Introduction
The management of multiple myeloma (MM) is a rapidly evolving field, with new treatment modalities and combinations continually improving patient outcomes. For clinicians in the United Kingdom, two key guidelines inform practice: the National Institute for Health and Care Excellence (NICE) and the European Society for Medical Oncology (ESMO). While both aim to provide evidence-based recommendations, their purposes, scope, and implementation differ significantly. NICE guidelines are definitive for NHS England and Wales, dictating funding and access through technology appraisals. In contrast, ESMO guidelines offer a broader, pan-European perspective, often incorporating newer evidence and acting as an educational resource. This comparison focuses on the anticipated 2025 updates, highlighting key differences and practical implications for UK practice.
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Diagnosis and Initial Assessment
NICE Approach
NICE guidelines (NG35 and its updates) provide a structured, step-wise approach to diagnosis, heavily integrated with UK diagnostic pathways. The focus is on confirming the diagnosis according to the International Myeloma Working Group (IMWG) criteria and conducting a risk-stratified assessment.
- Diagnostic Criteria: Adheres strictly to IMWG criteria, requiring evidence of end-organ damage (CRAB features: Hypercalcaemia, Renal impairment, Anaemia, Bone lesions) plus clonal bone marrow plasma cells ≥10% or a biopsy-proven plasmacytoma.
- Risk Stratification: Recommends FISH (Fluorescence In Situ Hybridisation) for key cytogenetic abnormalities (t(4;14), t(14;16), del(17p), gain(1q)) and the Revised International Staging System (R-ISS).
- Practical Focus: Emphasises the availability of tests within the NHS and the importance of urgent referral for suspected spinal cord compression.
ESMO Approach
The ESMO Clinical Practice Guidelines offer a similar diagnostic foundation but often incorporate newer biomarkers and imaging techniques more rapidly.
- Diagnostic Criteria: Also follows IMWG criteria but may more prominently discuss the role of biomarkers like serum free light chains (sFLC) ratio in defining myeloma-defining events, even in the absence of classic CRAB features (so-called "SLiM" criteria).
- Risk Stratification: Similarly uses FISH and R-ISS but may give more weight to the prognostic impact of specific abnormalities like gain(1q) and discuss gene expression profiling (GEP) as an emerging tool.
- Imaging: Stronger recommendation for whole-body imaging techniques like Low-Dose Whole-Body CT or PET-CT at diagnosis, beyond skeletal survey, to detect bone disease more sensitively.
Key Differences and UK Takeaway
The core diagnostic criteria are aligned. The main difference lies in imaging recommendations. While NICE acknowledges the superiority of modern imaging, its widespread adoption in the NHS can be variable due to cost and capacity. The UK clinician must often navigate local protocols, using skeletal survey where advanced imaging is not readily available, while being aware of the superior sensitivity of PET-CT or WBLDCT, especially for solitary plasmacytoma.
Treatment Recommendations: Transplant-Eligible Patients
Induction Therapy
- NICE: Strongly favours VRd (Bortezomib, Lenalidomide, Dexamethasone) as the preferred first-line option, supported by a positive technology appraisal. Alternatives include VCd (Cyclophosphamide, Bortezomib, Dexamethasone) or, less commonly, VTD (Bortezomib, Thalidomide, Dexamethasone). Daratumumab-based regimens are typically reserved for the relapse setting or within the CDF.
- ESMO: Presents a broader menu of options, often giving equal weight to Dara-VRd (Daratumumab, Bortezomib, Lenalidomide, Dexamethasone) and VRd, citing trials like GRIFFIN and PERSEUS showing deeper responses. Isatuximab-based regimens may also be mentioned.
Practical Takeaway: For a UK clinician, VRd is the standard, funded NHS option. Access to Dara-VRd upfront may be possible via the Cancer Drugs Fund (CDF) if it receives a positive NICE recommendation, but this cannot be assumed. ESMO provides the evidence context for more intensive regimens.
Autologous Stem Cell Transplant (ASCT) and Consolidation/Maintenance
- NICE & ESMO: Both recommend ASCT for eligible patients. For maintenance therapy, both strongly recommend Lenalidomide post-ASCT.
- Key Difference: ESMO may discuss the duration of Lenalidomide maintenance more flexibly and the potential use of proteasome inhibitor-based maintenance in high-risk disease, whereas NICE is firmly aligned with continuous Lenalidomide until progression, based on its appraisal.
Treatment Recommendations: Transplant-Ineligible Patients
First-Line Therapy
- NICE: The primary recommended regimen is VRd-lite (a modified, less intensive version) or DRd (Daratumumab, Lenalidomide, Dexamethasone), following a positive technology appraisal. Alternatives include VCD or VMD (Bortezomib, Melphalan, Dexamethasone).
- ESMO: Also recommends DRd and VRd-lite but places them alongside other daratumumab combinations like D-VMP (Daratumumab, Bortezomib, Melphalan, Prednisone) and isatuximab-based regimens, providing a wider array of choices.
