NCCN Continuing Education

Target Audience: This journal article is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

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Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit^™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-25-012-H01-P

PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until May 10, 2026. PAs should only claim credit commensurate with the extent of their participation.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/May2025; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.

Release date: May 10, 2025; Expiration date: May 10, 2026

Disclosure of Relevant Financial Relationships

None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

Overview

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that typically accumulate in bone marrow, leading to bone destruction and anemia as well as renal damage secondary to the secreted monoclonal protein. MM is most frequently diagnosed in individuals aged 65 to 74 years, with a median age of 69 years.¹ The American Cancer Society estimates 36,100 new MM cases and 12,030 deaths will occur in the United States in 2025.² Globally, age-standardized prevalence and mortality rates, as well as disability-adjusted life-years have all increased between 1990 and 2021. The number of MM cases, deaths, and disability-adjusted life-years is higher in males than in females.³

The NCCN Guidelines Panel for Plasma Cell Neoplasms has developed guidelines for managing patients with various plasma cell neoplasms, including monoclonal gammopathies of clinical significance, POEMS syndrome, solitary plasmacytoma, smoldering myeloma, MM, systemic light-chain amyloidosis, and Waldenström macroglobulinemia. These guidelines are updated annually or more frequently if new high-quality clinical data become available.

Significant updates have been made in Version 1.2025 of the NCCN Guidelines for MM. These NCCN Guidelines Insights focus only on important updates specific to treatment options for patients with newly diagnosed MM (NDMM) who are eligible or ineligible for hematopoietic cell transplant (HCT), recommendations for maintenance therapy, and treatment options for previously treated MM. For a complete list of updates in Version 1.2025, visit NCCN.org.

Updates to Treatment Options for Patients With NDMM

During the annual NCCN Guidelines panel meeting, the panel reviewed the list of regimens and the preference categories and added new regimens, reclassified the preference category, and updated categories of evidence and consensus based on new or updated evidence and panel consensus.

The panel added the 4-drug regimen daratumumab/bortezomib/lenalidomide/dexamethasone (d-VRd) as a preferred regimen for patients with NDMM who are eligible for transplant (Figure 1). The data for this regimen are derived from 2 trials.

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MYEL-G, 1 of 5. NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma, Version 1.2025.

Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.0023

The phase III PERSEUS trial evaluated the efficacy and safety of adding daratumumab to VRd in patients with NDMM who are eligible for transplant (n=709) and demonstrated a clear benefit of adding the monoclonal antibody.⁴ Patients were randomized to receive treatment induction with 4 cycles of d-VRd or VRd, followed by autologous HCT, 2 cycles of consolidation with the same regimen as induction, and then maintenance therapy with lenalidomide in the VRd group and daratumumab + lenalidomide in the d-VRd group. The addition of daratumumab to VRd significantly improved progression-free survival (PFS). Median PFS was not reached in either arm; at 47.5 months, the PFS rate was 84.3% (95% CI, 79.5%–88.1%) in the d-VRd group compared with 67.7% (95% CI, 62.2%–72.6%) in the VRd group, with a hazard ratio (HR) of 0.42 (95% CI, 0.30–0.59; P<.001), indicating a 58% reduction in the risk of progression or death.⁴ The d-VRd group also demonstrated a higher rate of complete response (CR) or better (87.9% vs 70.1%; P<.001).⁴ A substantial proportion of patients in the d-VRd group achieved minimal residual disease (MRD) at the <10⁻⁵ threshold (75.2% vs 47.5%; P<.001), suggesting deeper responses and potentially longer duration of remission. After at least 24 months of maintenance therapy, daratumumab was discontinued in patients who had achieved CR or better and had sustained MRD-negative status for at least 12 months. These patients continued to receive maintenance lenalidomide until disease progression or unacceptable toxicity. The percentage of patients with MRD-negative status for at least 12 months was higher in the d-VRd group than in the VRd group (64.8% vs 29.7%).⁴ The percentage of patients with MRD-negative status assessed at a sensitivity threshold of 10⁻⁶ was 65.1% in the d-VRd group and 32.2% in the VRd group.

