New EHA/EMN guidelines on the management of multiple myeloma

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Reference: August 2025 | Issue 8 | Vol 11 | Page 48

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Last month, the European Hematology Association (EHA) and the European Myeloma Network (EMN) issued new guidelines for the diagnosis, treatment, and follow-up of patients with multiple myeloma (MM).¹

Since the publication of the 2021 EHA clinical practice guidelines on the treatment of patients with smouldering multiple myeloma (SMM) and MM, there have been a number of developments in the management of MM.² A novel international staging system (R2-ISS) has been developed, and new prognostic factors are entering clinical practice. Furthermore, 14 novel regimens have been approved by the European Medicines Agency (EMA) and/or the US Food and Drug Administration (FDA) for the treatment of patients with MM.

Given the changes, the EHA and the EMN issued new guidelines for the diagnosis, treatment, and follow-up of patients with MM. The guidelines include key treatment recommendations for patients with newly diagnosed MM and those with relapsed and/or refractory MM, including advice on the use of established drugs and contemporary immunotherapies. The document also includes recommendations for myeloma-related complications and adverse events.

Diagnosis

The diagnostic criteria for MM and SMM defined in the 2021 EHA guidelines remain unchanged.²

The following blood tests are recommended at diagnosis:

• Full blood count (FBC) and blood smear;
• Serum electrophoresis and immunofixation;
• Serum free light chains (sFLC);
• Serum immunoglobulin levels;
• Renal (RFT) and liver (LFT) function tests;
• Calcium;
• Lactate dehydrogenase;
• Albumin and ß2 microglobulin;
• Flow cytometry (optional).

A urine sample from 24-hour urine collection should be checked for proteinuria and sFLC proteinuria, and electrophoresis and immunofixation should be carried out. Bone marrow cytology and biopsy is required to confirm plasmacytosis and monoclonality, and next-generation flow cytometry (NGF) or next-generation sequencing (NGS) should be performed to detect clonal plasma cells.

Cytogenetics investigations should include karyotype and FISH for detection of del17p, t(4;14), t(14;16), t (14;20), 1q gain or amplification, del1p32 and t(11;14), and NGS for TP53 mutations.

PET-CT or diffusion-weighted imaging (DWI) MRI is required at diagnosis. Whole-body low-dose (WBLD) CT should be used if PET-CT or DWI MRI are not available.

Staging

In 2022, the EMN published the second revision of the International Staging System (R2-ISS).³ The revised system is based on four prognostic markers, combining serum biomarkers and chromosomal abnormalities.

In the training cohort for the revised system (n=7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on progression-free survival (PFS) and overall survival (OS). These variables were all simultaneously present in 2,226 patients. A value was assigned to each risk feature according to their OS impact (ISS-III=1.5; ISS-II=1; del(17p)=1; high lactate dehydrogenase=1; and 1q+=0.5 points).

Risk groups were categorised according to the total additive score. Using R2-ISS, 0 points categorises low risk MM. Low-intermediate risk is defined as a score of 0.5-1 points, while scores of 1.5-2.5 and 3-5 points categorise intermediate-high and high risk, respectively. The score was validated in an independent cohort (n=3,771) which supported its prognostic value.

However, the guidelines state that the recently-updated International Myeloma Society (IMS) and International Myeloma Working Group (IMWG) definition of high-risk MM could soon affect the current staging systems (R-ISS and R2-ISS).^3-5 The updated definition of high-risk disease is:

• del(17p) (cancer clonal fraction ≥20% by analysis of CD138-positive/purified cells)  and/or TP53 mutation (using NGS);
• t(4;14), t(14;16) or t(14;20), co-occurring with increased 1q (gain=3 copies, amplification=≥4 copies of the long arm of chromosome 1), and/or del(1p32);
• Monoallelic del(1p32) along with 1q gain, or biallelic del(1p32);
• High β2 microglobulin (>5.5 mg/dl) with normal creatinine (<1.2 mg/dl).

The EHA and EMN advise that several techniques could soon change the routine management of patients with MM, including the assessment of circulating plasma cells (CPCs), the evaluation of M protein using mass spectrometry (MS), and gene expression profiling. An EMN committee is currently establishing a CPC cut-off percentage to be used in routine clinical practice. The combination of CPC assessment with R2-ISS score might further improve disease staging.⁶ CPC values determined using NGF might also be used for a more accurate diagnosis of plasma cell leukaemia, which is currently defined as ≥5 per cent of CPCs in peripheral blood smears.^7-9

Furthermore, quantitative immunoprecipitation (QIP) MS has been show to be more sensitive than immunofixation electrophoresis for detecting M protein, both at baseline and during treatment, and has greater predictive value.^10,11 The combination of QIP MS with CPC assessment has prognostic value and might be suitable for response assessment and minimal residual disease (MRD) evaluation in peripheral blood, according to the new guidance.¹² This approach is currently being tested in clinical trials. If successful, it would avoid the need for bone marrow sampling to assess response.