Practical Takeaway: DRd is a key, funded option in the UK for transplant-ineligible patients, representing a significant shift towards antibody-based induction. The choice between DRd and VRd-lite often depends on patient fitness, comorbidity profile, and local preference.
Maintenance Therapy
Both guidelines recommend continuous therapy. For patients responding to DRd, this means continuing Daratumumab and Lenalidomide. NICE provides specific funding directives for these continuous regimens.
Management of Special Situations
Renal Impairment (Myeloma Kidney)
- NICE: Advises urgent intervention with a cyclophosphamide and dexamethasone-based regimen (± bortezomib). Highlights the importance of avoiding NSAIDs and nephrotoxic agents.
- ESMO: Similar recommendations but may provide more detailed dosing adjustments for novel agents in severe renal failure.
Relapsed/Refractory Disease
This is an area of significant divergence, driven by the pace of NICE appraisals.
- NICE: Recommendations are contingent on positive technology appraisals. Options may include Daratumumab (if not used first-line), Carfilzomib-based combinations, Ixazomib, Panobinostat, and Selinexor. Access to BCMA-targeted therapies (e.g., Belantamab Mafodotin, Bispecific T-cell Engagers, CAR-T) is often limited to the CDF or specific commissioning routes.
- ESMO: Provides a comprehensive overview of all evidence-based options, typically including anti-BCMA therapies (CAR-T, bispecific antibodies), selinexor, and second-generation proteasome inhibitors and immunomodulatory drugs in various sequences, without funding constraints.
Key Difference: ESMO acts as a "menu" of global options. NICE defines the "available menu" for the NHS. UK clinicians must check the latest NICE TA and CDF listings to determine what is actually accessible for a specific patient at a specific line of therapy.
Practical Clinical Flow and Decision-Making
A practical UK pathway synthesises both guidelines with NHS reality:
- Diagnosis & Staging: Confirm with IMWG criteria. Perform FISH for risk stratification. Use best available imaging (aim for WBLDCT/PET-CT per ESMO, accept skeletal survey if necessary per local NICE pathway).
- Assess Eligibility: Determine fitness for ASCT (age, performance status, comorbidity).
- First-Line Therapy:
- Transplant-Eligible: Initiate NHS-standard VRd induction. Consider CDF for Dara-VRd if available.
- Transplant-Ineligible: Initiate DRd or VRd-lite.
- Post-ASCT/Continuous Therapy: Commence Lenalidomide maintenance (transplanted) or continue continuous therapy (non-transplanted).
- Relapse: Re-stage. Check latest NICE TA and CDF for funded options. Sequence therapy based on prior exposure, response duration, and risk status. Refer eligible patients for clinical trials or specialist centre evaluation for advanced therapies (e.g., CAR-T).
Frequently Asked Questions (FAQs)
1. Which guideline should I follow in the NHS?
Answer: NICE takes precedence for funding and standard-of-care decisions. ESMO is an invaluable resource for understanding the global evidence base, treatment sequences, and managing complex cases, especially when considering trials or individual funding requests (IFRs).
2. Is quadruplet therapy (Dara-VRd) available upfront in the NHS?
Answer: As of the anticipated 2025 guidelines, this is uncertain. It depends on a positive NICE technology appraisal. If approved, it will likely be available via the CDF initially. Check the NICE website for the latest appraisal status of daratumumab in first-line transplant-eligible settings.
3. How do I access CAR-T or bispecific antibody therapy for myeloma?
Answer: Access is highly restricted. These are typically available only within the CDF (following a NICE recommendation) or through commissioned specialised services. Patients must usually be triple-class exposed (refractory to a PI, IMiD, and anti-CD38 mAb) and are referred to a limited number of designated CAR-T centres.
4. What is the role of MRD (Minimal Residual Disease) testing in the NHS?
Answer: Both NICE and ESMO acknowledge the prognostic value of MRD. However, NICE does not yet routinely recommend it to guide treatment decisions due to a lack of evidence showing clinical utility (i.e., that changing therapy based on MRD status improves survival). It is primarily used in the context of clinical trials.
5. A patient is not fit for VRd or DRd due to comorbidities. What are the alternatives?
Answer: Both guidelines list alternatives. NICE-recommended options include doublets like Lenalidomide plus Dexamethasone (Rd) or Cyclophosphamide plus Dexamethasone. Dose-attenuated regimens are key. ESMO would provide a similar list, potentially including other doublets.
Source Links
- NICE Guideline NG35 (Multiple myeloma: diagnosis and management): NICE NG35
- NICE Topic Page on Multiple Myeloma (Links to all relevant Technology Appraisals): NICE myeloma topic hub
- ESMO Clinical Practice Guidelines (Multiple Myeloma): ESMO guidelines: haematological malignancies
- Cancer Drugs Fund (NHS England): NHS England: Cancer Drugs Fund