Multiple myeloma, MGUS, and smoldering myeloma

Malignant Hematology·Multiple Myeloma·2026

MGUS, Smoldering MM, and Multiple Myeloma

Overview and Epidemiology

MGUS: present in ~3% of adults >50 yr and ~4 to 5% >70 yr; most common isotype IgG > IgM > IgA. Can be seen with autoimmune disease and other malignancies.
Multiple myeloma: ~36,000 new US cases and ~10,850 deaths (ACS 2026 estimate); M>F, Black > White (2:1), median age ~70 yr; ~1.8% of all new cancers; 5-yr OS ~55%.
Progression rates (high-yield):
- MGUS → MM: ~1%/yr.
- SMM → MM: ~10%/yr in first 5 yr (cumulative ~50%), then ~3%/yr in yr 6 to 10 (cumulative ~66% at 10 yr), then ~1%/yr; total 15-yr risk ~73%.

Diagnostic Definitions (IMWG 2014/2018, updated 2024)

Plasma Cell Disorder Spectrum

MGUS subtypes: IgG/IgA/IgD MGUS (→ MM, AL); IgM MGUS (→ WM, AL); light-chain MGUS (→ AL, MM; involved FLC increased above reference range, abnormal ratio (<0.26 or >1.65), no heavy chain on IFE).
MGUS: M-protein <3 g/dL, clonal BMPC <10%, no myeloma-defining events (SLiM-CRAB).
Smoldering MM (SMM): M-protein ≥3 g/dL (or urine ≥500 mg/24 h) and/or clonal BMPC 10 to 60%, no myeloma-defining events.
Multiple myeloma: clonal BMPC ≥10% (or biopsy-proven plasmacytoma) PLUS ≥1 myeloma-defining event (SLiM-CRAB).

Myeloma-Defining Events: SLiM-CRAB

CRAB = end-organ damage; SLiM = biomarkers of malignancy added in IMWG 2014 that qualify as MM even without CRAB (also termed MDE: BMPC ≥60%, involved:uninvolved FLC ratio ≥100, >1 focal lesion ≥5 mm on MRI). Any one qualifies as MM.

Myeloma-defining events: CRAB and SLiMAny one qualifies as MM

Group	Criterion	Definition
CRAB	C Hypercalcemia	Serum Ca >1 mg/dL above ULN or >11 mg/dL
	R Renal	CrCl <40 mL/min or serum creatinine >2 mg/dL (myeloma-attributable)
	A Anemia	Hb >2 g/dL below normal or <10 g/dL
	B Bone	≥1 osteolytic lesion on skeletal radiography, CT, or PET-CT (if clonal BMPC <10%, more than one lesion required to distinguish solitary plasmacytoma)
SLiM	S Sixty	Clonal BMPC ≥60%
	Li Light chains	Involved:uninvolved serum FLC ratio ≥100 (involved FLC ≥100 mg/L)
	M MRI	>1 focal lesion ≥5 mm on MRI

SMM caveat: if any myeloma-defining event is present (BMPC ≥60%, involved:uninvolved FLC ratio ≥100, or >1 focal lesion on MRI), TREAT AS MM.
Serum FLC >1000 mg/L predicts risk of renal (cast nephropathy) damage.

MGUS Risk Stratification

Screening sensitivity: SPEP alone ~83%; SPEP + SIFE/FLC ~93%; SPEP + SIFE + sFLC + UPEP ~98%.
Mayo 3-factor model for MGUS progression: (1) serum M-spike ≥1.5 g/dL; (2) non-IgG isotype; (3) abnormal FLC ratio (<0.26 or >1.65).

MGUS risk stratification model

Risk group	Abnormal factors	20-yr risk
Low	0 factors	2%
Low-intermediate	1 factor	10%
High-intermediate	2 factors	18%
High	3 factors	27%

Percentages are absolute 20-yr risk of progression accounting for death as a competing risk (competing-risk adjusted).

Note on figures: the widely quoted Mayo raw (non-competing-risk) 20-yr risks are ~5% / 21% / 37% / 58% for the same 4 groups; the values above are the competing-risk-adjusted figures. Both derive from the same 3-factor model.
Light-chain MGUS: FLC >8 (involved), abnormal ratio, no intact heavy chain; risk of progression to light-chain MM / AL.
Workup if symptomatic: bone marrow biopsy plus skeletal imaging (whole-body low-dose CT).

Monoclonal Gammopathy of Clinical Significance (MGCS)

Small clones can produce severe manifestations from deposition of all or part of the monoclonal protein:
- Skin: xanthomatosis, cryoglobulinemia, bullous skin disease, cold agglutinin.
- Peripheral nerves: IgM-associated peripheral neuropathy, POEMS. (Neutrophilic dermatosis and scleromyxedema are skin MGCS.)
- Cornea: crystalline keratopathy.

Monoclonal gammopathy of clinical significance (MGCS)

Diagnosis	Presenting features
Scleromyxedema	Generalized papular and sclerodermoid eruption with waxy firm papules/plaques, mucin deposition, fibroblast proliferation, and fibrosis on histology. Systemic involvement (cardiovascular, GI, pulmonary, musculoskeletal, renal, nervous). Gammopathy usually IgG with λ predominance.
Capillary leak syndrome	Rare; episodes of severe hypotension, hypoalbuminemia, and hemoconcentration from extravasation of intravascular fluid; elevated VEGF and angiopoietin-2. Prodrome, then extravasation phase with edema, hypotension, hemoconcentration, sometimes compartment syndrome.
Schnitzler syndrome	Chronic urticaria with IgM monoclonal gammopathy (typically IgM κ); may have bone pain, skeletal hyperostosis, arthralgias, lymphadenopathy, intermittent fevers.
TEMPI syndrome	Telangiectasias, erythrocytosis with elevated erythropoietin, MGUS, perinephric fluid collections, and intrapulmonary shunting. Favorable responses to bortezomib.

Smoldering MM: Risk and Management

Progression: ~10%/yr in first 5 yr (cumulative ~50%), then ~3%/yr (yr 6 to 10, ~66% cumulative at 10 yr), then ~1%/yr; total 15-yr ~73%.
NEW 20/2/20 risk model (Mayo 2018), high-risk = ≥2 of the 3 factors:
- M-protein >2 g/dL
- BM plasma cells >20%
- FLC ratio >20
High-risk SMM (≥2 factors) → ~50% progression at 2 yr.
ECOG E3A06 (lenalidomide vs observation in intermediate/high-risk SMM): lenalidomide 25 mg days 1 to 21 q28d; PFS benefit overall (HR 0.28; 95% CI 0.12 to 0.62; P=.002) with NO OS difference. Mayo 2018 high-risk subgroup HR 0.09 (95% CI 0.02 to 0.44); intermediate-risk HR 0.52 (95% CI 0.15 to 1.85). Grade 3 to 4 nonhematologic AEs 28% (41% overall grade 3 to 4); higher second primary cancers (3-yr 5.2% vs 3.5%) and 51% discontinuation rate. Conclusion: early lenalidomide in high-risk SMM delays progression and end-organ damage.
Older Len+dex (PETHEMA/QuiRedex) improved PFS and OS but predated modern imaging and used older criteria (it did use multiparameter flow cytometry to define high-risk), and the lenalidomide-specific contribution is unclear (combination).
AQUILA (NEJM Dimopoulos 2024): daratumumab SC monotherapy delayed progression vs observation in high-risk SMM → supported FDA approval (Nov 6, 2025) of daratumumab + hyaluronidase for high-risk SMM (first approved SMM therapy).
Bottom line: for standard/low-risk SMM, observation remains the default; treat high-risk SMM on trial or with the above.

Diagnostic Workup (MM)

Initial: SPEP + IFE + UPEP + IFE + sFLC; BMPC by flow + cytogenetics/FISH; LDH, β2-microglobulin, albumin, calcium, creatinine, CBC; MRD assessment (NGS 10^-5 or 10^-6) at deep response.
Imaging: whole-body low-dose CT, PET-CT, or whole-body MRI REPLACE skeletal survey (plain X-rays insensitive).