The safety profile of d-VRd was consistent with known profiles of the individual agents. Common grade 3 or 4 adverse events observed more frequently in the daratumumab arm compared with the control arm included neutropenia (62.1% vs 51%) and thrombocytopenia (29.1% and 17.3%). Serious adverse events occurred in 57.0% of patients treated with d-VRd compared with 49.3% of those treated with VRd.⁴

The final analysis of the GRIFFIN trial also supports the clinical benefit of adding daratumumab to VRd, demonstrating a significant improvement in depth of response (stringent CR of 67% vs 48% with VRd) and a 4-year PFS rate of 87.2% versus 70% with VRd (HR, 0.45; 95% CI, 0.21–0.95).⁵

Lastly, a subgroup analysis comparing d-VRd versus VRd from a systematic review and meta-analysis of daratumumab-based quadruplet versus triplet induction regimens in patients with NDMM who are eligible for transplant (n=3,327) from 3 randomized controlled trials and 1 nonrandomized controlled study further confirmed significant improvements in both overall survival (OS) (pooled HR, 0.68; 95% CI, 0.48–0.97; P=.03; I²=0%) and PFS (pooled HR, 0.41; 95% CI, 0.31–0.54; P<.00001; I²=0%) with the addition of daratumumab.⁶

Therefore, because adding daratumumab to VRd showed significant improvement in PFS compared with VRd, the triple-drug regimen VRd (category 1) was moved from “Preferred” to “Other Recommended Regimens.” Based on a similar rationale, because the ENDURANCE trial⁷ demonstrated comparable PFS between carfilzomib/lenalidomide/dexamethasone and bortezomib/lenalidomide/dexamethasone, carfilzomib/lenalidomide/dexamethasone was also moved from “Preferred” to “Other Recommended Regimens” (Figure 1).

Isatuximab/bortezomib/lenalidomide/dexamethasone (Isa-VRd) was also added to the list of “Other Recommended Regimens” for patients who are HCT-eligible based on data from the phase III GMMG-HD7 trial (Figure 1). In this trial, patients with NDMM (n=660) eligible for autologous HCT were randomly assigned to receive three 42-day cycles of VRd induction therapy with or without isatuximab. An initial analysis found that Isa-VRd led to deeper responses and higher rates of MRD negativity (<10⁻⁵ by next-generation flow [NGF]) after induction (50% vs 36%; odds ratio [OR], 1.82; 95% CI, 1.33–2.48). The addition of isatuximab resulted in higher incidences of grade 3 or 4 neutropenia (23% vs 7%) and grade 3 or 4 infections (12% vs 10%). One treatment-related death (from septic shock) occurred in the isatuximab group, whereas 4 were reported in the VRd group (one due to cardiac decompensation, one from hepatic and renal failure, one from cardiac arrest, and one from drug-induced enteritis).⁸ The final analysis of outcomes following the first randomization to HCT has now been published. At the time of the publication of Version 1.2025 of the NCCN Guidelines, these data were not yet available. The NGF MRD-negative rates continued to deepen, and after HCT, they were 66% with Isa-VRd versus 48% with VRd.⁹ Importantly, at a median follow-up of 4 years from the first random assignment, the data showed that 18-week induction with Isa-VRd significantly prolonged PFS compared with VRd, regardless of maintenance therapy (HR, 0.70; 95% CI, 0.52–0.95; P=.0184), with PFS not yet reached in either arm.⁹

