Special Report

Monoclonal gammopathy of clinical significance: a novelconcept with therapeutic implicationsJean-Paul Fermand,1 Frank Bridoux,2 Angela Dispenzieri,3 Arnaud Jaccard,4 Robert A. Kyle,3 Nelson Leung,5 and Giampaolo Merlini6,7

1Service d’Immuno-Hematologie, Departement d’Immunologie Clinique, INSERM (Unite Mixte de Recherche 1126), and Intergroupe Francophone du Myelome,Hopital Saint-Louis, Paris, France; 2Service de Nephrologie and Centre de reference pour l’amylose AL et autres maladies par depots d’immunoglobulinesmonoclonales, Centre Hospitalier Universitaire de Poitiers, Poitiers, France; 3Division of Hematology, Mayo Clinic, Rochester, MN; 4Service d’Hematologie andCentre de reference pour l’amylose AL et autres maladies par depots d’immunoglobulines monoclonales, Centre Hospitalier Universitaire de Limoges, Limoges,France; 5Division of Nephrology, Mayo Clinic, Rochester, MN; 6Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a CarattereScientifico Policlinico San Matteo, Pavia, Italy; and 7Department of Molecular Medicine, University of Pavia, Pavia, Italy

Monoclonal gammopathy is a common condition, par-ticularly in the elderly. It can indicate symptomatic mul-tiple myeloma or another overt malignant lymphoiddisorder requiring immediate chemotherapy. More fre-quently, it results from a small and/or quiescent secretingB-cell clone, is completely asymptomatic, and requiresregular monitoring only, defining a monoclonal gammo-pathy of unknown significance (MGUS). Sometimes, al-though quiescent and not requiring any treatment perse, the clone is associated with potentially severe organdamage due to the toxicity of the monoclonal immuno-globulin or to other mechanisms. The latter situation isincreasingly observed but still poorly recognized andfrequently undertreated, although it often requires rapidspecific intervention to preserve involved organ func-tion. To improve early recognition and management of

these small B-cell clone–related disorders, we proposeto introduce the concept of monoclonal gammopathy ofclinical significance (MGCS). This report identifies thespectrum of MGCSs that are classified according tomechanisms of tissue injury. It highlights the diversity ofthese disorders for which diagnosis and treatment areoften challenging in clinical practice and require a mul-tidisciplinary approach. Principles of management, in-cluding main diagnostic and therapeutic procedures, arealso described. Importantly, efficient control of the un-derlying B-cell clone usually results in organ improve-ment. Currently, it relies mainly on chemotherapy andother anti–B-cell/plasma cell agents, which should aimat rapidly producing the best hematological response.(Blood. 2018;132(14):1478-1485)

IntroductionMonoclonal gammopathy is defined by the presence in serumand/or urine of a monoclonal immunoglobulin produced by anabnormal B-cell clone. The clone usually consists of plasma cellswhen themonoclonal immunoglobulin (MIg) is immunoglobulinG(IgG), IgA, IgD, or light chain (LC) only and lymphoplasmacyticwhen producing an IgM. It may remain quiescent over a pro-longed period, defining monoclonal gammopathy of undeter-mined significance (MGUS).1 Uncontrolled clonal expansioncausing end-organ damage defines malignant symptomaticlymphoproliferative disorder, usually multiple myeloma (MM) orWaldenstrom macroglobulinemia (WM).2,3 An intermediate con-dition results in an indolent “smoldering” disease.4

Manifestations associated with monoclonal gammopathies canresult from various, sometimes intertwined mechanisms: (1) ex-pansion of clonal malignant cells; (2) secretion of a large amountof MIg, which can cause tumor-mass–related manifestations, in-cluding hyperviscosity and LC cast nephropathy; (3) secondaryalterations of the host immune system causing immune deficiencyand autoimmune manifestations; and (4) pathogenic activities ofthe MIg or other mediators released by the clone.

Quiescent or indolent B-cell clones do not cause tumor symp-toms, and immunodepression is uncommon. However, even avery small clone can produce severe manifestations due totoxicity of theMIg or other mechanisms. The kidney is a frequenttarget and the concept of monoclonal gammopathy of renalsignificance (MGRS) has recently emerged.5 Other organs,particularly the skin and peripheral nerve, may be involved. Tobetter characterize these situations caused by a “dangeroussmall B-cell clone,”6 which are still poorly recognized and fre-quently undertreated, we propose extending the concept ofMGRS to that of monoclonal gammopathy of clinical significance(MGCS).

Types ofMGCS according tomechanismsof tissue injuryThe spectrum of MGCS is large because of the diversity of in-volved organs and pathogenic mechanisms. Lesions commonlyresult from deposition of all or part of the MIg as aggregates,amorphous, crystalline, microtubular, or fibrillar forms (Table 1).Other mechanisms include autoantibody activity against a tissueantigen, formation of immune complexes, and complement

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activation. In addition, even a small B-cell clone may absorb bi-ologically active molecules or induce cytokine secretion. In sometypes of MGCS, the pathogenesis remains unknown (Table 2).

MGCS due to MIg depositionMIg deposition is involved in many MGCS types, which may beclassified according to the ultrastructural appearance of de-posits, either organized or nonorganized (Table 1).7

Organized deposits display different patterns. Amyloid light-chain (AL) amyloidosis is the hallmark of MGCS with fibrillar de-posits.8 Acquired Fanconi syndrome features precipitation of LC(usually k) into crystals within renal proximal tubular cells.9 Ac-cumulation of MIg crystals in the lysosomes of macrophageswithin bone marrow, lymph nodes, and extralymphoid tissuecharacterizes crystal storing histiocytosis.10 Crystalline keratopathyusually results from formation of monoclonal immunoglobulin-derived crystals in the cornea.11 Some type I cryoglobulins arecrystalglobulins. Monoclonal and mixed cryoglobulins may dis-play microtubular deposits with or without vasculitic lesions,depending on cryoglobulin composition and involved organ.7,12

Immunotactoid glomerulopathy or glomerulonephritis with or-ganized microtubular MIg deposits is due to microtubular IgGdeposits (usually limited to the kidney), without features of cry-oglobulinemic glomerulonephritis.7,13

MGCS with nonorganized deposits are mainly represented bymonoclonal immunoglobulin deposition disease (MIDD), featuredby linear granular “powdery punctate” deposits along basal mem-branes. Usually, deposits contain the LC (LCDD), sometimes

the heavy chain (HCDD), or both (LHCDD). Although predomi-nantly involving glomerular and tubular compartments of thekidney, MIDDs are systemic.7,14 In proliferative glomerulonephritiswith monoclonal immunoglobulin deposits (PGNMID), the MIg(most commonly IgG3) and complement components are de-posited in the glomerular capillary walls and mesangium, mim-icking an immune complex–mediated glomerulonephritis7,15

(Figure 1A-C). In contrast to MIDD, PGNMID is limited to thekidney. Uncommonly, amorphousMIg deposits may involve othertissues, as in macroglobulinosis, featured by intradermis depositsof monoclonal IgM.16 Glomerular intracapillary monoclonal IgMthrombi, a now rare complication ofWMwith hyperviscosity,17 andLC cast nephropathy, which results from massive nephrotoxic LCsecretion, indicate a high tumor burden and do not belong to thespectrum of MGCS.18

MGCS due to autoantibody activity of MIgMIg can cause organ lesions through autoantibody activity againstvarious antigens. Anti-collagen IV or anti-phospholipase A2 re-ceptor reactivity of the MIg was documented in rare cases ofantiglomerular basement membrane disease and membranousglomerulopathy, respectively.19,20 MIg-related bullous skin dis-eases were reported due to autoantibody activity versus collagenVII.21 The diagnosis requires pathological demonstration of linearimmunoglobulin deposits in the dermoepidermal junction withthe same LC restriction as that of the circulatingMIg. Alternatively,immunostaining may show polytypic deposits, indicating that theautoantibody activity is not MIg related but produced by by-stander autoreactive polyclonal B cells, as in autoimmune cyto-penias associated with lymphoid disorders.21

Table 1. Current pathophysiological classification of themainMGCS-related disorders: MGCS due to deposition of all orpart of the MIg

Ultrastructuralappearance of

depositsMain characteristics of

monoclonal gammopathy Main organ(s) involved Reference

OrganizedAL amyloidosis Fibrillar l LC (75%), k LC (25%), IgM ,10% Systemic (heart 80%, kidney 70%) 8,57Type I cryoglobulinemia Microtubular/crystalline IgG or IgM Systemic (skin 111, kidney,

peripheral nerve, systemicsymptoms [crystalcryoglobulin])

12,28

Immunotactoid glomerulopathy/GOMMID

Microtubular CLL-like clonal proliferation (50%) Kidney 13

Acquired Fanconi syndrome Crystalline k LC (.90%, mostly Vk1) Kidney (proximal tubulopathy) 9Crystal storing histiocytosis Crystalline k LC Systemic (kidney, cornea, joints,

lymphoid tissue)10

Crystalline keratopathy Crystalline IgG Cornea 11

NonorganizedMIDD LCDD: LC only (usually k LC) (80%,

Vk1 and Vk4)HCDD: truncated HC only

(mostly g1 and g3)LHCDD: LC 1 truncated HC

Systemic (kidney [;100%,glomerular and tubularbasement membrane], liver[30%], heart [30%])

14,51,61

PGNMID Usually IgG3 Kidney 15Macroglobulinosis IgM Skin (dermis) 16

AL amyloidosis is themost frequent type, with an incidence of;10 permillion inhabitants per year inWestern countries.MIDD incidence is estimated to be 10-fold lower. Other types ofMGCSdue to deposition of MIg are rare (type I cryoglobulinemia and PGNMID), even scarcer (Fanconi syndrome), or exceptional (macroglobulinosis and crystalline keratopathy).

CLL, chronic lymphocytic leukemia, GOMMID, glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits; HCDD, heavy-chain deposition disease; LCDD, light-chain deposition disease; LHCDD, light- and heavy-chain deposition disease.

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Table 2. Current pathophysiological classification of the main MGCS-related disorders: cytokine mediated or MGCSdue to autoantibody activity, CAP activation, cytokine-mediated, or of unknown mechanism

Mechanism

Main characteristicsof monoclonalgammopathy Main organ(s) involved Reference

Autoantibody activityType II mixedcryoglobulinemia*

Rheumatoid IgM Immune complex–mediatedvasculitis; skin 111,kidney, peripheral nerve;may be systemic

28,60

C1 inhibitor deficiency C1 inhibitor Angioedema 25Von Willebrand disease vW factor Bleeding 26Bullous skin diseases Dermoepidermal junction

(collagen VII)Skin 21

Xanthomatosis Various lipoproteins Usually IgG Cholesterol accumulationin macrophages; skinand tendons; otherlocalizations (necrobioticxanthogranumathosis)

29,30

Cold agglutinin disease Red blood cell (Ii) IgM Cold-induced skinmanifestations 1intravascular hemolysis

27

IgM-associatedperipheral neuropathy

MAG 111 IgM Peripheral nerve;ataxic polyneuropathy(anti-MAG)

CANOMAD

22,23

Gangliosides

CAP* activationC3 glomerulonephritisAtypical hemolytic-uremic syndrome

Mechanism to bedetermined; autoantibodyactivity against CAPregulator protein (factor H)in some cases

IgG Kidney onlySystemic

31-34

Cytokine mediatedPOEMS syndrome VEGF l LC (;100%), Peripheral nerve (100%) and

various othermanifestations

35,36IgA 50%Vl1 (#100%)Osteosclerotic bone

lesions

Unknown mechanismSystemic capillary leaksyndrome

IgG, IgA (rare) Systemic 45

TEMPI syndrome IgG Systemic 46,47Neutrophilic dermatosis† IgA .80% (except Sweet

syndrome)Skin 111; different types

and different associatedmanifestations

39

Acquired cutis laxa Usually IgG; associationwith g HCDD

Skin 111

Other manifestations (lung,digestive tract)

43

Scleromyxedema IgG with slowelectrophoreticmobility

Skin 111; otherlocalizations

40,41,52

Scleroedema IgG Skin only 41Schnitzler syndrome Acquired autoinflammatory

syndrome by IL-1deregulation?

IgM Skin 111; systemicsymptoms; osteoscleroticbone lesions

44

Sporadic late-onsetnemaline myopathy

Exclusively muscles (skeletaland possibly cardiac)

48

CAP, complement alternative pathway; CANOMAD, chronic ataxic neuropathy, ophthalmoplegia, monoclonal IgM protein, cold agglutinins, anti-disialosyl antibodies; HCDD, heavy-chaindeposition disease; IL-1, interleukin 1; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; TEMPI, telangiectasias, erythrocytosis withelevated erythropoietin level, monoclonal gammopathy, perinephric fluid collection, and intrapulmonary shunting.

*Type II mixed cryoglobulinemia was observed in ;10% of patients with chronic virus C infection.

†Including pyoderma gangrenosum, Sweet syndrome, subcorneal pustular dermatosis, and erythema elevatum diutinum.

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An autoantibody activity against myelin-associated glycoprotein(MAG) may be responsible for IgM-associated peripheral neu-ropathy.22 The MIg usually recognizes a myelin-sulfated glucuronylepitope, shared by MAG and cross-reactive glycoconjugates. Pre-dominantly sensitive symmetric and distal demyelinating poly-neuropathy often accompanied by ataxia and tremor is the mainclinical manifestation. Monoclonal IgM autoantibodies against gan-gliosides containing disialosyl groups are less frequent andusually observed in CANOMAD syndrome (chronic ataxic neurop-athy, ophthalmoplegia, monoclonal IgM protein, cold agglutinins,anti-disialosyl antibodies).22,23 Antibodies against GM1 gangliosideassociatedwithmultifocalmotor neuropathy are usually of IgMclassbut polytypic; whether monoclonal IgM with anti-GM1 specificitycan cause weakness and motor conduction blocks is debated.24

Acquired C1 inhibitor deficiency and acquired von Willebranddisease can be due to autoantibody activity of MIg with directinhibitory effect or inducing formation of complexes acceleratingthe catabolism of the protein.25,26

In cold agglutinin disease, cold-triggered ischemic symptoms ofthe extremities and acute hemolysis are provoked by agglutinationof red blood cells due to the anti-Ii autoantibody activity of themonoclonal IgM.27 In type II mixed cryogloglobulinemia, mono-clonal IgM with rheumatoid activity triggers the deposition ofimmune complexes with polyclonal IgG in vascular walls, resultingin complement activation and formation of perivascular infiltratescharacteristic of leukocytoclastic vasculitis.28

MIg autoantibodies can become symptomatic by intracellularaccumulation of immune complexes. Xanthomatosis is charac-terized by the intracellular storage of cholesterol-rich materialin macrophages, accumulating in the skin and the tendons29

(Figure 2A). Xanthomas may be diffuse, predominating in thelimb skinfolds, or associated with an inflammatory reaction re-ferred to as necrobiotic xanthogranulomatosis.30 Particularly inthe normolipemic form, xanthomatosis is associated with MIgand complement abnormalities with low C4 serum levels. TheMIg may be involved through antigen-antibody interactionwith various lipoproteins resulting in the formation of immunecomplexes, complement activation, and subsequent lipid ac-cumulation in macrophages.29

MGCS secondary to CAP activationIn patients .50 years of age, C3 glomerulopathy (C3G) isfrequently associated with an indolent IgG monoclonalgammopathy.31,32 C3G, which is defined histologically by thepresence of glomerular electron dense deposits of C3 withoutimmunoglobulin deposit, derives from activation of the CAP(Figure 1D-F). The associated MIg probably plays a role, assuggested by the demonstration in some cases of its autoanti-body activity against CAP regulatory proteins, such as factor H,and by the beneficial effect of a clone-targeted chemotherapy.32

In atypical hemolytic uremic syndrome, the prevalence of mono-clonal gammopathy in older adults is also increased and an au-toantibody activity against factor H of the MIg has been similarlyreported.33,34 Altogether, these data suggest an under-recognized

A

B

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E

DFigure 1. Histopathological features of MGCS-relatedPGNMIDandC3glomerulonephritis. PGNMID (A-C). (A)Light microscopy with periodic acid–Schiff staining(original magnification 3400; scale bar, 50 mm). Mem-branoproliferative glomerulonephritis with mesangial andendocapillary hypercellularity. (B) Immunofluorescencestudy showing monotypic IgG glomerular deposits thatstained positive with the anti-gamma3 conjugate. Similarstaining was observed with the anti-k conjugate, whereasstaining with conjugates specific for a, m, gamma1,gamma2, and gamma4 heavy chains and l light-chainconjugate was negative (not depicted). Scale bar, 50 mm.(C) Electron microscopy confirmed the diagnosis ofPGNMID with granular nonorganized electron-densedeposits predominant in the subendothelial space (as-terisk), suggestive of immune complex–mediated glo-merulonephritis (original magnification 315 000; scalebar, 1 mm). (D-F) MGCS-associated C3 glomerulone-phritis. (D) Light microscopy showing a pattern of pro-liferative endocapillary glomerulonephritis (periodicacid-Schiff staining; original magnification 3400; scalebar, 50 mm). (E) By immunofluorescence, mesangial andglomerular capillary wall deposits stained positively withthe anti-C3 FITC-conjugate (original magnification 3200),whereas no staining was observed with conjugates spe-cific for g, a, and m heavy chains and with anti-k and anti-lconjugates (not depicted). Scale bar, 50 mm. (F) Electronmicroscopy demonstrated the presence of voluminoussubepithelial electron-dense deposits (humps, asterisk)and interrupted intramembranous dense deposits (ar-rows) (original magnification 315 000; scale bar, 1 mm)

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interaction between monoclonal gammopathy and CAP regula-tion that deserves further investigation. It may involve severalmechanisms, since an anticomplement autoantibody activity of theMIg appears uncommon.31,32

MGCS due to cytokine secretionThe acronym POEMS refers to the association of a plasma celldisorder with polyneuropathy, organomegaly, endocrinopathy,monoclonal gammopathy, and skin changes35 (Figure 2B). TheMIg is almost always of the l type with an overrepresentation ofIgA. The bone marrow usually contains ,5% plasma cells. Bonelesions, most commonly osteosclerotic, are almost always pre-sent and are usually focal. Their detection requires a carefulworkup. Indeed, efficient treatment of the plasma cell disorder,such as the irradiation of a solitary plasmocytoma, usually resultsin resolution of all manifestations. A characteristic feature is themarked elevation of serum vascular endothelial growth factor(VEGF) levels that correlates with disease activity.35 VEGF actionon vascular permeability and angiogenesis could account foredema in the myelin sheath, causing peripheral nerve involve-ment and skin manifestations, such as angiomata. In addition,osteosclerotic bone lesions could result from VEGF-inducedosteoblastic differentiation. Thus, abnormal VEGF secretion ap-pears to play a key pathogenic role. The l type restriction of theMIg and molecular studies showing that secreting clonal cells useonly 2 Vl1 germ line genes36 suggest an interaction with VEGFproduction through potential autoantibody activity or a ligand-receptor effect.

MGCS of unknown or putative mechanismMonoclonal gammopathy may cause various manifestations(particularly bleeding disorders) related to adsorption of bi-ologically active molecules on clonal cells or aggregated MIg.This is exemplified by GpIb-mediated selective adsorption ofvon Willebrand factor on clonal plasma cells37 and by factor Xadsorption on AL amyloid fibrils.38 MIg-mediated impaired

platelet function is a classical complication of symptomaticlymphoproliferation with high MIg serum levels. Whether lowMIg levels may affect platelet aggregation remains unclear.

In several diseases associated with a monoclonal gammopathy,the pathogenic link is likely but poorly understood. Most involvethe skin, including the group of neutrophilic dermatosis thatencompasses pyoderma gangrenosum, Sweet syndrome, sub-corneal pustular dermatosis, and erythema elevatum diutinum.Except for Sweet syndrome, .80% of cases of neutrophilicdermatosis with MIg are featured by monoclonal IgA, sug-gesting a role of IgA, IgA receptor, and/or mucosal immunity inthe emergence of neutrophilic tissular infiltrations.39

The presence of a monoclonal IgG is a diagnostic criterion ofscleromyxedema, characterized by papular and sclerodermoidskin lesions due to dermal mucin deposition, fibroblast pro-liferation, and fibrosis, with potential systemic extension.40,41

Scleredema also featuring mucin deposition is restricted to theskin and mainly affects the back and shoulders.41 A monoclonalgammopathy is also frequent in acquired cutis laxa that manifestswith the decreased elasticity of the skin and other tissues due tothe immunoglobulin-mediated breakdown of elastic fibers. Insome patients with g-HCDD, dermal deposition of monoclonal gheavy chains may result in elastic tissue destruction throughcomplement-mediated release of elastases.42,43 Schnitzler syn-drome is defined by the combination of a monoclonal IgM withrecurrent urticarial rash and mild dermal perivascular neutrophilicinfiltrates, without significant immunoglobulin or complementdeposition.44 The IL-1 receptor antagonist anakinra produces adramatic improvement of all manifestations, including fever,fatigue, musculoskeletal pain, and biological markers of inflam-mation, which frequently accompany skin symptoms (Figure 2C-E).Accordingly, Schnitzler syndrome may represent an acquiredcounterpart of hereditary autoinflammatory disorders also char-acterized by skin rashes and recurrent fever, in which IL-1 secretion

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Figure 2. Three different MGCS-associated skinmanifestations. (A) Normolipemic xanthoma with markedperiorbital involvement in a patient with decreased totalcomplement activity (CH50) and serum C4 level sug-gesting classical complement pathway activation by im-mune complexes. (B) Glomeruloid hemangiomata in apatient with POEMS syndrome, likely resulting from theeffects of VEGF on angiogenesis. (C-E) Skin lesions ofSchnitzler syndrome. (C) Typical pseudourticarial aspectpredominantly involving the back. (D-E) Close-up view oflesions of theupper limb in another patient illustrating theefficacy of anakinra and showing initial lesions (D) andnormal aspects (E) of the skin obtained after the firstinjection of the IL-1 antagonist. Skin lesions did not recurafter 2 years of follow-up from diagnosis on continuouslymaintained daily treatment.

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arises from deregulation of the inflammasome.44 Most patientswith idiopathic systemic capillary leak syndrome (Clarkson dis-ease) have a detectable serum MIg, whose role in increasedcapillary permeability and subsequent loss of protein-rich fluid tothe interstitial space is unclear.45 A monoclonal gammopathy(usually an IgGk) is often associated with TEMPI syndrome, whichincludes telangiectasias, erythrocytosis with elevated erythro-poietin levels, perinephric-fluid collections, and intrapulmonaryshunting.46 The efficacy of the proteasome inhibitor bortezomibsupports a causal role of the gammopathy.47 Similar therapeuticdata suggest a relationship between sporadic late onset nemalinemyopathy and MGUS.48

Diagnostic considerationsThe diagnosis ofMGCS implicates excluding a chance associationbecauseof the high prevalence ofMIg, particularly in the elderly.49

Establishing a causal relationship between monoclonal gamm-opathy and clinical manifestations may depend on the patho-logical demonstration of MIg deposition in the affected tissue ororgan. Immunohistological techniques using antibodies specificfor LC isotypes and, when appropriate, IgG subclasses should beused to demonstrate that immunoglobulin deposits match thecirculating MIg. Pathological studies may require electron mi-croscopy, which allows for proper characterization of the ultra-structural organization of immunoglobulin deposits.7 Importantly,the diagnosis of AL amyloidosis requires not only Congo redstaining of a biopsied tissue but the demonstration of theimmunoglobulinic nature of the fibrils using immunohistochem-istry and, eventually, immunoelectron microscopy or mass spec-trometry.8 This is necessary to exclude the coincidental associationof a monoclonal gammopathy with a late-onset hereditary formof amyloidosis or the wild-type transthyretin (senile cardiac am-yloidosis). Indeed, approximately one-quarter of patients withsenile amyloidosis (usually elderly males) present with a MIg.50

For the diagnosis of a MIg-mediated immune process, a high titerof autoantibody activity is important. The specificity of the MIgshould be defined and correlatedwith clinical data. In IgM-mediatedneuropathies, sensitive immunoblotting or enzyme-linked immuno-sorbent assays are usually required, since the monoclonal IgM maytarget hidden epitopes of nerve glycolipids or glycoproteins.22,23

Measurement of serum complement levels is often useful. LowCH50and C4 levels suggest activation of the complement classicalpathway by immune complexes, as in type II cryoglobulinemia andxanthomatosis, or by MIg aggregates, as in type I cryoglobulinemia.In g-HCDD, activation of the classical pathway is also common, fa-vored by partial deletion of the constant domain.51 Low C3 levelssuggesting CAP activation may be observed in C3G and thromboticmicroangiopathy associated with MIg.32

For conditions of unknown mechanism, the link with the associ-ated MIg is primarily suggested by epidemiological data. InSchnitzler syndrome and scleromyxedema, the association is sofrequent that the presence of MIg contributes to defining thedisease.40,44 Additionally, in scleromyxedema, the monoclonalIgG shows characteristic slow electrophoretic mobility.52 In allsituations where the pathogenic role of the MIg is questionable,comparison of V gene usage may be helpful for documentingcommon antibody reactivity.36 Even if epidemiologic and im-munological data suggest a relationship, the pathogenic role ofthe MIg remains putative, since the secreting B-cell clone may

have developed secondarily to the associated condition. Thus,in primary hyperparathyroidism, an association with monoclonalgammopathy has been reported and the emergence of theplasma cell clone in response to parathormone-induced IL-6 se-cretion has been hypothesized.53 Finally, clinical evidence maycorroborate a causal link when therapeutic measures targetingthe MIg or the secreting B-cell clone are effective, as in C3G,32

TEMPI syndrome,47 nemaline myopathy,48 and scleromyxedema.54

Treatment considerationsIndication for therapy in MGCS is driven by organ damage dueto the secreting clone, even though it would not have requiredany therapy per se. Currently, targeting this small “dangerous”B-cell clone relies upon anti–B-cell/plasma cell agents, includingmonoclonal antibody and, in selected cases, local irradiation.5

Treatment decisions should be made using a benefit-to-riskapproach while considering involved organs and natural dis-ease history. No one would question giving polychemotherapyor even high-dose therapy with autotransplantation to a patientwith MGCS and AL amyloidosis. In contrast, these therapeuticoptions are rarely used in patients with MGCS and a slowlyprogressive skin disorder.

Although treatment strategy should aim at producing the besthematological response, it should be also tailored to patient’s riskfactors, as illustrated by AL amyloidosis.8 If the clone is plasma-cytic, secreting a monoclonal IgG, IgA, or LC, then treatmentshould be basedon anti-MMagents.56 The current strategymainlyrelies on repeated courses of bortezomib, usually combined withan alkylating agent and dexamethasone (eg, theCyborD regimen)that produces rapid and deep hematological response. In addi-tion, bortezomibdoes not require dose adaptation in patients withimpaired renal function.55 In case of relapsing or refractory dis-ease, immunomodulatory drugs should be considered. Anti-CD38monoclonal antibodies, which are highly effective in symptomaticMM and currently being evaluated in AL amyloidosis,57 are likelyto be increasingly used in the treatment of various MGCS.

If the clone is lymphoplasmacytic or corresponds to chroniclymphocytic leukemia or B-cell lymphoma, then treatmentmust be adapted accordingly, usually based on an anti-CD20monoclonal antibody. When lymphoplasmacytic and associatedwith an IgM, the clone should be treated similarly to WM.58 Theplace of Bruton tyrosine kinase inhibitors and other non-conventional new agents remains to be assessed.58,59 Of note,whereas an anti-CD20 monoclonal antibody is appropriatein IgM-related disorders, particularly symptomatic type II cryo-globulinemia,60 it is not indicated for treating a plasmacyticclone, whose cells are usually CD20 negative.

Treatment management relies on the assessment of hematologicalresponse by serial measurement of the pathogenic MIg, mostcommonly its LC.55 Repeat evaluation of involved serum free LCis crucial in AL amyloidosis and LCDD, since the quality of thehematological response conditions organ response and patientsurvival.8,61 Why this correlation is less clear in anti-MAG IgM-associated polyneuropathy remains to be determined.22 However,achievement of the best hematological response is the goal oftreatment and themain criterion for determining its optimal duration.

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Besides targeting the pathogenic clone, other strategies can beconsidered, depending on each MGCS type. In MGCS due totissue deposition, particularly AL amyloidosis, potential clearanceof already deposited MIg material is currently under investigationbased on therapeutic monoclonal antibodies against amyloidconformational neoepitope or serum amyloid P component

High-dose IV immunoglobulins are sometimes proposed as analternative to chemotherapy, although their efficacy is nearly alwaystemporary. Long-term treatment may maintain benefit, but avail-ability, cost, and side effects (including renal toxicity) are concerns.Mechanisms of action may involve the inhibition of autoantibodyactivity, complement deviation, and cellular response.62 IV immu-noglobulinsmay be effective in someMGCSof autoimmune origin,such as anti-ganglioside IgM-associated polyneuropathy, but notin others (including anti-MAG polyneuropathy).23 Systemic capillaryleak syndrome63 or scleromyxedema40 may be improved, arguingin favor of an autoimmune activity of the MIg.

ConclusionThe evaluation of any MIg discovered by chance should bebased on a clinical approach, including careful clinical exam-ination and analysis of proteinuria. Conversely, searching for aMIg is justified in the presence of a wide range of manifesta-tions. These approaches may lead to the identification of asmall dangerous B-cell clone requiring aggressive therapybecause of its potentially devastating consequences. To clearlydistinguish this clonal disorder from an asymptomatic indolentgammopathy “of undetermined significance,” we introducethe concept of MGCS, thus extending the already established

concept of MGRS. Relevant situations should be recognizedby combining the term MGCS with disease characterization,introducing, for instance, the terminology “AL amyloidosis-related MGCS” or “cryoglobulinemia-related MGCS” to sep-arate these conditions from “MMwith AL amyloidosis” or “WMwith cryoglobulinemia.” Because of its therapeutic implications,MGCS must be considered as a separate entity within the spec-trum of monoclonal gammopathies.

AuthorshipContribution: All authors participated in the conception and in the writingof the manuscript.

Conflict-of-interest disclosure: The authors declare no competing fi-nancial interests.

ORCID profiles: F.B., 0000-0002-2005-8424; A.D., 0000-0001-8780-9512; A.J., 0000-0001-7091-8253; R.A.K., 0000-0003-4763-4580; N.L.,0000-0003-3532-4606; G.M., 0000-0001-7680-3254.

Correspondence: Jean-Paul Fermand, Division of Immuno-Hematology,Hopital Saint-Louis, 1 Ave Claude Vellefaux, 75010 Paris, France; e-mail:jpfermand@yahoo.fr.

FootnotesSubmitted 13 April 2018; accepted 22 June 2018. Prepublished online asBlood First Edition paper, 16 July 2018; DOI 10.1182/blood-2018-04-839480.

There is a Blood Commentary on this article in this issue.

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