Cytogenetics and Risk Groups

MM translocations and IgH partners

Risk	Translocation	Gene
Standard	t(11;14)(q13;q32)	CCND1 (cyclin D1); venetoclax-sensitive
	t(6;14)(p21;q32)	CCND3 (cyclin D3)
	Hyperdiploidy	Recurrent trisomies of odd-numbered chromosomes: 3, 5, 7, 9, 11, 15, 19, 21
Intermediate	del(13) by metaphase cytogenetics, hypodiploidy (isolated del(13q) by FISH is not independently high-risk)	RB1 region / non-hyperdiploid
Poor	t(4;14)(p16;q32)	FGFR3 and MMSET/WHSC1
	t(14;16)(q32;q23)	C-MAF
	t(14;20)(q32;q11)	MAFB
	del(17p) / TP53, gain/amp 1q21, del(1p)	TP53 loss; 1q gain/amp; 1p deletion

Classic high-risk cytogenetics: del(17p), t(4;14), t(14;16) (and t(14;20), gain/amp 1q). Bortezomib can partially overcome t(4;14) and del(17p); carfilzomib can overcome t(4;14); pomalidomide can overcome del(17p) but not t(4;14).

Staging: ISS, R-ISS, R2-ISS

ISS staging

ISS stage	Criteria	Median survival (mo)
I	β2m <3.5 mg/L and albumin ≥3.5 g/dL	62
II	Not stage I or III	44
III	β2m ≥5.5 mg/L	29

R-ISS (adds LDH and high-risk FISH): Stage I = ISS-I + standard cytogenetics + normal LDH; Stage III = ISS-III AND (high-risk cytogenetics OR ↑LDH); Stage II = neither.
R2-ISS (2022): points-based, adds 1q gain to ISS, LDH, del(17p), t(4;14); stratifies into 4 groups (low, low-intermediate, intermediate-high, high).

IMWG Response and MRD Criteria

Assess 3 components: (1) biochemistry (serum/urine M-spike and FLC), (2) bony lesions or soft-tissue plasmacytoma, (3) BM plasma cell involvement.
MRD-negative: absence of clonal plasma cells in marrow by an assay with sensitivity ≥1 in 10⁵ nucleated cells (flow or NGS). Sustained MRD-negative: negativity confirmed ≥1 yr apart. Imaging + MRD-negative: marrow negativity plus resolution of PET-CT uptake (IMWG criteria, Kumar, Lancet Oncol 2016).

IMWG 2016 response and relapse criteria

Group	Category	Definition
Response	Stringent CR (sCR)	CR plus normal FLC ratio and absence of clonal cells in marrow by IHC (κ/λ ratio ≤4:1 or ≥1:2 as appropriate, ≥100 plasma cells counted).
	CR	Negative serum and urine immunofixation, disappearance of soft-tissue plasmacytomas, and <5% BM plasma cells.
	VGPR	M protein detectable by immunofixation but not electrophoresis, OR ≥90% reduction in serum M protein plus urine M protein <100 mg/24 h.
	PR	≥50% ↓ serum M protein PLUS urine M protein ≥90% ↓ (or <200 mg/24 h). If not measurable, ≥50% ↓ in involved-minus-uninvolved FLC; if FLC also not measurable, ≥50% ↓ in BMPC (baseline ≥30%). Also ≥50% ↓ in plasmacytoma size if present.
	Minimal response (MR)	25 to 49% ↓ serum M protein and 50 to 89% ↓ urine M protein; 25 to 49% ↓ in plasmacytoma size.
	Stable disease	Not meeting CR, VGPR, PR, MR, or PD (best described by time-to-progression).
Progression and relapse	Progressive disease (PD)	≥25% ↑ from nadir in: serum M protein (absolute ≥0.5 g/dL; ≥1 g/dL if nadir ≥5 g/dL), urine M protein (absolute ≥200 mg/24 h), delta FLC (>10 mg/dL; only if serum and urine M-protein not measurable) or BMPC (≥10% absolute) New or ≥50% ↑ (and ≥1 cm) in plasmacytoma/bone lesions ≥50% ↑ circulating plasma cells (min 200/µL)
	Clinical relapse	New end-organ dysfunction (CRAB: Ca >11 mg/dL; Hb ↓≥2 g/dL; Cr rise ≥2 mg/dL (increase from therapy start, myeloma-attributable); hyperviscosity), or new/≥50% ↑ (and ≥1 cm) plasmacytoma/bone lesions.
	Relapse from CR (for DFS endpoints)	Reappearance of serum/urine M protein by IFE or electrophoresis; ≥5% BM plasma cells; or any other sign of progression (new plasmacytoma, lytic lesion, hypercalcemia).

Drug Classes and Mechanisms

Proteasome inhibitors (PI): bortezomib (neuropathy, zoster reactivation; can overcome t(4;14) and del(17p)); carfilzomib (cardiac toxicity: HTN, HF, arrhythmia; overcomes t(4;14)); ixazomib (oral).
Immunomodulatory drugs (IMiDs, cereblon binders): lenalidomide; thalidomide (minimal myelosuppression but neuropathy, constipation); pomalidomide (overcomes del(17p), not t(4;14)).
Anti-CD38 mAbs: daratumumab (IgG1-κ; ADCP, ADCC, CDC; interferes with blood-bank antibody screen, do type/screen before starting); isatuximab (IgG1-κ, binds distinct CD38 epitope).
Anti-SLAMF7: elotuzumab (IgG1; Elo-Rd for ≥1 prior line; Elo-Pd for ≥2 prior lines including len + PI).
Nuclear export inhibitor: selinexor (XPO1 inhibitor; keeps tumor-suppressor proteins in nucleus; inhibits NF-kB and translation of c-myc/cyclin D).
BCL-2 inhibitor: venetoclax (t(11;14) MM overexpressing BCL-2; ORR ~21% monotherapy).
HDAC inhibitor: panobinostat (aggresome inhibition; removed from NCCN options).
CELMoDs (next-gen cereblon modulators): iberdomide, mezigdomide, active in len/pom-refractory disease (iberdomide FDA accelerated approval Aug 13, 2026 with daratumumab + dexamethasone after ≥1 prior line incl PI and IMiD, EXCALIBER-RRMM; mezigdomide investigational).

AEs by drug (high-yield)

VTE: IMiDs. Neuropathy: bortezomib, thalidomide. Myelosuppression: all except corticosteroids and thalidomide. Thrombocytopenia: all, most with PIs (transient, cyclic, rapid recovery). Infection/zoster: PI and daratumumab (acyclovir ppx). Diarrhea: bortezomib, carfilzomib, panobinostat, and long-term lenalidomide (bile-acid malabsorption, use a bile-acid sequestrant). Constipation: thalidomide.

Frontline MM Treatment

Induction principle: IMiD + steroid + PI (triplet); quadruplets add anti-CD38 for deeper responses and higher MRD-negativity (per SMART-MM guidance for high-risk).
Transplant-eligible (TE), induction: quadruplet (Dara-VRd, Isa-VRd) is now standard.
- PERSEUS (Sonneveld NEJM 2024): Dara-VRd then D-R maintenance; superior MRD-negativity and PFS vs VRd. FDA approval Dara-VRd Jul 30, 2024 for newly dx TE MM.
- IsKia (EMN24, Nat Med 2026): Isa-KRd vs KRd induction, ASCT, then consolidation; higher post-consolidation MRD negativity (10^-5 77% vs 67%; 10^-6 68% vs 48%).
- Triplet backbones: VRd (SWOG S0777 VRd > Rd; category 1); E1A11 VRd = KRd (VRd more neuropathy, KRd more cardiorenal); KRd (good if neuropathy, no cardiopulmonary comorbidity); VTd; CyBorD (use in renal failure/AKI); IRd (all oral). Dara-VTd, Dara-RVd, Dara-KRd (MASTER) are quadruplet options.
ASCT (autologous): melphalan 200 mg/m² is the best myeloablative conditioning (oral cryotherapy during infusion to reduce mucositis; antimicrobial ppx; growth factors). DETERMINATION (Richardson NEJM 2022): RVd + ASCT vs RVd alone PFS 67.5 vs 46.2 mo (HR 1.53 favoring ASCT) but NO OS benefit at 76 mo. Tandem ASCT (second within ~6 mo) may benefit high-risk t(4;14)/del(17p) or those failing to achieve CR; STAMINA showed no PFS/OS difference single vs tandem. Second ASCT reasonable if first remission ≥18 mo (no maintenance) or ≥36 mo (on maintenance). Deferred ASCT is debated in MRD-negative quad responders (PERSEUS, IsKia, MIDAS evolving).
Transplant-ineligible (TIE): Dara-Rd (MAIA, Facon NEJM 2019, OS benefit), Dara-VMP (ALCYONE), VRd-lite, Dara-VRd-lite. Doublets (Vd or Rd, reduced dose) for frail.
- IMROZ (Facon, NEJM 2024; PMID 38832972): Isa-VRd vs VRd in newly dx TIE MM ≤80 yr, 5-yr PFS 63.2% vs 45.2% (HR 0.60). FDA Sep 20, 2024, Isa-VRd for TIE MM.
- BENEFIT / IFM 2020-05 (Leleu, Nat Med 2024): Isa-VRd vs Isa-Rd, MRD-neg 10^-5 at 18 mo 53% vs 26% (P<.0001).
- CEPHEUS (Usmani, Nat Med 2025): Dara-VRd vs VRd in TIE / transplant-deferred, sustained MRD-neg ≥12 mo 49% vs 26% (P<.0001). FDA Jan 27, 2026, Dara-VRd label expanded to TIE.
Older/frail adjustments: neuropathy, use weekly SC bortezomib with low-dose prednisone, or RD; renal failure, use KTd or dose-adjusted len; cardiac, avoid carfilzomib; VTE, low-dose len with low-dose steroid and aggressive prophylaxis.

Maintenance

Lenalidomide 10 to 15 mg until progression improves PFS and (per CALGB 100104/IFM meta-analysis) OS.
High-risk: add a PI, i.e. lenalidomide + bortezomib (or carfilzomib), or daratumumab + lenalidomide. Single-agent PI (bortezomib or ixazomib) or daratumumab also used.

Relapsed/Refractory MM (RRMM)

General principle: switch class; consider fitness, prior exposures, refractoriness, and depth-of-response goal. Post-ASCT biochemical relapse can be a MGUS/SMM-like state and observed.
If progression on lenalidomide maintenance (len-refractory): use a len-refractory-active regimen, e.g. Dara-Kd, Isa-Kd, pomalidomide-based (Dara-Pd; Isa-Pd or EPd once ≥2 prior lines incl. len + PI), or Seli-Vd; not Rd-based triplets.
Lenalidomide-refractory: use IMiD-free triplet (Dara-Vd, Dara-Kd, Seli-Vd) OR substitute pomalidomide (Elo-Pd, Dara-Pd, Isa-Pd).
1st-relapse triplets: Dara-Kd, Isa-Kd, Dara-Pd, KRd, DRd, IRd, selinexor-Vd (BOSTON); Isa-Pd and EPd are labeled after ≥2 prior lines incl. len + PI.
Penta-refractory (2 PIs, 2 IMiDs, anti-CD38: bortezomib, carfilzomib, lenalidomide, pomalidomide, anti-CD38): BCMA-directed therapy dominates.

BCMA- and GPRC5D-Directed Therapies (CAR-T, ADC, Bispecifics)

BCMA CAR-T, idecabtagene vicleucel (Abecma): Mar 26, 2021, R/R MM after ≥4 prior LOT (KarMMa); Apr 4, 2024, earlier line after ≥2 prior LOT (KarMMa-3, Rodriguez-Otero NEJM 2023; PFS 13.3 vs 4.4 mo, HR 0.49). 4-1BB CAR.
BCMA CAR-T, ciltacabtagene autoleucel (Carvykti): Feb 28, 2022, after ≥4 prior LOT (CARTITUDE-1); Apr 5, 2024, after ≥1 prior LOT and len-refractory (CARTITUDE-4, San-Miguel NEJM 2023; PFS NR vs 11.8 mo, HR 0.26). Tandem dual-VHH binder, 4-1BB. Class warning: movement and neurocognitive toxicity (parkinsonism, cranial nerve palsies, distinct from ICANS); secondary T-cell malignancies (FDA black-box, all CAR-T).
BCMA bispecific, teclistamab (Tecvayli): Oct 25, 2022, after ≥4 prior LOT (MajesTEC-1, Moreau NEJM 2022; ORR 63%). Weekly SC, then Q2W after ≥CR maintained ≥6 mo.
Teclistamab + daratumumab SC (MajesTEC-3): FDA Mar 5, 2026, RRMM after ≥1 prior LOT incl PI and IMiD; PFS HR 0.17 and OS HR 0.46 vs DPd/DVd.
BCMA bispecific, elranatamab (Elrexfio): Aug 14, 2023, after ≥4 prior LOT (MagnetisMM-3, Lesokhin Nat Med 2023; ORR 61%). SC weekly then Q2W.
BCMA bispecific, linvoseltamab (Lynozyfic): Jul 2, 2025, after ≥4 prior LOT (LINKER-MM1, Bumma JCO 2025; ORR 70%, ≥CR 45%).
GPRC5D bispecific, talquetamab (Talvey): Aug 9, 2023, after ≥4 prior LOT (MonumenTAL-1, Chari NEJM 2022; ORR 72 to 74%). Unique on-target off-tumor toxicity: dysgeusia, dysphagia, skin/nail toxicity, weight loss; less infection than BCMA agents.
BCMA ADC, belantamab mafodotin (Blenrep): originally Aug 2020 mono, withdrawn Nov 2022 (DREAMM-3), RE-APPROVED Oct 23, 2025 in combination (Bela + bortezomib + dex, BVd) after ≥2 prior LOT (DREAMM-7, Hungria NEJM 2024; PFS 36.6 vs 13.4 mo BVd vs DVd, HR 0.41; DREAMM-8 supportive). Major ocular toxicity (any-grade 92%, G3/4 77%), REMS, slit-lamp monitoring.
CAR-T toxicities (myeloma): CRS (lower grade than in ALL; tocilizumab + steroids), ICANS, prolonged cytopenias, hypogammaglobulinemia, movement/neurocognitive toxicity (especially cilta-cel). Long PFS but typically not curative.
Bispecific class effects: CRS (mostly grade 1 to 2, cycle 1, subcut step-up dosing), infections (T-cell directed, opportunistic; PJP/HSV/VZV prophylaxis, IVIG to keep IgG >400).
Sequencing: BCMA CAR-T → BCMA bispecific (possibly less responsive from clonal BCMA loss) vs switch to GPRC5D bispecific (talquetamab, different target).

MajesTEC-9 (Mina, ASCO 2026): teclistamab monotherapy vs PVd/Kd in RRMM 1 to 3 prior LOT (prior anti-CD38 and lenalidomide); PFS HR 0.29, OS HR 0.60; supports earlier-line bispecifics.
CARTITUDE-6 / EMagine (anticipated 2026): cilta-cel vs Dara-VRd/ASCT in newly dx TE MM (first randomized 1L CAR-T trial in transplant-eligible MM; CARTITUDE-5 is the earlier randomized 1L cilta-cel trial in transplant-not-intended pts); interim MRD readouts positive.
RedirecTT-1 (Cohen ASH 2024): dual bispecific talquetamab + teclistamab (GPRC5D + BCMA) in RRMM including extramedullary disease, ORR 84%; RedirecTT-2 ongoing.

Other Therapies

Selinexor: XPO1 inhibitor; STORM (penta-refractory) and BOSTON (SVd vs Vd); AEs cytopenias, hyponatremia, GI.
Venetoclax: t(11;14) MM; BELLINI (with Vd, PFS benefit in t(11;14), excess deaths in non-t(11;14)); not FDA-approved in MM, used off-label in t(11;14).