Another anti–CD-38 regimen, isatuximab/carfilzomib/lenalidomide/dexamethasone (Isa-KRd), was added by the panel to the list of regimens “Useful in Certain Circumstances” based on data from the phase II GMMG-CONCEPT trial and the phase III IsKia trial (Figure 1). The GMMG-CONCEPT trial evaluated Isa-KRd for the treatment of high-risk NDMM in patients who were HCT-eligible and HCT-ineligible (n=125). High-risk disease was defined by ISS stage II or III and specific cytogenetic abnormalities, such as del(17p), t(4;14), t(14;16), or >3 copies of 1q21. Patients received induction therapy followed by consolidation with Isa-KRd plus maintenance therapy with Isa-KR. Patients eligible for transplant received high-dose melphalan followed by HCT, whereas those not eligible for transplant received 2 additional cycles of Isa-KRd after initial treatment. The primary endpoint was a MRD negativity rate of <10⁻⁵ by NGF after consolidation, with PFS as the secondary endpoint. After consolidation, the MRD negativity rates were 67.7% in patients eligible for HCT and 54.2% in those who were ineligible. In total, 81.8% of patients who were HCT-eligible achieved MRD negativity, with 62.6% sustaining it for at least 1 year. At the time of publication, the median PFS had not yet been reached in either group.¹⁰ The phase III IsKia trial assessed the efficacy and safety of Isa-KRd compared with KRd in patients with NDMM who are eligible for transplant, finding that Isa-KRd significantly increased MRD negativity rates after induction and consolidation phases, with 77% of patients in the Isa-KRd group achieving MRD negativity by next-generation sequencing (NGS) at the <10⁻⁵ threshold after consolidation, compared with 67% in the KRd group. Isa-KRd also demonstrated higher MRD negativity rates across all subgroups, including patients with high-risk MM.¹¹

Additionally, regimens that are no longer used as first-line therapy in the United States and were previously listed as “regimens useful in certain circumstances” were removed from the guidelines in Version 1.2025. These include bortezomib/doxorubicin/dexamethasone and the thalidomide-containing 4-drug regimen daratumumab/bortezomib/thalidomide/dexamethasone (Figure 1).

For patients ineligible for HCT, Isa-VRd was included as a category 1 option for those aged <80 years who are not frail, based on data from the following trials (Figure 2). The registrational, phase III, open-label IMROZ trial randomized patients (n=446) aged ≤80 years with NDMM who were not eligible for autologous stem cell transplantation to receive either Isa-VRd or VRd in four 6-week cycles, followed by continuous treatment in 4-week cycles of Isa-Rd versus Rd, respectively. At a median follow-up of 59.7 months, the estimated PFS was 63.2% in the Isa-VRd group compared with 45.2% in the VRd group, with a 40% reduction in risk of disease progression or death (HR, 0.60; 95% CI, 0.44–0.81; P=.0009). The rate of CR or better was significantly higher in the isatuximab group (74.7% vs 64.1%; P=.01), and the proportion of patients achieving both MRD-negative status (<10⁻⁵ by NGS) and CR was also higher (55.5% vs 40.9%; P=.003).¹² Notably, patients aged ≥65 years were deemed ineligible for HCT, and those aged >80 years were ineligible for the study. The incidence of peripheral sensory neuropathy was not higher with Isa-VRd than with VRd in this trial (all grades, 54.4% vs 60.8%, respectively); this high rate reflects the use of twice-weekly bortezomib dosing.

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MYEL-G, 2 of 5. NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma, Version 1.2025.

Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.0023

The nonregistrational phase III BENEFIT/IFM2020-05 study demonstrated the efficacy and safety of isatuximab combined with weekly VRd compared with the triplet combination of isatuximab + lenalidomide/dexamethasone in patients with NDMM who are ineligible for HCT.¹³ The NGS MRD negativity rate at 10⁻⁵ at 18 months was significantly higher in the quadruplet arm, with 71 patients (53%; 95% CI, 44%–61%) achieving MRD negativity compared with 35 patients (26%; 95% CI, 19%–34%) in the triplet arm. The OR for MRD negativity in the quadruplet group, compared with the triplet group, was 3.16 (95% CI, 1.89–5.28; P<.0001).¹³ The weekly and bimonthly schedule of subcutaneous bortezomib (cycles 1–12 and 13–18, respectively) in the Isa-VRd arm led to a higher rate of peripheral neuropathy: grade ≥2 occurred in 37 (27%) patients (4 had grade 3 neuropathy) in the Isa-VRd arm versus 13 (10%) patients (1 had grade 3 neuropathy) in the Isa-Rd arm. However, as expected, the incidence was lower than with twice-weekly dosing.

The panel also voted to move daratumumab/cyclophosphamide/bortezomib/dexamethasone, which was previously included based on the LYRA study,¹⁴ from the list of “Other Recommended Regimens” to “Useful in Certain Circumstances,” because it is mainly used as a treatment option for patients with renal insufficiency or acute kidney injury at the time of presentation (Figure 2). Although randomized controlled efforts are still lacking, mounting evidence highlights the feasibility and importance of early initiation of daratumumab-based treatment in patients with MM who present with acute kidney injury in order to induce rapid and significant reductions in disease burden, improve renal outcomes, and provide a plasmapheresis-free approach.¹⁵

Isa-KRd was added to the list of regimens “Useful in Certain Circumstances” for patients ineligible for HCT who have high-risk cytogenetics based on the results of the GMMG-CONCEPT trial (Figure 2). However, because this trial included very few patients who were ineligible for HCT, the data supporting its inclusion for non-HCT candidates are based more on extrapolation from the HCT-eligible population. As a result, there was no uniform consensus on the use of this regimen in this setting, given the availability of other treatment options, and therefore it is a category 2B recommendation.

Ixazomib-containing regimens are currently FDA-indicated for the treatment of patients with MM who have received at least one prior therapy. In the updated version, the panel has added a footnote noting that in patients with NDMM who are receiving regimens containing bortezomib or carfilzomib, these drugs may be substituted with ixazomib only in select patients with intolerance to bortezomib/carfilzomib¹⁶ or for logistical reasons.¹⁷ The panel discussed examples of the logistical reasons for considering the use of ixazomib, which included patients who are assessed as very frail with many comorbid conditions, those unable to travel to a treatment site, or situations arising during public health emergencies.

Updates to Maintenance Therapy Recommendations

The NCCN panel clarified in the algorithm section that the maintenance regimens are appropriate for patients who have received autologous HCT and classified them as either Preferred, Other Recommended, or Useful in Certain Circumstances. For patients who are not eligible for autologous HCT, in general, primary therapy is continued until progression, with de-escalation of therapy or modifications to dose and duration based on treatment response and toxicity, as needed. Therefore, given the nuances needed in this setting, such as needing to continue induction therapy, de-escalate therapy as appropriate, make dose modification, or discontinue treatment, the panel removed the list of maintenance options previously included for those not eligible for autologous HCT.

Based on the results of the phase III PERSEUS trial⁴ and the phase II GRIFFIN trial,⁵ the panel moved daratumumab/lenalidomide as a maintenance therapy option from “Useful in Certain Circumstances” to “Other Recommended Regimens” (Figure 1). It is important to note that these trials did not randomize the maintenance therapy after induction plus consolidation, and therefore it is unclear whether the MRD negativity and PFS benefit observed with daratumumab were due to the induction followed by consolidation therapy with the daratumumab-containing regimen, or whether adding daratumumab to the maintenance regimen provided additional benefit. The panel strongly encourages enrolling patients in clinical trials in general, and especially to clarify remaining questions around maintenance therapy.

Based on the results from the FORTE¹⁸ and ATLAS¹⁹ trials, the panel moved carfilzomib/lenalidomide as maintenance option from “Useful in Certain Circumstances” to “Other Recommended Regimens” (Figure 1). The FORTE trial demonstrated improved PFS with carfilzomib/lenalidomide maintenance compared with lenalidomide maintenance (3-year PFS from randomization to maintenance, 75% vs 65%; HR, 0.64; 95% CI, 0.44–0.94; P=.023). The randomized phase III ATLAS trial evaluated carfilzomib/lenalidomide/dexamethasone versus single-agent lenalidomide as maintenance therapy following autologous HCT in patients with newly diagnosed MM. After a median follow-up of 33.8 months, the carfilzomib/lenalidomide/dexamethasone group demonstrated a median PFS of 59.1 months, compared with 41.6 months in the lenalidomide group, representing a 49% reduction in the risk of disease progression or death.

Bortezomib monotherapy is included as a maintenance therapy option based on the results of the HOVON²⁰ and UPFRONT²¹ study data. However, the isolated benefit of bortezomib monotherapy in the maintenance setting is unclear. Therefore, given the availability of other maintenance options, the NCCN Multiple Myeloma Panel members moved bortezomib monotherapy as a maintenance therapy option to “Useful in Certain Circumstances,” such as when a patient is unable to tolerate lenalidomide due to toxicity (Figure 1).

Updates to Treatment Options for Previously Treated MM

Editor’s Note: Updates included in Version 2.2025 were not available at press time, these can be found at NCCN.org.

The choice of appropriate therapy for a specific patient with relapsed/refractory disease depends on the context of the clinical relapse, such as prior treatment and duration of response. As a general principle, to maximize the benefit of systemic therapy, if disease relapse occurs at least 6 months after stopping therapy, previous regimens may be reconsidered or repeated. For patients still sensitive to daratumumab, bortezomib, and/or lenalidomide, any of the regimens listed in guidelines for previously treated MM may be appropriate. However, because daratumumab-, bortezomib-, and lenalidomide-containing regimens are often given as induction therapy, it is likely that the disease may not be sensitive to one or more of these agents at relapse or if relapse is well within 6 months of primary treatment completion. In such cases, regimens that do not include previously used agents are preferred. Most of the updates in this setting in Version 1.2025 were for disease relapses after 1 to 3 prior therapies.

Considering that anti-CD38–containing regimens are listed as “Preferred” for primary therapy in patients with MM, the NCCN panel has provided a list of regimens for anti-CD38–refractory disease in Version 1.2025. In the previous version of the guidelines, the panel included a list of regimens for bortezomib-refractory and lenalidomide-refractory disease (Figure 3).

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MYEL-G, 3 of 5. NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma, Version 1.2025.

Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.0023

The preferred regimens for anti-CD38–refractory disease include the following non–anti-CD38–containing regimens: carfilzomib/pomalidomide/dexamethasone, carfilzomib/lenalidomide/dexamethasone, pomalidomide/bortezomib/dexamethasone, and elotuzumab/pomalidomide/dexamethasone.

Carfilzomib/lenalidomide/dexamethasone has been specified as a category 1 option (assigned to situations where patients are refractory to anti-CD38 antibody but not to lenalidomide treatment) based on the results of the randomized, multicenter, phase III ASPIRE trial.²² This trial studied the combination of lenalidomide and dexamethasone with or without carfilzomib in patients (n=792) with relapsed/refractory MM who had received 1 to 3 prior lines of therapy and were sensitive to both lenalidomide and dexamethasone. The primary endpoint of the study was PFS. The results showed that adding carfilzomib to lenalidomide + dexamethasone significantly improved PFS by 8.7 months (26.3 months for the carfilzomib arm vs 17.6 months for the lenalidomide + low-dose dexamethasone arm; HR for progression or death, 0.69; 95% CI, 0.57–0.83; P=.0001). The median duration of treatment was longer in the carfilzomib group (88 vs 57 weeks). The incidence of peripheral neuropathy was identical in both arms (17%). Nonhematologic adverse effects (grade ≥3) that were more common in the carfilzomib group compared with lenalidomide + dexamethasone included dyspnea (2.8% vs 1.8%), cardiac failure (3.8% vs 1.8%), and hypertension (4.3% vs 1.8%). Fewer discontinuations due to side effects occurred in the carfilzomib arm (15.3% vs 17.7%). Patients in the carfilzomib arm reported superior health-related quality of life compared with those receiving lenalidomide + dexamethasone alone.

