Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper

• DOI: 10.1111/bjh.19333
• Publication Date: 2024-02-23T16:27:10Z
• Authors: Daniel Hughes; Kwee Yong; Karthik Ramasamy; Simon Stern; Eileen Boyle; John Ashcroft; Faisal Basheer; Neil Rabin; Guy Pratt
• Keywords: Hematology; Myeloma protein

Multiple myeloma is a bone marrow-based plasma cell tumour that develops from asymptomatic pre-cursor conditions smouldering and monoclonal gammopathy of uncertain significance all are characterised by the presence protein in blood. Diagnosis distinction between these based on blood tests, marrow biopsy cross sectional imaging. There various risk stratification models group patients with into groups progression to symptomatic disease. Management mainly observational for although clinical trials high-risk disease may be available. Restaging required if evidence progression. This good practice paper was compiled according British Society Haematology (BSH) process at (https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf). The Grading Recommendations Assessment, Development Evaluation (GRADE) nomenclature used evaluate levels assess strength recommendations. BSH produces papers recommend areas where there limited base, but which degree consensus or uniformity likely beneficial patient care. A literature search performed using EMBASE MEDLINE databases following terms: undetermined significance, multiple myeloma, (smoldering) myeloma; gammopathy, MGUS. Review manuscript Haemato-Oncology Task Force, Guidelines Committee sounding board BSH. It has also been reviewed UK Myeloma UK. (MM) clonal disorder cells. MM preceded precursor (MGUS) (SMM). SMM sits MGUS MM, representing clone (10%–59%) without organ tissue impairment. In retrospective data, prior updated IMWG criteria, progressing related 10% per year first 5 years after diagnosis, 3% next 1% 10 years1 biological behaviour ranging MM.2 time diagnosis is, however, random given it an condition, therefore, most will have had some unknown before diagnosis. Similar genetic changes detected MGUS, include hyperdiploidy (typically trisomies odd chromosomes 3, 5, 7, 9, 11, 15, 19, 21) translocations involving immunoglobulin loci (common translocation partners: MMSET/FGFR3, CCND1, CCND3, MAF, MAFB1).3-6 Copy number alterations (commonly del(13q), gain(1q), del(14q), del(1p), del(17p))6 single nucleotide variants (SNVs) generally increase genomic makeup nearly fully acquired majority cases.5, 7 keeping timepoint mutational signatures reconstruct chronological development abnormalities, initiating leading transformation post-germinal centre B cells occur second third decade life.8 2014, diagnostic criteria were International Working Group (IMWG) biomarkers ≥60% cells, ratio involved uninvolved light chains ≥100 FLC >100 mg/L (using FREELITE assay), >1 focal lesion MRI.9 update prompted derived overall survival benefit therapy10 demonstration cohorts associated ultra-high (>80% 2 years).1, 11-18 meta-analysis, shown significantly lower more recent studies untreated who met BMPC SFLC.19 relate measurements assay other assays epidemiology poorly defined estimated lifetime prevalence United Kingdom.20 Data Swedish Registry demonstrate 14.4% incidence 0.4/100,000/year.21 iStopMM study offered screening adults over 40 old Iceland included 75 422 identified much higher SMM. population 0.53% (95% CI 0.49–0.57%) being common men increasing age median 70 years. should noted this represents ethnically homogenous, almost entirely Caucasian, population.22 (0.69%) than women (0.39%) increased 1.08% 70s 1.59% those 80 old.22 greater described nature population-based accurate identifying patients, particularly low SMM, previous epidemiological studies. S Li Involved chain (with mg/L) M More one MRI >5 mm size C Hypercalcaemia (>2.75 > 0.25 mmol/L above upper limit normal)a R Renal impairment (serum creatinine >177 μmol/L clearance <40 mL/min)a Anaemia (Hb <100 ≥20 g/L below One osteolytic XR, CT PET-CT (>5 size)b role premalignant disorders uncertain. knowledge reduces late presentations poorer outcomes.23, 24 currently lack support early intervention. provide further information regarding potential benefits approach, its practicality cost-effectiveness larger diverse populations remains undetermined.22 To predict developing population, PROMISE USA screens people Black ethnicity family history haematological malignancy aged 30 over.25 monitoring warranted, use targeted approach improve continual re-appraisal balance as intervention condition continues evolve. Patients suspected investigated tests referred Table including cross-sectional imaging.22-25 suspecting not any end-organ damage. features suggestive amyloid damage (CRAB features, unexplained proteinuria, cardiomyopathy neuropathy), consider investigating found—monoclonal levels: IgG >15 g/L, IgA >10 >500 profound immunoparesis. high–intermediate-risk (see guidelines26). published model probability finding ≥10% examination, routine testing during work-up help select biopsy.27 FBC Urea Calcium Immunoglobulins serum electrophoresis Immunofixation Serum-free Bone aspirate trephine phenotyping Imaging—in order preference WB-MRI (diffusion weighted), low-dose WB-CT guidelines imaging myeloma) Tests estimate burden prognosis FISH Analyses t(4;14), t(14;16), t(11;14), 17p-, 1q+, 1p- Consider t(14;20), 13q- β2 microglobulin LDH Albumin Testing urinary Bence Jones no longer recommended (BSH)28 National Institute Health Care Excellence (NICE)29 myeloma. However, analysis series SFLC ≥ 100 showed (undetectable <200 mg/24 h) excretion 2-year (13.5% vs. 36.2% >200 h), noting even proteinuria rates compared previously reported far threshold 80% justify treatment SLIM criteria.30 Spot ±24 h urine collection considered prognostication high chains. Urine albumin:creatinine along troponin N-terminal pro-B-type natriuretic peptide (NT-proBNP) can useful tool detecting critical explore examination. Cast nephropathy unusual free <500 renal impairment.31 Imaging discussed detail international guidelines32-35 mandatory. As guidelines,28 samples quantification well fluorescence situ hybridisation (FISH)28 look cytogenetic abnormalities inform influence management future (particularly del(17p) gain(1q)). del(13)/del(13q) prognostic markers within their score.36 Repeat line current recommendations newly diagnosed MM28; significant interval initial percentage residual non-malignant cells.37 cut-off values define positive results, affected specificity relevance small clones.28 EMN suggested conservative cut-offs 20% copy (CNAs) signify results.38 score, incorporates records participating sites FISH36 deriving significance. We seen >20% MM.28 many CNAs secondary events often subclonal yet driving missed overly thresholds detection cut-off.5, 39 complicated remaining CD138-selection examined.37 Therefore, <20% cannot excluded understood. next-generation sequencing panel developed validated against whole-genome FISH40 utilised SMM.39 At present, use, interest molecular profiling setting. Several scores exist large identified. advantages disadvantages summarised review Lussier et al.41 3. Although continue evolve imperfect distinguishing progressors non-progressors years, iterations guide counselling practical approaches. 20-2-20 Mayo largely bulk, while features; both easy apply distinguish highest (50%–60%) lowest (6%–10%) years.36 discordance assessment models.42, 43 two incorporating 145 rate agreement 2008, 2018 PETHEMA only 16.6% ability classify versus non-high-risk different implications enrolment therapeutic trials.42 ≥95% atypical phenotype flow (1) Immunoparesis Low (0 RF) Intermediate (1 High (2 years—4% years—46% years—72% NR 73 23 Requires aberrant PC multiparameter universally available nor <10% paraprotein >30 ≤30 ≥30 years—15% years—43% years—69% 228 93 27 Purely reliant bulk Paraprotein Serum <0.125 >8 (3 5years—25% years—51% years—76% 120 61.2 22.8 Simple Widespread demonstrating utility serum-free measurement (no (any No weighting implication Not Low-risk GEP4, (<30 g/L) preserved albumin (≥35 (≥30 (<35 High-risk GEP4 years—9.4% years—52% years—81.8% data routinely collected >20 Involved: RFs) (≥2 years—10% years—26% years—47% 109.8 45.1 22.6 Well Demonstrated dynamic ≥23 (0) Low-intermediate years—5.3% years—7.5% years—44.8% years—81.3% cytogenetics [t(4;14), −13 del(13q)] (≥3 years—6% years—23% years—63% Incorporates biology probes (i.e. Ch13) (≥1 years—14.4% 86.4 14.4 Dynamic version does require Patient-specific probabilities Patient education psychosocial important. quality-of-life impact examined study44 symptoms tiredness, weakness, pain emotional such anxiety daily life.44 arterial venous thrombosis contributing mechanisms identified.45-52 demonstrated thrombosis.53-55 confidence whether relates MGUS/SMM itself underlying prompt investigations reveal diagnosis56 made. Infection cause death due immunodeficiency direct effects immune system,57-59 damage60-62 itself.63-65 infections MGUS.66, 67 Vaccination infection MM,68 vaccination suboptimal57 impaired responses vaccination69-72 need repeated dosing.73-75 prevention active MM68, 76 assessment,77 vaccination,78 antimicrobial prophylaxis79 reducing infectious complications specific Recurrent bacterial (>2 12 months) defining event80 removed 2014 revision specificity9 would warrant myeloma-directed therapy. absence applicable we suggest restaging, considering prophylactic antibiotics IV Ig recurrent severe infective episodes malignancies careful risks. MM-related results interaction malignant osteocytes, osteoblasts osteoclasts.81-84 microarchitectural present stages85 fracture risk.86 Bisphosphonates decrease skeletal-related (SREs) equivalence pamidronate zoledronic acid. PFS OS advantage network meta-analysis acid pamidronate,87 bisphosphonates requiring regardless lesions.88 Studies pamidronate89, 90 zoledronate91, 92 survival, SREs placebo. tolerated documented discontinuation 8%–10% mild side effects.93 serious adverse studied osteoporosis around 1.6%.94-96 bisphosphonate ideally treated part trial.88 Dual-energy X-ray absorptiometry (DEXA) scanning mineral density osteoporosis97 therapy factors insufficiency staging Monitoring allows SLiM CRAB frequency irreversible damage.24, 98, 99 Stratified proposed, progression, refined.100, 101 For low- intermediate-risk regular advised.29, 32, 102, 103 laboratory tests: full count; function; profile; immunoglobulins; electrophoresis; assay.29 According European Network (EMN) IMWG, every 2–3 months 6–12 diagnosis.102, If stable, followed 4–6 thereafter.102, NICE advise 3 diagnosis,29 across board, agree decided long-term stability guidelines, and/or annually suspicion/pain progressive M-component observed.32, detailed algorithm imaging.32 feature asymptomatic.99, 104 Diffusion-weighted sensitive modality lesions diffuse infiltration SMM35, 105, 106 hold value disease.98 serial randomised assessments health economic impacts capacity performed. Evidence-based optimal SMM.107 Definitions differ trials, making comparisons challenging.107 Clinicians model, entry patients. Early effect mortality controversial interventions treatment-related toxicity. eight RCT comparing deferred SMM108 reduced (RR = 0.53, 95% CI: 0.33–0.87, p 0.01), 0.51, CI:0.37–0.70, 0.0001).108 Treatment 0.29–0.96, 0.04).108 Various ongoing Tables 4 pivotal lenalidomide here. trial examining QuiRedex trial, 125 dexamethasone (Rd) observation 3-year arm.109 Longer term follow-up 201610 2022110 12.5 (range 10.4–13.6) TTP 2.1 arm 9.5 (hazard (HR) 0.28, 95%CI 0.18–0.44) 8.5 reached Rd (HR 0.57, 0.34–0.95) difference progression.110 Despite become standard Notably, enrolled 2007 2010, inadequate (skeletal survey protocol) exclude poor sensitivity. thus now raises questions outcomes. Induction ORR 79%, ≥CR 14% Maintenance 90%, 26% Median 9.0 8.0 1 84.5% 74.4% 23.5 NCT01402284131 Pilot NCT01572480132 Phase II Estimated 8 91.2% 100% SWOG E3A06 182 intermediate- continuous alone 2013 2017, aiming overcome limitations, Lonial al. 2020.111 35-month follow-up, 91% 66% (p 0.002) HR 0.46 0.08–2.53). Cross-over formal allowed data.112 Importantly, (24% years), perhaps relating amendment allowing rather solely suggesting truly population. Additionally, grade occurred 41% stopped decline patient-reported health-related quality life measures initiation either group.111 Genomic (and MGUS) similar landscape static evolution model; inherently develop manifestations increases.5, 39, 113, 114 Thus, least, ratio, decreasing haemoglobin, dynamically risk. evaluation applying post-diagnosis re-stratification led consistency categories baseline score.115 2- 5-year remained same category.115 applicability studied. evolving serological markers, repeat follow-up. evaluated varying definitions (paraprotein rise, Hb) combined BM percentage116-121; see 6. 5.1 (3.4–7.6) recognition 'evolving' 1.1 3.8 eMP 6 m ≥25% baseline) eHb (haemoglobin ≥5 m)a OR 8.2 (3.19–21.05), 63.8% 5.86 (2.13–16.2), 64.6% wMP + 81.5% +BMPC 90.5%) Group-based trajectory modelling: (median 64% increase), 15.7 decrease), eFLCr 169% increase) m, 36% 26 43% 45 30% Individualised Available www.pangeamodels.org/ PANGEA multivariate Cox regression time-varying 6441 (1510 SMM) three availability marrow, cytogenetics.117 online calculator individual (www.pangeamodels.org/).118 Haem-Onc task force members writing guideline Nil Parry-Jones (Chair), Tracey Chan, Andrew Clark, Dima Al-Sharkawi, Toby Eyre, Rob Sellar, Simon Stern Matthew Wilson. authors like thank them, committee preparing guideline. All made declaration interests Force Chairs viewed request. Chair new becomes alter document render obsolete. regularly relevant re-run systematically missed. archived website made, addendum (www.b-s-h.org.uk/guidelines). While advice guidance believed true going press, neither authors, publishers accept legal responsibility content guidance.