Recent Advances in Multiple Myeloma: The MRCP Update You Need

Multiple myeloma has quietly become one of the fastest-moving stories in clinical medicine. Between 2023 and 2025, quadruplet induction therapy, earlier CAR-T cell therapy, and off-the-shelf bispecific antibodies have rewritten the treatment pathway — and MRCP question writers have taken notice. Whether you are preparing for Part 1, Part 2 Written, or PACES, this update covers the advances that are now exam-relevant, distilled into an examiner-friendly format.

Why Myeloma Is Guaranteed MRCP Material

Myeloma is the second commonest haematological malignancy in the UK, typically affecting patients over 65 — precisely the demographic that populates MRCP data-interpretation questions. It cuts across renal medicine (cast nephropathy, hypercalcaemia), bone health, immunology (paraproteins, hypogammaglobulinaemia), and prescribing safety (VTE prophylaxis, drug toxicities). In PACES Station 5, the classic presentation of back pain, anaemia, and renal impairment in an older patient remains a reliable test of structured clinical reasoning.

Diagnostic and Staging Advances

From CRAB to SLiM-CRAB

The 2014 International Myeloma Working Group (IMWG) criteria remain a favourite discriminator in Part 1 and Part 2. Patients can now be treated before end-organ damage develops if they meet one of three biomarkers of malignancy:

• Sixty percent or more clonal plasma cells on bone marrow biopsy or imaging

• Light chain ratio: involved/uninvolved serum free light chain (FLC) ratio ≥100 with involved FLC ≥100 mg/L

• More than one focal lesion on MRI (each ≥5 mm)

Retain the classic CRAB features — hyperCalcaemia, Renal impairment, Anaemia, Bone lesions — but recognise that SLiM criteria allow earlier intervention.

Exam pearl: Plasma cell leukaemia is defined as circulating plasma cells >2 × 10⁹/L or >20% of peripheral white cells, and carries a poor prognosis.

Imaging

Whole-body low-dose CT or whole-body MRI with diffusion weighting has largely replaced the plain radiographic skeletal survey in UK practice. PET-CT carries prognostic value, with residual metabolic activity post-induction predicting outcome — a bridge into the minimal residual disease (MRD) era.

Risk Stratification: R-ISS and R2-ISS

• R-ISS combines ISS stage, LDH, and adverse cytogenetics [del(17p), t(4;14), t(14;16)].

• R2-ISS refines this by adding gain(1q), which independently worsens outcomes — increasingly referenced in updated texts.

Minimal Residual Disease (MRD)

Next-generation flow cytometry or sequencing can detect one myeloma cell among 100,000 (10⁻⁵), with newer assays reaching 10⁻⁶. Key exam-relevant framing:

• MRD negativity strongly predicts progression-free survival (PFS).

• Sustained MRD negativity (≥12 months) is now the benchmark endpoint in frontline trials.

• MRD-guided treatment de-escalation remains investigational — do not present it as standard care.

Frontline Therapy: Welcome to the Quadruplet Era

Transplant-Eligible Patients: PERSEUS and D-VRd

The PERSEUS trial (NEJM 2023) cemented daratumumab plus bortezomib–lenalidomide–dexamethasone (D-VRd) as the preferred induction for transplant-eligible patients:

• 4-year PFS: 84.3% vs 67.7% in favour of D-VRd

• MRD negativity (10⁻⁵): 75.2% vs 48.1%

The regimen continues through autologous stem cell transplant, consolidation, and maintenance.

The DETERMINATION trial clarified that early autologous transplant after VRd improves PFS but has not shown an overall survival advantage — a nuance examiners may test when weighing treatment sequencing discussions.

Transplant-Ineligible Patients: MAIA

The MAIA trial established daratumumab–lenalidomide–dexamethasone (DRd) for transplant-ineligible patients, improving both PFS and overall survival compared with Rd alone. Frailty assessment (IMWG frailty index) increasingly guides dose intensity in this group — a geriatric-medicine crossover examiners appreciate.

The Relapsed/Refractory Revolution

CAR-T Cell Therapy

Two BCMA-directed CAR-T products dominate:

• Ide-cel (KarMMa trial)

• Cilta-cel (CARTITUDE-1): overall response rate ~98%, with stringent complete responses in the majority, even in heavily pre-treated disease

The practice-changing moment came with CARTITUDE-4 (NEJM 2024), which compared cilta-cel against standard regimens (PVd or DPd) in lenalidomide-refractory patients after only 1–3 prior lines. Cilta-cel reduced the risk of progression or death by over half — moving CAR-T earlier in the pathway rather than as a last resort.

