it was fairly comparable from the quadruplet to the triplet arm.

Marc J. Braunstein, MD, PhD, FACP, and Olivia Main, MD, discuss the patient case with Peers & Perspectives in Oncology.

DEPTH OF RESPONSE

BRAUNSTEIN: That was a great overview of those randomized studies. Dr Main, what do you consider to be adequate or successful treatment response in your patients following their induction therapy in the real-world setting?

MAIN: This is a great question. This is what we’re looking to achieve after our induction therapy. I think a very good partial response [VGPR] would be an adequate response. Of course, we’re hoping for the greatest step that we can achieve, so seeing a CR or a stringent CR would be preferable, but a VGPR has been a standard that I would look for.

Dr Braunstein, when do you typically assess these patients for MRD status following their initial therapy?

BRAUNSTEIN: I agree with your last response. Depth of remission is key in myeloma because it correlates with longer-term remissions and duration of response. Our deepest remissions that we can assess are MRD. When it comes to MRD, there are different ways of assessing it, but most of the techniques we use rely on a bone marrow biopsy, although it can also be done with lower sensitivity on blood biopsy. When it comes to doing a bone marrow biopsy, I don’t do them more frequently than every 6 months, and typically after induction, I will do one then about 100 days following their transplant, and then approximately once a year, as the patient allows, after their transplant while they’re on maintenance therapy to assess for MRD. As you showed very nicely in presenting the GRIFFIN data, the rates of MRD and the rates of overall response may continue to improve during the post-transplant maintenance phase as well.

CASE UPDATE

• D-RVd induction therapy was initiated for the patient.
• She achieved a VGPR post-induction therapy.
• She underwent stem cell mobilization and 2 months later underwent an autologous stem cell transplant (ASCT).
• Post-ASCT response: stringent CR, MRD positive

ADVERSE EVENTS AND CONSOLIDATION

BRAUNSTEIN: Dr Main, how do you manage adverse events for patients receiving induction therapy? You showed from the PERSEUS study that there were slightly higher rates of myelosuppression, for example. Would you say that when you’re treating patients in first line that you may see more different adverse events between triplet and quadruplet therapies?

MAIN: I would say the adverse events are fairly comparable, as we discussed. But for those patients who do have more cytopenias, we may perhaps need to dose-reduce their regimen slightly, whether that be the lenalidomide or bortezomib. Should patients need transfusions, they can be offered transfusion support and things like that. But for the most part, in either arm, the adverse events were fairly similar. Of course, we’re assessing for things such as neuropathy while they’re on these medications. Should other things arise, we can always offer supportive measures, for example, perhaps antibiotic prophylaxis if they become neutropenic.

BRAUNSTEIN: I think prevention is the best medicine. [This includes options such as] bringing them on herpes simplex virus prophylaxis, monitoring every visit for neuropathy, and keeping a close eye on their cytopenias, giving growth factors as needed, and making dose adjustments to get the patients to quadruplet therapy regimen.

MAIN: Dr Braunstein, does your choice of induction therapy impact your choice of consolidation or maintenance therapy in these patients who are transplant eligible?

BRAUNSTEIN: If we’re sticking to the way the GRIFFIN and PERSEUS studies were done—studies that have looked at quadruplet induction with transplant—there were additional cycles, typically 2 cycles of consolidation with the quadruplet regimen that were given prior to maintenance. In my practice, I don’t necessarily give the consolidation to all patients, especially if they’ve achieved a deep remission that’s MRD negative. In someone who’s MRD positive, you might argue that those 2 cycles of consolidation are meaningful, since they may push the patient to an MRD-negative state. In terms of maintenance, if you’re sticking to the way that GRIFFIN and PERSEUS were done, you would give the monoclonal antibody and lenalidomide maintenance as a doublet therapy.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma; version 1.2025. Accessed October 7, 2024. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf}

_{2. 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}

_{3. Sonneveld P, Dimopoulos MA, Boccadoro M, et al; PERSEUS Trial Investigators. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054}