Bone Disease and Supportive Care

Bone-modifying agents: zoledronic acid (preferred; slight OS benefit) or denosumab (equal efficacy, preferred if CrCl <30). Reassess by ~2 yr; in VGPR+ after ≥12 mo monthly ZA may reduce frequency or stop; denosumab needs ZA cover to avoid rebound. IMWG: give bisphosphonate to all patients with active MM regardless of overt bone disease. Teriparatide can accelerate MRONJ healing in selected non-cancer patients but should be avoided in skeletal malignancy or bone metastases (osteosarcoma warning; boxed warning removed 2020); avoid in myeloma bone disease.
Zoledronic acid renal dosing: CrCl >60 → 4 mg; 50 to 60 → 3.5 mg; 40 to 49 → 3.3 mg; 30 to 39 → 3.0 mg; <30 → do not give.
ONJ: dental clearance before starting; avoid invasive dental procedures.
Hypercalcemia: IV fluids + bisphosphonate; calcitonin acutely; denosumab if refractory or renal failure.
Cord compression: dexamethasone + spinal radiation + urgent surgical evaluation.
Infection: PJP (TMP-SMX) during dex-based regimens; HSV/VZV (acyclovir) with bortezomib/anti-CD38; pneumococcal, influenza, COVID vaccines; IVIG for hypogammaglobulinemia with recurrent infection.

MM and AKI / renal impairment (RI)

CyBorD is standard induction with kidney dysfunction; can start Vd and add lenalidomide later (continue as RVd).
IMWG RI recommendations: (1) bortezomib-based regimens are the cornerstone (grade A); (2) high-dose dexamethasone at least the first month (grade B); (3) thalidomide effective, no dose change (grade B); (4) lenalidomide effective mainly in mild/moderate RI, dose-reduce and monitor in severe RI/dialysis (grade B); (5) ASCT feasible with reduced melphalan 100 to 140 mg/m² (grade C); (6) carfilzomib safe if CrCl >15 mL/min; (7) ixazomib-Rd safe if CrCl >30 mL/min (grade A).
Lenalidomide renal dosing: CrCl >60 no change; 30 to 60, 10 mg daily (may increase to 15 mg); <30, 15 mg q48h; <30 on dialysis, 5 mg daily (after dialysis).
Bortezomib: if total bilirubin >1.5× ULN, start 0.7 mg/m². Pomalidomide: reduce 25% in severe RI on dialysis (take after HD).

Bortezomib neuropathy grading and dose modification

Grade 1 (loss of DTRs, paresthesia without loss of function): no dose change.
Grade 1 with pain or Grade 2 (interferes with function, not ADLs): reduce to 1.0 mg/m² (or switch to 1.3 once weekly).
Grade 2 with pain or Grade 3 (interferes with ADLs): hold until resolution, resume 0.7 mg/m² weekly.
Grade 4 (disabling, paralysis): discontinue permanently. Neuropathy is less common with weekly and SC dosing.

VTE prophylaxis (IMPEDE-VTE and SAVED scores)

IMPEDE-VTE points: IMiD +4; BMI ≥25 +1; pelvic/hip/femur fracture +4; ESA +1; doxorubicin +3; dexamethasone low-dose +2 / high-dose +4; prior VTE +5; tunneled central line/CVC +2. Reductions: Asian/Pacific ethnicity −3; existing prophylactic LMWH/ASA −3; therapeutic LMWH/warfarin −4.
If IMPEDE score ≥4: prophylactic-dose LMWH, rivaroxaban 10 mg daily, apixaban 2.5 mg BID, fondaparinux, or warfarin (INR 2 to 3). Continue prophylaxis while on thrombogenic (IMiD-based) therapy; reassess agent, intensity, and duration as risk changes. Low-risk patients on IMiDs may use ASA 81 mg.

High-Risk MM Features (CRITICAL)

Cytogenetic high risk: del(17p)/TP53, t(4;14), t(14;16), t(14;20), 1q gain/amp, MYC translocations, complex karyotype.
Plasma cell leukemia: ≥5% circulating plasma cells (IMWG 2021 update, was 20%); poor prognosis; aggressive quad + ASCT + maintenance, consider CAR-T.
Extramedullary disease: worse prognosis; PET imaging important.
Functional high risk: early relapse (within 12 mo of initial therapy or 18 mo of ASCT).

Veli Bakalov MD, Board Review Notes 2026