Carfilzomib/pomalidomide/dexamethasone has been included as a treatment option for patients who are refractory to anti-CD38 antibody treatment, based on data from several phase II trials.^23,24 The first was a phase II trial that investigated carfilzomib/pomalidomide/dexamethasone, followed by continuous pomalidomide/dexamethasone, as second-line therapy for relapsed/refractory MM in patients whose disease progression during lenalidomide maintenance therapy and in those eligible for HCT who had not yet received it. On this regimen, 75% of patients experienced at least a very good partial response (VGPR), and 37% reached a CR or better. At 40-months of follow-up, the median PFS was 26 months for patients who received therapy with HCT, and 17 months for those who received carfilzomib/pomalidomide/dexamethasone therapy without HCT. The median OS was 67 months, with the most common grade 3 and 4 adverse events related to treatment including hematologic toxicity (41%), cardiovascular events (6%), respiratory (3%) events, and infections (17%).²³ Because its inclusion is based on the results of a phase II study, it is included as a category 2A recommendation.

Pomalidomide/bortezomib/dexamethasone has also been included as a category 1 option based on the results of the OPTIMISMM study, a phase III open-label, multicenter, randomized trial.²⁵ The trial compared pomalidomide/bortezomib/dexamethasone (n=281) versus bortezomib/dexamethasone in patients (n=278) with relapsed or refractory MM who had previously received lenalidomide.²⁵ After a median follow-up of 15.9 months, the pomalidomide arm showed a significantly improved PFS (median, 11.20 vs 7.10 months; HR, 0.61; 95% CI, 0.49–0.77; P<.0001). The most common grade 3/4 treatment-related adverse events in the pomalidomide arm were neutropenia, infections, and thrombocytopenia.²⁵ A post hoc subgroup analysis of the OPTIMISMM trial evaluated outcomes in 226 patients at first relapse who had received only one prior line of therapy. Analyses were conducted based on lenalidomide-refractory status, prior bortezomib exposure, and prior HCT. Statistically significant improvements in PFS were observed in both patients with lenalidomide-refractory disease (17.8 vs 9.5 months; P=.0276) and those with lenalidomide-nonrefractory disease (22.0 vs 12.0 months; P=.0491). There were also statistically significant improvements in PFS among patients who had received prior bortezomib (17.8 vs 12 months) and those with (22 vs 13.8 months) and without (16.5 vs 9.5 months) prior HCT.²⁶

Elotuzumab/pomalidomide/dexamethasone (EPd) is included as an option for patients who have received at least 2 prior therapies including an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI). In a phase II study, 117 patients with refractory/relapsed MM refractory to lenalidomide and a PI were randomized to receive either pomalidomide/dexamethasone or elotuzumab/pomalidomide/dexamethasone.²⁷ After a follow-up of 9.1 months, the median PFS and overall response rate (ORR) were both more than double with elotuzumab (PFS, 10.3 vs 4.7 months; ORR, 53% vs 26%).²⁷ A more recent follow-up analysis showed that median OS was also significantly improved with elotuzumab/pomalidomide/dexamethasone compared with pomalidomide/dexamethasone (29.8 vs 17.4 months; HR, 0.59; 95% CI, 0.37–0.93; P=.0217).²⁷ Of note, daratumumab had not yet been approved for use in earlier lines of therapy at the time of this study (only 3 patients received daratumumab as prior therapy). Therefore, further exploration of the use of EPd in patients who are refractory to anti-CD38 antibodies is warranted.²⁸

Ixazomib/pomalidomide/dexamethasone has been included as an option for patients who experience relapse after 2 prior therapies, including an immunomodulatory drug and a PI, with disease progression on/within 60 days of completing the last therapy. This is based on data from the following trials. In the phase I/II Alliance A061202 study (n=29), patients with lenalidomide/PI-refractory MM were treated with ixazomib/pomalidomide/dexamethasone. In this trial, 51.7% of patients achieved at least a partial response (PR), with a median PFS of 4.4 months, a median response duration of 16.8 months, and a median OS of 34.3 months. Common adverse events included hematologic toxicity and gastrointestinal events.²⁹ Another phase I/II study evaluated the safety and efficacy of ixazomib/pomalidomide/dexamethasone in patients who received multiple prior therapies.³⁰ With a median follow-up of 11.9 months, at an established ixazomib dose of 4 mg, 48% of patient achieved at least a PR, with 20% achieving a VGPR and 76% having stable disease. The most common grade ≥2 adverse events reported were anemia, neutropenia, thrombocytopenia, and infections.³¹

Updates to CAR-T Cell Therapy for Previously Treated MM

The panel discussed the inclusion of CAR T-cell therapies for early relapse, based on the FDA approvals and the results of the CARTITUDE-4 trial³² for ciltacabtagene autoleucel (cilta-cel) in patients who have received at least one prior line of therapy, including a PI and an IMiD, and are refractory to lenalidomide. The panel also considered the results of the KarMMa-3 trial³³ for idecabtagene vicleucel (ide-cel) in patients with triple-class–exposed relapsed/refractory MM who had received 2 to 4 prior lines of therapy.

In the phase III CARTITUDE-4 study, patients treated with cilta-cel therapy (n=208) were compared with those treated with standard regimens (n=211).³² In the cilta-cel arm, the rate of CR or better was 73.1%, compared with 21.8% in the standard regimen arm (OR, 10.3; 95% CI, 6.5–16.4). The ORRs in the cilta-cel and standard-regimen arms were 84.6% and 67.3%, respectively (OR, 3.0; 95% CI, 1.8–5.0). MRD negativity (<10⁻⁵ determined by NGS) was higher in the cilta-cel arm, at 60.6%, compared with 15.6% in the standard regimen arm (OR, 8.7; 95% CI, 5.4–13.9). At a median follow-up of 15.9 months (range, 0.1–27.3), the median PFS was not yet reached with cilta-cel and was 11.8 months with standard regimens (HR, 0.26; 95% CI, 0.18–0.38; P<.001).³² Based on these data, the panel included cilta-cel as an option for patients after one prior line of therapy, including an IMiD and a PI, and whose disease is refractory to lenalidomide (Figure 3). Importantly, after median follow-up 33.6 months, cilta-cel significantly improved OS, with a 30-month OS of 76.4% versus 63.8% in the standard regimen arm (HR, 0.55; 95% CI, 0.39–0.79; P=.0009), with consistent OS benefit observed across prespecified subgroups.³⁴ The peer-reviewed publication of this key follow-up analysis is awaited.

In the phase III KarMMa-3 trial, patients treated with idecabtagene vicleucel (ide-cel; n=254) were compared with those treated with standard regimens (n=132).³³ In this trial, 66% of the patients had triple-class–refractory disease, and 95% had daratumumab-refractory disease. At a median follow-up of 18.6 months, the median PFS was 13.3 months (95% CI, 11.8–16.1) in the ide-cel arm, compared with 4.4 months (95% CI, 3.4–5.9) in the standard-regimen arm, leading to a 51% reduction in the risk of disease progression or death (HR for disease progression or death, 0.49; 95% CI, 0.38–0.65; P<.001). Ide-cel also demonstrated an improvement in ORR versus standard regimens, with 71% (95% CI, 66%–77%) of patients achieving a response, compared with 42% (95% CI, 33%–50%) of those who received standard regimens (P<.0001).³³ Based on these results, the panel included ide-cel as an option for patients after 2 prior lines of therapy, including an IMiD, an anti-CD38 monoclonal antibody, and a PI (Figure 3).

Conclusions

The NCCN Guidelines are in continuous evolution, with updates occurring annually or more frequently if new, high-quality clinical data become available. These NCCN Guidelines Insights highlight the important updates in Version 1.2025 of the NCCN Guidelines for MM specific to the systemic therapy options for newly diagnosed and previously treated MM. The recommendations in the NCCN Guidelines are based on evidence from clinical trials. Expert clinical judgment is required when applying these guidelines in the context of individual clinical circumstances to provide optimal care. The physician and the patient have the responsibility to jointly explore and select the most appropriate treatment from among the available options. Consistent with NCCN philosophy, when possible, the panel strongly encourages participation in prospective clinical trials when available and applicable.