NCCN Guidelines Prioritize Quad Therapy in Multiple Myeloma

When the National Comprehensive Cancer Network (NCCN) guidelines for multiple myeloma were updated on September 17, 2024—their most recent update, although additional updates are expected in 2025—for the first time, a quadruplet regimen became a category 1 recommendation and the preferred first-line treatment option for transplant-eligible patients and transplant-ineligible patients.¹

Daratumumab, lenalidomide, bortezomib, and dexamethasone comprise the new category 1 preferred regimen for patients eligible for transplant, moving up from the category of “Other recommended regimens.” Those ineligible for transplant can also receive the quad therapy, but only if they are not considered frail and are younger than 80 years; also for this patient group, an important subheading was added: “In general, continue primary therapy until progression with de-escalation of therapy (modification of dose and duration) as needed.”

Overall, in this most recent iteration of the guidelines, adjustments were made to the categories of primary therapy and maintenance therapy for patients who are and are not eligible for transplant; 5 recommended regiments were added for patients who have anti–CD-38 refractory disease, and 2 of them are category 1 recommendations; bortezomib- and lenalidomide-refractory columns were added; the section on chimeric antigen receptor (CAR) T-cell therapy was updated; and adjustments were made to diagnostic workup procedure and imaging principles.

Regimen Adjustments

In transplant-eligible patients, beyond the new quadruplet category 1 recommendation, the primary regimens of bortezomib/lenalidomide/dexamethasone (category 1) and carfilzomib/lenalidomide/dexamethasone were moved to “other recommended,” and that section also added isatuximab-irfc/bortezomib/lenalidomide/dexamethasone (also added to “useful in certain circumstances”). Maintenance therapy recommendations now include carfilzomib/lenalidomide and daratumumab/lenalidomide, but the preferred maintenance regimen is lenalidomide (category 1). Useful in certain circumstances are bortezomib with or without lenalidomide and ixazomib.

In transplant-ineligible patients, beyond the new preferred regimen, daratumumab/bortezomib/melphalan/prednisone (category 1) was removed as a recommended regimen and 2 regimens were added under “useful in certain circumstances”: daratumumab/cyclophosphamide/bortezomib/dexamethasone and isatuximab-irfc/carfilzomib/lenalidomide/dexamethasone (category 2B).

In this most recent update to the National Comprehensive Cancer Network guidelines for multiple myeloma, a quadruplet regimen became the preferred first-line treatment option for transplant-eligible and -ineligible patients. | Image Credit: © momius-stock.adobe.com

For patients who have anti–CD-38 refractory disease, here are the 5 added regimens:

• Carfilzomib/lenalidomide/dexamethasone (category 1)
• Carfilzomib/pomalidomide/dexamethasone
• Pomalidomide/bortezomib/dexamethasone (category 1)
• Elotuzumab/pomalidomide/dexamethasone, after 2 prior therapies that include lenalidomide and a proteasome inhibitor (PI)
• Ixazomib/pomalidomide/dexamethasone, after 2 prior therapies including an immunomodulatory drug (IMiD) and a PI and with disease progression on/within 60 days of completion of last therapy

Changes were also instituted for patients who have bortezomib-refractory disease or lenalidomide-refractory disease. For patients who have bortezomib-refractory disease, the regimen of elotuzumab/pomalidomide/dexamethasone was added as a recommendation for use in patients after 2 prior therapies that include lenalidomide and a PI. For patients who have lenalidomide-refractory disease, the triplet of selinexor/bortezomib/dexamethasone (category 1) was moved to “other recommended” and elotuzumab/pomalidomide/dexamethasone is now a recommendation for use after failure on 2 prior therapies, including lenalidomide and a PI.

For CAR T-cell therapies, there were notable additions for its use after 1 and 2 prior lines of therapy,¹ both category 1 recommendations and approved on April 5 by the FDA for earlier use in patients who have relapsed/refractory multiple myeloma^2,3:

• Ciltacabtagene autoleucel (cilta-cel; Carvykti; Janssen/Johnson & Johnson) is now recommended for use among patients after 1 prior line of therapy that included an IMiD and a PI, and who are refractory to lenalidomide.
• Idecabtagene vicleucel (ide-cel; Abecme; Bristol Myers Squibb/2seventy bio) is now recommended for use among patients after 2 prior lines of therapy that included an IMiD, an anti–CD-38 monoclonal antibody, and a PI.