Examiner-favourite toxicities:

• Cytokine release syndrome (CRS): fever, hypotension, hypoxia → tocilizumab ± corticosteroids

• Immune effector cell-associated neurotoxicity syndrome (ICANS): corticosteroids first-line

• With cilta-cel specifically: delayed movement and neurocognitive events, including parkinsonism-like syndromes and cranial nerve palsies

• Prolonged cytopenias and hypogammaglobulinaemia (consider IVIG for recurrent infections)

Bispecific T-Cell Engagers: The Off-the-Shelf Option

Bispecific antibodies link CD3-positive T cells to myeloma targets, offering CAR-T-like activity without individualised manufacturing delay:

• Teclistamab (BCMA × CD3; MajesTEC-1): overall response rate ~63%, complete response ~39% in heavily pre-treated patients

• Talquetamab (GPRC5D × CD3; MonumenTAL-1): overall response rate ~70%

• Elranatamab (BCMA × CD3; MagnetisMM-3): overall response rate ~61% in BCMA-naive patients, with extended-interval dosing after response

Key safety points:

• Step-up dosing schedules mitigate CRS, which is common but usually grade 1–2

• Talquetamab causes distinctive dysgeusia and skin/nail toxicity (GPRC5D is expressed on keratinocytes and oral mucosa)

• Infection prophylaxis mirrors CAR-T: antivirals, Pneumocystis cover, and vigilance for hypogammaglobulinaemia

Beyond BCMA

• Selinexor (exportin-1 inhibitor; BOSTON trial): improved PFS vs bortezomib–dexamethasone

• Venetoclax shows biomarker-driven activity in t(11;14) myeloma — personalised therapy in action

• Next-generation cereblon E3 ligase modulators (CELMoDs) such as mezigdomide are generating impressive response rates and represent the next wave to watch

Supportive Care: Where MRCP Questions Actually Live

Examiners test supportive care harder than induction regimens. Master these:

Landmark Trial Cheat Sheet

How the Examiners Test This Material

Part 1 Style

Expect mechanism-based questions: how bispecific antibodies recruit T cells, the pharmacology of proteasome inhibition, FLC assay physiology, cytogenetic prognostic markers, and adverse effect profiles of anti-CD38 antibodies.

Part 2 Written Style

Data interpretation dominates: an elderly patient with normocytic anaemia, back pain, and either hypercalcaemia or renal impairment — the single best next investigation is serum protein electrophoresis with immunofixation plus serum free light chains (urine Bence Jones protein as a supporting test). Trial-abstract questions may ask you to interpret hazard ratios and MRD endpoints from PERSEUS-type data.

PACES Relevance

Station 5 can present a patient with established myeloma on modern therapy: review complications, counsel about CAR-T risks, or demonstrate safe prescribing discussions (VTE prophylaxis, infection prevention). Senior-level awareness of bispecifics and CAR-T complications distinguishes strong candidates.

Three Rapid Self-Test Questions

Question 1: A 70-year-old presents with three months of lumbar back pain. Hb 9.8 g/dL, corrected calcium 2.95 mmol/L, creatinine 198 μmol/L. What is the most appropriate initial investigation?

Answer: Serum protein electrophoresis with immunofixation and serum free light chain assay. The CRAB constellation in an older patient makes myeloma the leading diagnosis; tissue diagnosis follows, but the paraprotein screen comes first.

Question 2: A patient on daratumumab requires transfusion. The group and screen shows pan-agglutination. What is the most appropriate next step?

Answer: Inform the transfusion laboratory so that dithiothreitol-treated red cells can be used. This is a well-known CD38-related interference — not autoimmune haemolysis.

Question 3: Five days after cilta-cel infusion, a patient develops fever, hypotension, and hypoxia with a rising CRP. What is the most appropriate immediate treatment?

Answer: Tocilizumab (with corticosteroids if severe or refractory). Recognising cytokine release syndrome post CAR-T is now core examinable knowledge.

Ten Take-Home Points

1. SLiM-CRAB criteria allow treatment before end-organ damage.

2. Whole-body low-dose CT or MRI has replaced the skeletal survey.

3. D-VRd (PERSEUS) is the frontline standard for transplant-eligible patients.

4. DRd (MAIA) is standard for transplant-ineligible patients.

5. CARTITUDE-4 moved CAR-T earlier in the treatment sequence.

6. Bispecifics (teclistamab, talquetamab, elranatamab) offer off-the-shelf efficacy.

7. Talquetamab = dysgeusia and skin/nail toxicity; know your toxicity fingerprints.

8. CRS is managed with tocilizumab; ICANS with corticosteroids.

9. Always warn the blood bank about daratumumab — the Coombs conundrum.

10. High cut-off dialysis for cast nephropathy is not routine practice.

Final Word

Myeloma has shifted from a uniformly fatal disease to one where deep, sustained remissions are achievable for many. For MRCP candidates, the message is simple: the question banks are catching up with the trials. Build your core knowledge on SLiM-CRAB diagnostics and supportive care, layer the PERSEUS and CARTITUDE-4 headline data on top, and you will handle whatever the examiners serve up — at a desk or at the bedside.