Considering NCCN Guidelines to Determine Maintenance Therapy Multiple Myeloma

The Expert Panel

The panel was led by Beth Faiman, CNP, PhD, an adult nurse practitioner in the Department of Hematology/Oncology at Cleveland Clinic. Additional panelists included Larry Anderson, MD, PhD, FACP, director of the Myeloma, Waldenström’s, and Amyloidosis Program at UT Southwestern Harold C. Simmons Comprehensive Cancer Center, leader of the Hematologic Malignancies and Cellular Therapy Clinical Research Program, and codirector of the Phase I Clinical Trial Research Program and the Cellular Immunotherapy and Autologous Stem Cell Transplant Program; Cristina Gasparetto, MD, professor of medicine, hematologic malignancies and cellular therapy at Duke Health; Andrzej Jakubowiak, MD, PhD, director of the Myeloma Program and professor of medicine at the University of Chicago Medicine; Hans Lee, MD, director of multiple myeloma clinical research, Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, and associate professor in the Department of Lymphoma/Myeloma; Amrita Krishnan, MD, executive medical director of hematology at City of Hope Orange County, director of the Judy and Bernard Briskin Multiple Myeloma Center, and professor in the Department of Hematology and Hematopoietic Cell Transplantation; Ajay K. Nooka, MD, MPH, FACP, associate director of clinical research, scientific director of Winship Data and Technology Applications Shared Resource at Winship Cancer Institute of Emory University, and director of the Myeloma Program in the Department of Hematology and Medical Oncology at Emory University School of Medicine; Ariel Grajales-Cruz, MD, assistant member in the Department of Malignant Hematology, Multiple Myeloma Section at Moffitt Cancer Center​, and assistant professor at the University of South Florida​; Krina K. Patel, MD, MSc, Multiple Myeloma Section Chief​, associate professor in the Department of Lymphoma/Myeloma, Division of Cancer Medicine​ at The University of Texas MD Anderson Cancer Center​; and Ravi Vij, MD, MBA, medical director of Siteman Cancer Center and professor of medicine in the Section of Bone Marrow Transplantation and Leukemia at Washington University in St. Louis School of Medicine​.

Specifically, panelists focused on treatment combinations, the current recommended and preferred use for maintenance therapy, and bone-modifying therapy. These discussions helped to inform clinicians’ next steps on how to best approach multiple myeloma treatment.

Maintenance Therapy After First-Line Treatment

For patients who are transplant candidates, the NCCN category 1
preferred regimen for maintenance therapy is lenalidomide (Revlimid) with other regimens, including carfilzomib (Kyprolis) plus lenalidomide, or daratumumab (Darzalex) plus lenalidomide.¹ For patients who are not transplant candidates, the guidelines state to continue primary therapy until patients experience progression with de-escalation of therapy as needed.

“After transplant, I base [my decision] on partly the patient’s risk factors, their chromosomes, and their response. There were thoughts of doing some consolidation if the patients had not experienced a complete response [CR]. Those are the patients for [whom] I would typically have the daratumumab plus lenalidomide ongoing for at least 2 years and then see [whether] they become MRD negative or not, [and] if they’re high risk, potentially extending that daratumumab plus lenalidomide [combination],” Anderson said.

Jakubowiak gave some pushback, stating carfilzomib has shown a better response than lenalidomide, based on results from the phase 3 ATLAS trial (NCT02659293).² However, results from the phase 3 PERSEUS trial (NCT03710603) led many institutions to implement extended treatment post transplant with either daratumumab plus lenalidomide or daratumumab plus bortezomib (Velcade), lenalidomide, and dexamethasone (D-VRd), among other combinations.³ However, he is unsure if daratumumab plus lenalidomide vs carfilzomib plus lenalidomide and dexamethasone (KRd) would be better. Patel often uses carfilzomib if patients are ultra high risk or they are young with plasma cell leukemia. Typically, the treatment is given in a quadruplet fashion.

Krishnan noted that if she has patients who have been taking lenalidomide for 1 or 2 years and are doing well, she likely will not consider switching them.

It is likely that daratumumab plus lenalidomide will become the standard of care, according to Lee. For his patients, he employs a core cytogenetic risk-adapted approach plus dual maintenance of a proteasome inhibitor plus immunomodulatory drugs.

“In patients who are MRD positive after consolidation, there [were] some nice data at the American Society of Clinical Oncology [2024 meeting] showing a higher MRD conversion rate from positive to negative in patients who did get daratumumab plus lenalidomide vs lenalidomide. Certainly, those are patients [for whom] I would do the daratumumab plus lenalidomide maintenance approach,” said Lee.

According to Nooka, as the frontline space changes, the options for maintenance therapy will also change. Certain situations in which patients would need to receive daratumumab plus lenalidomide include those where they did not have an optimal response in earlier lines of treatment, those where they did not have a CR post transplant, and those where patients were referred from another center.

Treatment Approach to Bone-Modifying Therapy

Faiman asked her colleagues how they handle bone-modifying therapy. She wants to make sure supportive care is highlighted in this population as well.

In Gasparetto’s clinic, they use zoledronic acid (Zometa) for a minimum of 3 months. Pamidronic acid is also considered, especially for older patients, and can be decreased over time. Finally, for those with renal insufficiency, denosumab (Xgeva) is used. Few data exist surrounding denosumab use, but when the agent is stopped, zoledronic acid is typically used as a follow-up about 6 months later. Gasparetto believes clinicians need to educate the community more on these regimens to help with supportive care.

Faiman mentioned denosumab is a big reimbursement, but Gasparetto countered that it was important to use. Zoledronic acid can be tapered after about 24 months if there is an aggressive presentation. Additionally, bone density tests can be used to guide treatment options.

Nooka, however, does not agree with this approach. To begin, zoledronic acid is significantly cheaper than denosumab. If a patient has been off bone-modifying therapy because of a relapse, they will be given zoledronic acid once a month until remission or over a 1-year period.

Further, denosumab treatment cannot be stopped abruptly because of rebound osteoplastic activity. For patients with profound hypokalemia, calcium and vitamin D must be given in conjunction with these agents.

MRD in Multiple Myeloma

The PERSEUS trial examined rates of MRD negativity at 10^–5 and 10^–6, which was the intent-to-treat population. In the D-VRd arm, rates between the 10^–5 and 10^–6 threshold at the end of consolidation were 34.4% and 57.5%, respectively, 43.9% and 65.1% at up to 12 months, 57.7% and 72.1% at up to 24 months, and 63.9% and 74.6% at up to 36 months. Corresponding rates in the VRd arm were 16.1% and 32.5%, 20.9% and 38.7%, 27.4% and 44.9%, and 30.8% and 46.9%, respectively.

The sustained MRD negativity rate at 12 months or more in the D-VRd arm at 10^–5 was 47.3%, and 64.8% at 10^–6. For the VRd arm, rates were 18.6% and 29.7%, respectively. Sustained MRD negativity rates at 18 months or more in the D-VRd arm were 42.0% at 10^–5 and 59.4% at 10^–6, and in the VRd arm they were 15.0% and 25.1%, respectively.

“One of the key differences between the PERSEUS and phase 2 GRIFFIN [NCT02874742] trials is that in the GRIFFIN trial, we didn’t see the benefit in the 2 or more high-risk cytogenetic abnormalities, whereas [in] PERSEUS we may be starting to see a little difference because we’re extending the daratumumab; as long as they’re MRD positive, they stay on daratumumab indefinitely,” Anderson said.

Faiman asked when MRD negativity was checked and how these results helped to drive the panel’s decision-making. Anderson continues to check MRD negativity beginning at 3 months and continuing every 12 months. He noted unless patients are experiencing severe toxicities with sustained MRD activity, most of the time, they won’t act on MRD.

Anderson did want to include a note about the phase 3 AURIGA study (NCT03901963), the results of which he believes adds to the body of evidence for multiple myeloma.⁴ The trial assessed patients with newly diagnosed multiple myeloma who were MRD positive and anti-CD38 naive post transplant. He mentioned that this shows patients probably need a CD38 antibody while continuing treatment.

Lee typically checks MRD after induction to help guide decisions and whether to proceed with or defer transplant.

“If a patient is in their 70s with standard-risk multiple myeloma and had already attained MRD negativity, then I do have some patients [who] opt to collect stem cells but defer transplant after discussion of risks and benefits. That’s relevant, at least for me, that I’ve used MRD negativity,” Lee said.

Nooka questioned at which threshold he was following should he make that decision. Lee responded that this is typically for patients who are standard risk, and if they are high risk, this would not be a discussion.

“It would be interesting to see the differences between standard risk and high-risk post induction, because we achieve rapid responses in the high risk. We know that they’re not sustainable with the standard risk. It takes longer, and so the number is probably lower.” Gasparetto said.

Because of this, she checks on MRD later for those patients who are at standard risk, and this helps guide her treatment decisions.

Looking down the road to 3, 5, or 7 years, Faiman wondered if anyone was stopping maintenance therapy. Gasparetto eventually stops when it is based on standard-risk or MRD sustainability. Sometimes she checks MRD sustainability sooner, especially with patients who convert quickly.

Trials are underway to test if stopping maintenance will sustain MRD, according to Nooka. One such trial conducted by the Greek Myeloma Study Group for patients who are standard risk is looking at patients after 3 years of maintenance and whether they achieve MRD 10^–6 and sustain that for 1 year. To date, among the 50 patients enrolled, there has been no resurgence. Nooka hopes to expand maintenance to the entire practice one day.

As the discussion came to a close, the panelists provided some key takeaways. Grajales-Cruz noted that treatment for multiple myeloma is not a one-size-fits-all approach, and that although one wants the best response up front, it cannot be at the expense of the patient’s quality of life. Vij highlighted the heterogeneity in practice but wants to see increased trials and treatments involving chimeric antigen receptor T-cell therapy and bispecifics.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2025. Accessed January 8, 2025. https://shorturl.at/yMel9
2. Kubicki T, Dytfeld D, Wrobel T, et al. Longitudinal assessment of minimal residual disease (MRD) in the ATLAS randomized phase 3 trial of post-transplant treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide (R) alone in patients with newly diagnosed multiple myeloma (NDMM). Blood. 2023;142(suppl 1):4715. doi:10.1182/blood-2023-189850
3. Sonneveld P, Moreau P, Dimopoulos MA, et al. Daratumumab + bortezomib/lenalidomide/dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma: analysis of minimal residual disease in the phase 3 PERSEUS study. Presented at: 2024 SOHO Annual Meeting. September 4-7, 2024; Houston, TX. Abstract MM-355.
4. Badros AZ, Foster L, Anderson LD Jr, et al. Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study. Blood. Published online September 27, 2024. doi:10.1182/blood.2024025746