Among the imaging and workup changes in these guidelines are the following¹:

• For patients suspected of having myeloma or solitary plasmacytoma, the first bullet was updated to say that FDG-PET/CT (preferred) or whole-body low-dose CT is recommended for initial diagnostic workup, but skeletal survey is acceptable in certain circumstances.
• For imaging of solitary plasmacytoma:
  • The first choice for initial and continued evaluation of solitary extraosseous plasmacytoma is now whole-body FDG-PET/CT, and when that is not available, whole-body MRI is the first choice for initial evaluation of solitary osseous plasmacytoma.
  • Due to the high likelihood of relapse or progression to multiple myeloma, the guidelines now recommend use of the imaging technique used at initial diagnosis over the first 5 years and then only when there are clinically or laboratory-confirmed signs and symptoms of disease.

Linvoseltamab Update

This so-far investigative bispecific antibody was expected to be added to this guidelines update for use in patients with relapsed/refractory disease after 3 or more lines of treatment; however, Regeneron Pharmaceuticals received a complete response letter from the FDA on August 20 that was related to a preapproval inspection at a manufacturing plant for another company’s product.^4,5 The drug’s efficacy and safety were never in question.

The biologics license application was originally accepted by the FDA in February 2024 and filed for this indication using a backbone of data from the phase 1/2 LINKER-MM1 trial (NCT03761108).^6-8 At a dose of 200 mg, linvoseltamab produced an objective response rate (ORR) of 71%, and 46% of these patients achieved a complete response (CR) or better over a median 11 months. Further, data presented during the European Hematology Association 2024 Congress show even better results.⁹ Over a median 14.3 months, the 71% ORR endured with 200 mg and more patients (50%) achieved a CR or better. Stringent CR, CR, very good partial response, and partial response were also seen in 44.4%, 5.1%, 13.7%, and 7.7% of patients, respectively.

Linvoseltamab is also under investigation in the phase 3 confirmatory LINKER-MM3 trial (NCT05730036) for use in heavily pretreated patients who have relapsed/refractory disease, with an expected completion date of December 26, 2032.¹⁰

References

1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): multiple myeloma. Version 1.2025. September 17, 2024. Accessed November 22, 2024. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf

2. Shaw M. FDA approves cilta-cel for earlier treatment of RRMM. AJMC^®. April 6, 2024. Accessed November 26, 2024. https://www.ajmc.com/view/fda-approves-cilta-cel-for-earlier-treatment-of-rrmm

3. Bonavitacola J. Ide-cel receives approval for earlier treatment for relapsed, refractory multiple myeloma. AJMC. April 5, 2024. Accessed November 26, 2024. https://www.ajmc.com/view/ide-cel-receives-approval-for-earlier-treatment-for-relapsed-refractory-multiple-myeloma

4. Klein H. FDA issues CRL for linvoseltamab in R/R multiple myeloma. AJMC. August 21, 2024. Accessed November 26, 2024. https://www.ajmc.com/view/fda-issues-crl-for-linvoseltamab-in-r-r-multiple-myeloma

5. Regeneron provides update on biologics license application for linvoseltamab. News release. Regeneron. August 20, 2024. Accessed November 26, 2024. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application-0

6. Linvoseltamab BLA for treatment of relapsed/refractory multiple myeloma accepted for FDA priority review. News release. Regeneron. February 21, 2024. Accessed November 26, 2024. https://investor.regeneron.com/news-releases/news-release-details/linvoseltamab-bla-treatment-relapsedrefractory-multiple-myeloma

7. Phase 1/2 study of REGN5458 in adult patients with relapsed or refractory multiple myeloma (LINKER-MM1). ClinicalTrials.gov. Updated June 25, 2024. Accessed November 26, 2024. https://www.clinicaltrials.gov/study/NCT03761108

8. Updated linvoseltamab pivotal data demonstrated strong rates and depth of response in patients with heavily pre-treated multiple myeloma. News release. Regeneron. December 7, 2023. Accessed November 26, 2024. https://investor.regeneron.com/news-releases/news-release-details/updated-linvoseltamab-pivotal-data-demonstrated-strong-rates-and

9. McCormick B. Dr Suzanne Lentzsch highlights promising linvoseltamab results in treating RRMM. AJMC. June 21, 2024. Accessed November 26, 2024. https://www.ajmc.com/view/dr-suzanne-lentzsch-highlights-promising-linvoseltamab-results-in-treating-rrmm

10. A trial to learn how well linvoseltamab works compared to the combination of elotuzumab, pomalidomide and dexamethasone for adult participants with relapsed/refractory multiple myeloma (LINKER-MM3). ClinicalTrials.gov. Updated November 25, 2024. Accessed November 26, 2024. https://clinicaltrials.gov/study/NCT05730036