Gene expression profiling has also shown independent prognostic value, especially in patients with newly diagnosed MM (NDMM).^13-15

Assessing response

The following blood tests are recommended for assessment of treatment response: FBC, blood smear, electrophoresis and immunofixation, sFLC, serum immunoglobulin levels, RFT, LFT, calcium, and lactate dehydrogenase levels. Albumin, β2 microglobulin and flow cytometry are not required for response assessment.

The IMWG criteria define bone marrow MRD negativity as the absence of malignant plasma cells within 100,000 nucleated bone marrow cells (sensitivity threshold <10-5). However, the IMS and IMWG have revised the response criteria and these are expected to be published later this year.

A meta-analysis found that DWI MRI is significantly more sensitive than PET-CT in depicting abnormal areas in the bone marrow of patients with MM.¹⁶ Furthermore, DWI MRI is effective for predicting sustained imaging MRD negativity.¹⁷ Hence, the new guidelines recommend that both PET-CT and DWI MRI are complementary to bone marrow MRD for the evaluation of MRD negativity.

The new guidelines state that urine-based tests are not obligatory for the assessment of response or during follow-up, but should be performed at diagnosis and at the time of each relapse to exclude other pathologies, such as light chain amyloidosis or free light chain deposition disease.

Smouldering MM

Currently, a watch-and-wait approach is the standard management strategy recommended for patients with SMM.^1,2,18 The new guidelines recommend that patients with low-risk or intermediate-risk SMM should be evaluated every six months or every three-six months, respectively, to assess their risk of progression to MM. Risk assessment should be performed using the IMWG classification models.

However, trials have shown that patients with high-risk SMM who received lenalidomide plus dexamethasone (Rd) or lenalidomide (R) alone had longer PFS than those in the observation group.^19-20 This has raised the prospect of delaying progression to MM. Trials testing this approach have used the anti-CD38 antibody daratumumab (Dara).

In the phase II Centaurus trial, at a median follow-up of 85 months, the median PFS was not reached in patients receiving long-term IV daratumumab, while the median PFS was 84.4 months and 74.1 months with daratumumab schedules of intermediate and short intensity, respectively.^21-22

In the phase III Aquila trial, patients with high-risk SMM who receive subcutaneous daratumumab for three years had a five-years PFS of 63.1 per cent versus 40.8 per cent in the active-monitoring groups. OS was 93.0 per cent versus 86.9 per cent.²³ PFS in the next following line of treatment was also superior in patients receiving daratumumab. Hence, the guidelines state that although approval is pending, a three-year course of daratumumab monotherapy can be considered in patients with high-risk SMM.

Newly diagnosed

In the 2021 EHA guidelines, the recommended treatment for transplant-eligible patients with newly diagnosed MM (NDMM) was induction regimens such as bortezomib (V) plus Rd or daratumumab in combination with bortezomib, thalidomide (T), and dexamethasone (DaraVTd), followed by one or two cycles of high dose melphalan (HDM), autologous stem cell transplantation (ASCT), and lenalidomide maintenance.

However, the results of the phase 3 Perseus trial published last year provided evidence supporting the use of new standard of care (SOC) regimens for induction, consolidation (both with DaraVRd) and maintenance (DaraR) in these patients.²⁴ The subsequent publication of results from the phase 3 Auriga trial further reinforced the value of DaraR maintenance.²⁵

In the phase III GMMG-HD7 trial, the MRD negativity rate after ASCT was higher with the anti-CD38 monoclonal antibody isatuximab (Isa) with the standard bortezomib, lenalidomide, and dexamethasone (VRd) regimen (IsaVRd).²⁶ Long-term follow-up results from the phase III Cassiopeia trial confirmed DaraVTd as a SOC induction and consolidation regimen, and supported daratumumab monotherapy maintenance as a subsequent option in transplant-eligible patients with NDMM.²⁷

Hence, the 2025 guidelines recommend DaraVRd and IsaVRd as the new SOC regimens for induction therapy before ASCT, despite not being approved yet by the EMA. DaraVTd is recommended as another valid option in this setting, although it has not been compared directly with DaraVRd. If the above regimens are not available, VRd can be used. For all induction regimens, four to six cycles are recommended.

HDM 200mg/m² is the recommended SOC conditioning regimen before ASCT. In patients who have received only four cycles of DaraVRd induction, two cycles of DaraVRd consolidation should be considered.

The guidelines also state that tandem ASCT may be suitable for patients with genetically-defined high-risk disease or in patients who have received induction with bortezomib, dexamethasone, and cyclophosphamide.

On the basis of PFS results from the Perseus trial, the addition of daratumumab to lenalidomide is the new SOC maintenance treatment after ASCT in all patients with MM.²⁴

Patients who are not eligible for ASCT but have an IMWG FS of <2 and are more than 80 years old can receive two new SOC regimens: IsaVRd and DaraVRd (pending approval by the EMA). A dexamethasone-sparing strategy (DaraR) should be considered for patients with an IMWG frailty score ≥2. If none of the above-mentioned options is available, the guidelines advise that daratumumab in combination with bortezomib, melphalan, and prednisone (DaraVMP) or VRd can be used.

Relapsed/refractory MM

In patients who have received a bortezomib-based regimen upfront without lenalidomide or an anti-CD38 antibody, and have bortezomib-refractory disease, the preferred regimens are DaraRd, daratumumab plus carfilzomib (K) and dexamethasone (DaraKd), and isatuximab (Isa) plus carfilzomib and dexamethasone (IsaKd). Other recommended regimens include KRd, as well as ixazomib (Ixa) or elotuzumab (Elo) plus Rd. In patients who have received lenalidomide, belantamab mafodotin (Bela) can also be used.

Patients who have received a bortezomib-based regimen upfront without lenalidomide or an anti-CD38 antibody, and have bortezomib-sensitive disease should receive DaraRd, DaraKd, IsaKd or BelaVd. Other approved regimens include KRd, IxaRd, EloRd, SelVd, and Kd and selinexor (Sel) plus Vd. Belantamab mafodotin, bortezomib, and dexamethasone (BelaPd) is an option in patients who have received lenalidomide. DaraVd or PVd can also be used if BelaVd
or BelaPd, respectively, is unavailable.

Patients who are eligible for CAR T cell therapy and who have disease refractory to first-line lenalidomide but have not received or have disease sensitive to anti-CD38 antibodies, should receive ciltacabtagene autoleucel (cilta-cel), if available. Other options for patients with lenalidomide-refractory disease include DaraKd, IsaKd, BelaPd, BelaVd, DaraPd, and SelVd. Combinations of anti-CD38 antibodies with Kd or BelaPd are preferred. PVd or DaraVd can be used if BelaPd or BelaVd, respectively, are unavailable.

Patients with disease refractory to both lenalidomide and bortezomib, and who have not received or have disease sensitive to anti-CD38 antibodies, should receive cilta-cel, BelaPd, DaraKd or IsaKd, or DaraPd. Cilta-cel and BelaPd are the preferred options. SelVd, BelaVd, and Kd can be used if the previous options are unavailable, but only in patients with bortezomib-sensitive disease.

In patients with limited access to novel regimens, second-line ASCT is recommended as an option for those who received primary therapy, including an ASCT followed by lenalidomide maintenance, and had an initial remission duration of ≥36 months.

In the third or fourth line of treatment, patients can receive treatments that they have not been previously exposed to, including cilta-cel, idecabtagene vicleucel (ide-cel), BelaPd, DaraPd, IsaPd, EloPd, BelaVd, or other regimens.

Retreatment with an anti-CD38 antibody after disease progression on this therapeutic class is not recommended. If retreatment is the only option, it should be started only after an anti-CD38 antibody-free interval of at least one year.

Patients with triple-class refractory MM can receive cilta-cel or ide-cel, teclistamab, elranatamab, linvoseltamab, talquetamab, or BelaPd. These patients can also receive melflufen if they have not previously undergone ASCT or if the time to disease progression after ASCT is  more than three years. Sel-d is recommended as another option.

In patients with triple-class refractory MM that is also refractory to CAR T cells or an ADC, options include talquetamab, teclistamab, elranatamab, and linvoseltamab, as well as melflufen and Sel-d if no other option is available.

While the optimal sequencing of immunotherapies in patients with relapsed/refractory MM (RRMM) has not yet been established, currently available data suggest that CAR T cell therapies might need to be given to eligible patients before antibody-drug conjugates (ADCs) targeting the B-cell maturation antigen (BCMA) or bispecific T cell engagers. The guidelines also state that bispecific T cell engagers can be effective immediately after disease progression on CAR T cells, and talquetamab may deliver better outcomes in this setting.

Summary

These updated guidelines on MM take into account new data that has emerged since the previous EHA guidelines were published in 2021. This has produced several changes in terms of diagnosis, treatment, and follow-up. In addition to setting out the diagnostic and staging criteria, the document includes important changes to the recommended management of both newly diagnosed and relapsed/refractory MM. The document also includes recommendations for the management of myeloma-related complications and adverse events, such as bone disease, renal impairment and infections, as well as for those associated with T cell-mobilising therapies, such as cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome.