Notable 2024/Early 2025 Multiple Myeloma NCCN Guideline Updates Feature Quadruplets and More

Shaji Kumar, MD

One of the most notable changes to the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of patients with multiple myeloma is the addition of a quadruplet regimen as the primary therapy for patients who are transplant candidates. With the category 1 recommendation of daratumumab (Darzalex) plus lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (VRd) for this patient population, triplets have moved to other recommended regimens, making the quadruplet the sole preferred regimen.¹

“The main message is [the treatment paradigm for] myeloma, and I’m sure other cancers, is rapidly changing with the introduction of new therapies,” chair of the multiple myeloma NCCN guidelines Shaji Kumar, MD, said in an interview with OncLive®. “The NCCN guidelines represent state-of-the-art [guidelines that are] quite often current with the available evidence. It’s something that you should always periodically update yourselves with in terms of changes so they can be reflected in routine practice.”

The Most Notable 2024/First Quarter of 2025 NCCN Revisions in Multiple Myeloma:

• Imaging adjustments have been made
• For primary therapy for transplant candidates:
  • Daratumumab plus VRd has moved from an other recommend regimen to a preferred regimen (category 1)
  • Carfilzomib (Kyprolis)/lenalidomide/dexamethasone was moved from a preferred regimen to an other recommended regimen
  • VRd was moved from a preferred regimen to an other recommended regimen (category 1)
  • Isatuximab-irfc (Sarclisa)/bortezomib/lenalidomide/dexamethasone (Isa-VRd) was added to other recommended regimens
  • 2 regimens were removed from useful in certain circumstances, and 1 regimen was added to this section
• For maintenance therapy:
  • Carfilzomib plus lenalidomide, as well as daratumumab with or without lenalidomide, were moved from useful in certain circumstances to other recommended regimens
  • A regimen under useful in certain circumstances was modified to bortezomib with or without lenalidomide
• For primary non-transplant candidates:
  • Isa-VRd for patients younger than 80 years of age who are not frail was added to preferred regimens (category 1)
  • Daratumumab/bortezomib/melphalan/prednisone was removed from other recommended regimens (category 1)
  • Regimens under useful in certain circumstances were adjusted
• A new column containing 5 regimens for patients with anti-CD38–refractory disease was added
• A regimen was added to the Bortezomib-Refractory column, and a regimen moved in the Lenalidomide-Refractory column
• The CAR T-cell therapy section was adjusted

In the interview, Kumar detailed notable updates and revisions made to the multiple myeloma NCCN guidelines in 2024 and the first version of the 2025 guidelines. Kumar is research chair in the Division of Hematology, a consultant in the Division of Hematology, and a professor of medicine at Mayo Clinic in Rochester, Minnesota.

OncLive: What 2024 and first quarter of 2025 multiple myeloma NCCN updates have had an immediate influence on how you practice?

Kumar: The updates focused on a few different aspects of myeloma therapy. One of the important changes has been the introduction of quadruplet regimens for newly diagnosed myeloma. Several phase 3 trials have come out supporting the use of quadruplet regimens in transplant-eligible as well as -ineligible patient populations. We made some changes in the recommendations for newly diagnosed myeloma [making] the quadruplet regimens a standard of care.

We also expanded upon the use of 2-drug maintenance [therapy regimens] in certain settings; increasingly, we have tried to give a bit more direction towards the use of specific therapies, on one hand based on evidence from phase 3 trials, but also giving some directions in terms of specific patient characteristics [regarding] using the specific regimens. That’s one change.

We also did a major update for the treatment of relapsed/refractory disease, wherein the major change has been the introduction of immunotherapy over the past year; even though some of the agents were already there, we restructured the approach to relapsed myeloma [management], incorporating some of the recent changes in the indications for CAR T-cell therapy. For example, the use of CAR T-cell therapy in earlier lines of therapy is [now] incorporated into the NCCN guidelines.

There is a separate section [with] a box that highlights the 3 bispecific antibodies, as well as the 2 CAR T-cell therapies, that we have available for the management of myeloma. We also made many modifications in terms of the diagnostic approach, highlighting the data that are out there for potential early intervention in smoldering myeloma. Some of these aspects were part of the guidelines before, but we added more clarifications and so forth.

Over the years, we also have been working on adding more content to the guidelines, particularly with respect to supportive care management. For example, thromboprophylaxis for patients with myeloma, management of some uncommon manifestations, [and] some of the associated conditions in addition to amyloidosis—like POEMS [syndrome]—have been added over time. [Guidelines regarding the management of] monoclonal gammopathy of renal significance or other monoclonal gammopathies of clinical significance have already been updated. This is an ongoing process. We have managed to add few additional updates with respect to the uncommon plasma cell disorders, and we’ll continue to work on that aspect in the future [with] versions [that address diseases] like plasma cell leukemia, central nervous system [CNS] myeloma, and so forth.

What other notable guideline updates would you like to share?

The main update is the different diagnostic perspective. The emphasis on the use of PET/CT [at] baseline is a strong recommendation. It’s important from the point of view of diagnosis and has prognostic value because if you find extramedullary disease, that can modify the outcomes of patients with myeloma.

We made some clarifications in terms of the necessary testing. We emphasized the fact that we should consider CAR T-cell therapy early on, so patients are not late in the course of the disease before we collect lymphocytes. We strengthened some of the radiation therapy approaches [with] a bit more clarity around the doses that should be used in the clinical scenarios where radiotherapy would be of benefit for these patients and [noted] where it should be avoided. [Additionally], a lot was added on infection prophylaxis, particularly around the use of intravenous immunoglobulin for prophylaxis.

Then, as with all versions, we go through all the regimens, and we phased out a few regimens that we don’t use commonly, especially the regimens that use thalidomide, which is hardly used nowadays in practice. Also, traditional regimens like those including doxorubicin were removed. A few regimens moved between different sections in terms of preferred vs other recommended.

Infection prophylaxis is one area where we added many different updates, especially in light of the [development of] immunotherapies, which increase the risk of infections in these patients.

What is key to note for community oncologists who are adapting to recent guideline changes?

When you have a newly diagnosed patient with myeloma, doing imaging to make sure you make an accurate diagnosis of myeloma vs one of the precursive conditions is important, and [this imaging can] also [rule] out concurrent amyloidosis in some of these patients if the clinical presentation makes you suspect that.

The use of the quadruplet regimens in patients with newly diagnosed myeloma, especially those who are fit and proceeding to an autologous stem cell transplant [is notable]. [Also], the use of immunotherapy is important if you have a patient from the first relapse onwards—it is good to have that discussion with respect to the use of CAR T-cell therapy, and having the patients at least referred to a CAR T center for that discussion is important. Bispecific antibodies are increasingly going to be used in community practice, so that’s going to be important in the years to come [as well].

Have you faced any challenges integrating updates to the guidelines into your practice?

Not really. Many of the [changes] that get incorporated are updates that are already starting to affect practice by the time they [become incorporated into the guidelines], especially in the context of the referral institutions because they end up being part of lot of [the pivotal] clinical trials.

How do you communicate guideline changes to your patients who are receiving treatment?

The guidelines change often. They don’t necessarily change ongoing therapy because these [changes] are applicable to certain points in the disease journey. For a patient who’s already a few cycles into treatment for newly diagnosed myeloma, these changes probably won’t be applicable. They may be applicable the next time [the patient] needs a new treatment; [at that point, the patient] may [receive a regimen that is] different than what was originally planned for them at that point.

What changes to the guidelines do you anticipate will occur in 2025?

It’s hard to predict, but it’s all going to be driven by the new data that will appear between now and then. Certainly, we have more data with respect to the use of quadruplets, even in older patients, so that’s going to [be] increasingly reflected. We’ll have more immunotherapy agents and more data around sequencing of immunotherapy agents, as well as combinations. I suspect these will find their way [to the guidelines]. We’re working on additional guidance in terms of some of the difficult-to-treat [conditions] like CNS myeloma and so forth, and some of those recommendations will also make their way to the guidelines.

Reference

NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2025. Accessed November 5, 2024. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf