Skin reaction with Eosinophilia and Systemic Symptoms after lenalidomide in peritoneal Dialysis


The Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a fatal and immune-mediated idiosyncratic drug reaction, with symptoms of fever, skin eruptions (that involves more than half of the body surface), facial oedema and hematological disorders, all presenting within the latent period following drug intake. Effects can also be seen on multiple organs, most notably hepatitis in liver and acute interstitial nephritis in kidney, generally post-administration of allopurinol. The European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) classifies the DRESS Syndrome cases as “definite”, “probable” or “possible”, based on clinical and laboratory features. Different pathogenetic mechanisms have been involved in this disease, including immunological reactions and HHV-6 reactivation. In our experience, a 72-year-old male, affected by myeloma in peritoneal dialysis, developed a rare case of DRESS syndrome after lenalidomide administration (less than ten cases are known) with HHV-6 reactivation. According to literature, we withdrew the drug and gave methylprednisolone 0,8 mg/kg orally and IVIG 1 gr/kg for two days. Despite this therapy, DRESS syndrome relapsed during steroid taper with rash, thrombocytopenia, hepatitis and high troponin level. A single cycle of intravenous immunoglobulin 0,5 g/kg for four days was enough for syndrome remission. Only few cases are reported in literature, but because of the increasing use of lenalidomide and the autoimmune sequelae of DRESS syndrome, a broad workup and a multidisciplinar careful approach could help in diagnosis, treatment and follow-up.

Keywords: eosinophilia, systemic drug reaction, DRESS Syndrome, interstitial nephritis, multiple myeloma, Lenalidomide


Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a rare, immune-mediated idiosyncratic and fatal drug reaction, characterized by a latent period after intake of the inciting drug (2-6 weeks). Other signs and symptoms are fever higher than 38,5°C, skin eruptions, eosinophilia (in 66-95% of patients), mononucleosis-like atypical lymphocytes (27-67% of patients), thrombocytopenia, lymphadenopathy (in 54% of patients), and multiple organ involvement. The prevalence ranges from 1:1000 to 1:10000 of drug exposures; mortality has been estimated to be up to 10% because of myocarditis and liver failure [1]. It is difficult to pinpoint the exact moment at which the organ damage and blood alterations occur, except in the cases of already hospitalized patients [2]. Generally, the rash covers more than half of the body surface. Cutaneous lesions have polymorphic presentations: maculopapular, urticarial, exfoliative, lichenoid, pustular, bullous, target-like or eczema-like lesions. The facial oedema (found in 76% of patients) is the hallmark feature of the disease. In 50-60% of patients, two or more organs are affected, most frequently liver (hepatomegaly, hepatitis with ALT> 2 times and ALP> 1,5 times the upper limit), kidney (acute interstitial nephritis, most often induced by allopurinol) and lung (interstitial pneumonia). Cardiovascular involvement occurs lately (up to four months after recovery) with myocarditis, decreased LV function and elevated troponin [3]. The nomenclature of this syndrome has significantly evolved over the last 80 years. The current name, DRESS, as defined in 1996 by Bocquet et al [4], but in the past it was named “drug induced pseudolymphoma”, “anticonvulsant hypersensitivity syndrome” and “drug induced hypersensitivity syndrome” (DIHS). This syndrome requires a high index of suspicion by clinicians and exclusion of infectious, inflammatory, autoimmune and neoplastic conditions, besides other similar cutaneous drug reactions. DRESS syndrome could have long-term sequelae like the development of autoimmune disease, including thyroiditis, diabetes mellitus type I and systemic erythematosus lupus [5]. These manifestations can occur early, like in our patient, to years following the initial episode. There is no pathognomonic sign or diagnostic test for DRESS. The leucocyte transformation/activation test (LAT) measures T cells response to a drug. It lacks of sensitivity, but a positive LAT is useful to confirm the diagnosis, because of very low false positive results (only 2%) [6, 7]. Confirmation or exclusion of DRESS syndrome diagnosis is based on clinical and laboratory features. The European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) classifies the cases as “definite”, “probable” or “possible”.


Case Report

A 72-year-old male, affected by end-stage kidney disease (ESKD) because of nephroangiosclerosis and ischemic nephropathy in peritoneal dialysis, was diagnosed with micromolecular multiple myeloma kappa in June 2019. In November he stared lenalidomide 5 mg days 1-21 in 28-days cycle without steroids because of his comorbidities. The patient suffered from hypertension, ischemic cardiomyopathy with reduced ejection fraction of 25% (he had two NSTEMI, the last in March 2019), and chronic kidney disease for about six years and started automated peritoneal dialysis in March 2019.

After 18 days of therapy with lenalidomide, he presented a violet maculopapular rash covering more than 50% of his body, fever (38,5 °C), and leukopenia with negative C-reactive protein. Lenalidomide was withdrawn and oral steroid with anti-histamine were administered. One week later he was admitted to our Nephrology Unit for a syncopal episode. Laboratory tests revealed leukocytosis (white blood cells were 12250/mm3), eosinophilia (until 56%, 4550/mm3), and cholestatic-cellular liver damage (ALT 1448 U/l, ALP 308 U/l) requiring albumin infusion. In suspicion of a hidden infection, blood/peritoneal cultures and viral/bacterial tests were performed and a broad-spectrum empirical therapy was prescribed. In the absence of liver and vascular abnormalities during an ultrasound abdominal study, an autoimmune workup was performed: ANA, ANCA, SMA, LKM, AMA were negative. Blood markers of HBV, HCV and herpetic viruses were negative, except for Human herpes virus 6 (HHV-6) reactivation with 420 copies/ml. Because of the persistence of the rash, the patient underwent a skin biopsy, that demonstrated sparse vacuolization of epidermis and dermal-epidermal inflammation with some eosinophils and CD8+ T cells, suggesting a drug reaction (shown in Figures IA and IB).

Histopathological examination of the skin biopsy specimen revealing hyperkeratosis, spongiosis.
Figure IA: Histopathological examination of the skin biopsy specimen revealing hyperkeratosis, spongiosis, dermis swelling and chronic perivascular inflammation with some eosinophils. IB: Immunohistochemical examination revealing CD8+ T cells dermal-epidermal infiltration, suggesting a drug reaction.

For clinical, laboratory and pathological features, according to RegiSCAR score system this case has been evaluated as “definite DRESS” with score 6, because of rash, eosinophilia and liver damage. We started intravenous immunoglobulin 1 g/kg for 2 days and oral methylprednisolone with reduced dose for comorbidities (50 mg/die for 0,8 mg/kg daily). After one week the patient had fully recovered and was discharged home with methylprednisolone 37,5 mg/die (for 0,6 mg/kg). Seven days after discharge, the patient showed a pruritic rash. Laboratory tests showed elevated ALT, AST and troponin (until 330 ng/l) and thrombocytopenia (platelets 50.000/mm3). HHV-6 was undetected. Hospital admission was not necessary and an outpatient follow-up was started. Because of the high risk of late onset of myocarditis with elevated troponin, we performed an electrocardiogram (normal) and an echocardiogram that showed a low ejection fraction like the previous. Despite the clinical suspicion, heart magnetic resonance imaging (MRI) ruled out this complication. Most likely, the elevation of troponin was related to an increased hydro-saline retention, which was responsive to the enhancement of peritoneal dialysis treatment. Taking into account the renal failure, the chronic ischemic heart disease and the DRESS syndrome relapse, we treated the patient with only intravenous immunoglobulin (IVIG) 0,5 g/kg for four consecutive days with clinical and laboratory benefits. After recovery, a multiple myeloma second-line therapy with orally Cyclophosphasmide 300 mg once weekly and prednisone 25 mg/die was started, but it was interrupted two weeks later because of melena and clinical worsening. Sixteen weeks after discharge the patient is still alive, he undergoes nephrological/hematological outpatient visits twice a week and receives palliative therapy. Liver tests and troponin levels are normal.



DRESS syndrome is an idiosyncratic hypersensitivity reaction to a medication. Mortality has been estimated to be up to 10% because of myocarditis and liver failure. Renal involvement is usually secondary to liver (about 11-28% of patients); renal damage could be related to interstitial nephritis or to acute tubular necrosis, but sometimes the patient could develop vasculitis with renal failure. Sometimes patients need short-term or long-term hemodialysis. In a survey conducted by Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR) on 145 patients affected by DRESS syndrome [5], four of them with underlying diseases (IgA nephritis, renal disease and chronic renal failure) developed end-stage renal disease and culprit drug was allopurinol in two cases. 24 patients with Drug-Induced Hypersensitivity Syndrome were evaluated in a French study [8]: 11 patients on 24 (46%) were immunocompromised, the median latency time of onset was 15 days and myocarditis appeared in several cases with hypotension. Our patient developed these features and the suspicion of late myocarditis was very high because of troponin elevation, low cardiac ejection fraction and severe clinical impairment; however cardiac MRI showed that it was secondary to hyperhydration and previous cardiac disease. Furthermore, several studies suggest that myocarditis is often underestimated, because it needs a post-mortem histopathologic examination. The pathogenic bases of DRESS syndrome are still unclear. Some authors suggest that drug reactive metabolites, secondary to detoxification defect, could stimulate a delayed immunological reaction mediated by CD-8 T-lymphocyte and eosinophil degranulation; interestingly, the medication could also trigger viral reactivation, usually HHV-6. Cacoub et al reported 172 cases of DRESS: the most frequent “trigger-drugs” were carbamazepine, allopurinol, sulfasalazine, phenobarbital, nevirapine, and HHV-6 reactivation was positive in 80% of studied cases [9].

Generally, patients affected by DRESS syndrome develop renal complications presenting with creatinine elevation, sterile pyuria and sometimes with proteinuria and hematuria [10]. In our experience it was not possible to identify renal involvement, because our patient was already treated with peritoneal dialysis. Genetic predisposition to DRESS syndrome has been demonstrated: HLA-B*5801 in Chinese population treated with allopurinol is associated to kidney involvement in DRESS syndrome [11]. A French study [8] highlighted that 20 of 24 patients developed DIHS during winter, as our case, and that 75% of them had low level of Vitamin D. It is widely known that the nephrological population has chronic Vitamin D deficiency and that it has anti-inflammatory properties, so we can believe that it could be a risk factor for our patients treated with “trigger” drugs. Nevertheless, assessing clinical features of patients affected by DRESS syndrome described in literature, chronic kidney disease does not represent a risk factor for this syndrome (shown in Table 1).

Cacoub et al [9] Mona Ben m’rad et al [8] Kano Y et al [5]    Avancini J et al [15]
Number of patients 172 24 145 27
Age (years) 40,7 ± 20,9 50,4 ± 17,1 51 ± 18,8 36 ± 16,4
Male 53 % 50 % 40,7 % 62,9 %
Onset weeks (mean) 3,9 ± 2,3 2 5,6 ± 5,3
Liver involvement 94 % 54 % 85,2 % (23 patients)
Kidney involvement 8 % 17 % HD in 4 patients with pre-existing renal disease 33,3 % (9 patients)
Cases resulting in death 5,2 % 0 % 3,7 % (1 patients)
Autoimmune sequelae 23,4 % (34 patients)
Table 1: Comparison of clinical features and outcomes of patients affected by DRESS syndrome observed in four different mentioned studies. HD: chronic hemodialysis.

As described by Vlachopanos [12], DRESS syndrome after receiving Lenalidomide for multiple myeloma in people in renal replacement therapy has a very unfavorable course. According to literature (Table 2), the culprit drug should be withdrawn and, in cases of visceral involvement, systemic steroids are indicated (oral methylprednisolone 1 mg/kg/die with slow taper over 3-6 months). Rapid tapering is associated with relapse, like in our patient, and the benefit of antiviral medications is unclear. In severe and corticosteroid-resistant cases, other immunosuppressant medications including cyclosporine, azathioprine, and mycophenolate have been used, sometimes alongside adjunctive treatment with IVIG and plasmapheresis [13, 14]. In our experience IVIG has been a good ally to control DRESS syndrome relapse.

Primary disease Age Medical history Therapy Time after LND Virus Systemic involvement Treatment Reference


IgG kappa

65 years UN LND 25 mgA – DXSB 6 weeks No AIN


PS 80mg Shaaban H. et al [16]


IgG lambda

75 years Diabetes mellitus

hypertension heart failure

CKD stage III

LND 5 mgA – DXSB 4 weeks UN Acute on CKD MPSL 80 mg Shanbhag A. et al [17]
MM 78 years Hypertension

Diabetes mellitus

LND 25 mgA 4 weeks HHV-6 AKI


PS 20mg Foti C. et al [18]
MM 62 years CKD on hemodialysis LND 5 mgA 5 days UN Non erosive oropharyngeal  mucositis dysphagia PSL Vlachopanos G. et al [12]
MM 59 years UN Bortezomib-DXSB-LND 5-6 weeks HHV-6


None PS 20 mg/die Osada S. et al [19]


IgA lambda

67 years UN Carfilzomib-DXS-

LND 25 mgA

7 weeks CMV Hepatitis PSL 1mg/kg/die Relapse: IVI

G 0,5 g/kg/die for 4 days

Gajewska M. et al [20]
Table 2: Summary of lenalidomide-induced DRESS syndrome described in literature. Comparison of clinical features, multiple myeloma therapy, organ involvement of DRESS syndrome, virus reactivation and therapy.
Abbreviations: Multiple Myeloma: MM; Lenalidomide: LND; Dexamethasone: DXS; Prednisone: PS; Methylprednisolone: MPSL; Prednisolone: PSL; Unavailable: UN. A: Lenalidomide 25 mg/die on days 1-21 in 28-days cycle. B: Dexamethasone 40 mg/die once a week in 28-days cycle.


  1. The variety of drugs, the clinical course with slow resolution and relapse and HHV-6 reactivation suggest that drugs cannot be the sole etiology of DRESS.
  2. Drugs with immunomodulatory activity or immunosuppression could contribute to the hypersensitivity reaction of DRESS syndrome.
  3. Few cases of DRESS syndrome in end-stage kidney disease are reported in literature, but because of the increasing use of drugs and its several autoimmune sequelae, a broad workup and a multidisciplinary careful approach could help in diagnosis, treatment and follow-up.
  4. Patients affected by chronic kidney disease may develop renal failure if DRESS Syndrome is complicated by severe acute interstitial nephritis or vasculitis.
  5. Therapy: oral methylprednisolone 1 mg/kg/die with slow taper over 3-6 months; quick taper encourages relapse, which could be treated only with IVIG 0,5 g/kg for 4 days.



  1. Tennis P, Stern RS. Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study. Neurology 1997; 49:542.
  2. Cho YT, Yang CW, Chu CY. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System. Int J. Mol Sci 2017, 18, 1243.
  3. James J, Sammour Y M, Virata A R, Nordin TA, Dumic I. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome Secondary to Furosemide: Case Report and Review of Literature. Am J Case Rep. 2018 Feb 14;19:163-170.
  4. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg. 1996 Dec;15(4):250–7.
  5. Kano Y et al. Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR). J Dermatol 2015 Mar;42(3):276-82.
  6. Mori F, Caffarelli C, Caimmi S et al. Drug reaction with eosinophilia and systemic symptoms (DRESS) in children. Acta Biomed. 2019; 90(Suppl 3): 66–79.
  7. Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy 2004 Aug;59(8):809-20
  8. Ben m’rad M, Leclerc-Mercier S, Blanche P, Franck N, Rozenberg F, Fulla Y, et al. Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients. Medicine (Baltimore). 2009 May;88(3):131-40.
  9. Cacoub P et al. The DRESS Syndrome: a Literature review. The American Journal of Medicine, Vol 124, No7, July 2011.
  10. Isaacs M, Cardones AR, Rahnama-Moghadam S. DRESS syndrome: clinical myths and pearls. Cutis. 2018 Nov;102(5):322-326.
  11. Martínez-Cabriales SA, Rodríguez-Bolaños F, Shear NH. Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS): How Far Have We Come? Am J of Clin Dermatol volume 20, pages 217–236 (2019).
  12. Vlachopanos G, Kokkona A, Zerva A, Stavroulaki E, et al. A. Atypical DRESS Syndrome Induced by Lenalidomide in Chronic Hemodialysis J Clin Exp Pathol 2016, 6:3
  13. Joly P, Janela B, Tetart F, et al. Poor benefit/risk balance of intravenous immunoglobulins in DRESS. Arch Dermatol 2012; 148:543.
  14. Singer EM, Wanat KA, Rosenbach MA. A case of recalcitrant DRESS syndrome with multiple autoimmune sequelae treated with intravenous immunoglobulins. JAMA Dermatol 2013; 149:494.
  15. Avancini J, et al. Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome: clinical features of 27 patients. Clin Exp Dermatol. 2015.
  16. Shaaban H. et al. A case of DRESS (drug reaction with eosinophilia and systemic symptoms) with acute interstitial nephritis secondary to lenalidomide. Oncol Pharm Pract. 2014 Aug;20(4):302-4.
  17. Shanbhag A. et al. Highly Probable Drug Reaction With Eosinophilia and Systemic Symptoms Syndrome Associated With Lenalidomide. Hosp Pharm. 2017 Jun;52(6):408-411.
  18. Foti C. et al. Drug reaction with eosinophilia and systemic symptoms caused by lenalidomide. Eur J Dermatol. Nov-Dec 2012;22(6):799-800.
  19. Osada S. et al. Drug-induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms Caused by Lenalidomide: Case Report and Review of the Literature. Acta Derm Venereol. 2021 May 28;101(5):adv00468.
  20. Gajewska M. et al. DRESS syndrome after KRd (carfilzomib, lenalidomide, dexamethasone) therapy in a patient with multiple myeloma. Pol Arch Intern Med. 2021 Oct 27;131(10):16056.

Multiple myeloma, plasma cell dyscrasias and kidneys: a few symptoms, extensive damage


Multiple myeloma represents one of the main universal oncological diseases. Due to its clinical characteristics, it is often diagnosed only too late, when it has already determined systemic effects; this results in greater therapeutic difficulty and worse prognostic results. Through the clinical case discussed in this article, we want to focus on the often aspecific manifestations of this pathology and on the need for a correct clinical and diagnostic framework. The main renal manifestations secondary to the deposition of immunoglobulins in both the glomerular and tubular areas will also be examined.

Keywords: AKI, multiple myeloma, plasma cell dyscrasias, kidney injury

Sorry, this entry is only available in Italian.


Il mieloma multiplo (MM) è una patologia che rientra nel gruppo delle neoplasie ematologiche associate a discrasie plasmacellulari (PCD). È la diretta conseguenza di una proliferazione incontrollata di un clone plasmacellulare cui consegue l’anomala produzione di immunoglobuline monoclonali (Ig) o di catene leggere libere (free light chain, FLC) che, una volta eliminate dalla circolazione ematica attraverso l’emuntorio renale, determinano sovente un danno d’organo [1]. Le PCD comprendono uno spettro relativamente ampio di malattie come: il mieloma multiplo, l’amiloidosi AL, il plasmocitoma solitario e la gammopatie monoclonale di incerto significato (MGUS). La distinzione tra le varie forme di mieloma dipende da alcune caratteristiche quali la quantità di proteina monoclonale sierica, la percentuale di plasmacellule nel midollo osseo e la presenza di danno d’organo.

Recentemente è stato introdotto il termine di gammopatia monoclonale a significato renale (MGRS) che sottolinea il ruolo diretto che le immunoglobuline hanno sull’eziopatogenesi del danno d’organo anche in assenza dei criteri necessari per la diagnosi di mieloma multiplo [2].


La visualizzazione dell’intero documento è riservata a Soci attivi, devi essere registrato e aver eseguito la Login con utente e password.

A case of AL amyloidosis with fulminant evolution


Amyloidosis represents a heterogeneous group of pathologies characterized by the deposit, in the form of fibrils, in the various organs and tissues of the body, of abnormal proteins; the deposits made up of these fibrils are called amyloid or amyloid substance. AL amyloidosis, also called “light chains”, is a primary form characterized by deposits of light chains of monoclonal immunoglobulins, proteins that are produced by the bone marrow with the aim of protecting the body from pathological processes; for unknown reasons, these immunoglobulins, once fulfilled their function, do not dissolve but, on the contrary, they transform into amyloid fibrils and accumulate progressively, transported by the bloodstream, in the various organs and tissues. Below we report the case of a 77-year-old Caucasian male patient hospitalized at our Operative Unit for nephrotic syndrome and creatinine increase in the last couple of months, compared to previous normal tests. The patient underwent a renal biopsy and a bone marrow smear with evidence of AL amyloidosis (or primary amyloidosis) and of the presence, at serum immunofixation, of small IgG multiple myeloma k. Treated with bortezomib (1 mg/m2) and soldesam (10 mg) first and with lenalidomid after, the patient had a clinical course burdened by symptomatic hypotension, due to severe dysautonomia. He had to start replacement treatment with haemodiafiltration for terminal kidney disease two months after the onset of illness. He died 4 months after the first hospitalization for nephrotic syndrome.


Keywords: AL amyloidosis, multiple myeloma, renal failure, haemodiafiltration

Sorry, this entry is only available in Italian.


L’amiloidosi è una patologia caratterizzata dal deposito di una proteina con ripiegamento beta-shift. Attualmente si conoscono circa 30 tipologie di amiloidosi, ereditarie o meno, classificate in base ai segni clinici ed alle caratteristiche biochimiche della sostanza amiloide coinvolta [1]. Alcune delle forme più frequenti sono l’amiloidosi AL (amiloidosi da immunoglobuline/catene leggere), l’amiloidosi AA (infiammatoria/reattiva) e l’amiloidosi ATTR (da accumulo di transtiretina).

L’amiloidosi AL (o amiloidosi primaria) è la forma più comune, con un’incidenza di circa 0,8 casi ogni 100.000 abitanti per anno, ed anche quella con la prognosi peggiore. In questa variante della malattia, il cosiddetto “clone amiloidogeno” è rappresentato da frammenti delle catene leggere delle immunoglobuline (anticorpi dalle plasmacellule midollari, cellule linfoidi giunte a maturazione in grado di sintetizzare immunoglobuline) che formano fibrille le quali si depositano nei tessuti. In questo caso, l’amiloidosi rientra nelle “discrasie plasmacellulari” ed è una patologia che si può manifestare con una grande varietà di segni e sintomi che dipendono dagli organi colpiti [2]. Può presentarsi come patologia isolata o in associazione con il mieloma multiplo. Gli organi più frequentemente coinvolti dal deposito delle fibrille sono il cuore (nel 75% dei pazienti), i reni (nel 65% dei casi), l’apparato gastrointestinale, il fegato (20%), la cute, i nervi periferici che trasmettono la sensibilità dai piedi e dalle mani e quelli che regolano la pressione arteriosa (20%) e gli occhi.

Molto utile alla determinazione della sopravvivenza dei pazienti affetti da amiloidosi AL può risultare la misurazione di biomarkers di danno cardiaco quali i peptidi natriuretici, ovvero la porzione amino-terminale del peptide natriuretico di tipo B (NT-proBNP) e delle troponine cardiache (cTn) [34].

I sintomi che possono far sospettare un’amiloidosi sono numerosi ed alcuni sono tipici della malattia: una proteinuria fino alla sindrome nefrosica, disturbi del ritmo cardiaco per infiltrazione del sistema di conduzione, ipertrofia del ventricolo sinistro con ispessimento ed irrigidimento delle pareti ventricolari e del setto interatriale, ipotensione ortostatica, sincope, vertigini, epatomegalia senza cause apparenti, polineuropatia, sindrome del tunnel carpale, porpora periorbitale (per fragilità capillare dovuta a deposito vascolare di amiloide), macroglossia. La comparsa di stanchezza e dimagramento inspiegabili è un sintomo frequente nel paziente con amiloidosi [59].

Le terapie impiegate nell’amiloidosi AL sono atte a contrastare le plasmacellule che producono la paraproteina e si basano su combinazioni di diversi farmaci [10].  

Per i pazienti giovani, con condizioni generali buone è possibile eseguire l’autotrapianto di cellule staminali, una procedura che si avvale di chemioterapia ad alta dose, che elimina tutte le cellule del midollo osseo, che viene poi ricostituito grazie alle cellule staminali del paziente, prelevate in precedenza e crioconservate [11].

Tra i farmaci usati nel trattamento dell’amiloidosi AL spicca l’azione di due classi: l’inibitore del proteasoma, bortezomib e gli immunomodulatori, derivati dalla talidomide, lenalidomide e pomalidomide.

Negli ultimi anni si è affermato anche il ruolo dell’immunoterapia con anticorpi monoclonali antiCD-38, diretti contro le plamascellule, come il Daratumumab.

Il proteasoma è un complesso multiproteico presente in tutte le cellule dell’organismo, con il ruolo di degradare i polipeptidi all’interno della cellula. La sua inibizione porta ad un arresto del ciclo cellulare ed alla morte per apoptosi. Tra gli effetti collaterali degli inibitori del proteasoma vi è la riattivazione dell’Herpes Zoster, la neuropatia periferica, la leucoencefalopatia multifocale progressiva (PML), l’ipotensione ortostatica, l’insufficienza cardiaca [1216].


Caso clinico

Riportiamo un caso di un paziente 77enne, di razza caucasica, con una storia anamnestica di cardiopatia ischemica all’età di 62aa e di TIA nel 2010, iperteso in terapia con amlodipina 5 mg, ramipril 5 mg ed amiloride/idroclorotiazide 2.5/25 mg. Nel luglio 2012 tumore corde vocali trattato con radioterapia.

Nel dicembre 2018 si ricovera per alcuni giorni, dal 22 al 31, presso la nostra unità di Nefrologia per inquadramento clinico-diagnostico in funzione di una proteinuria significativa allo spot urinario (2.6 g/l), edemi declivi, ipertensione; all’ingresso si mette in evidenza un aumento della creatinina (1.4 mg/dl) che fino ad allora era sempre stata nella norma (creatinina di 1 mg/dl all’ultimo controllo del novembre 2018). Un’ecocardiogramma di fine dicembre 2018 mostrava un ventricolo sx di normali dimensioni, con lieve ipertrofia settale ed acinesia inferiore basale; funzione contrattile globale discretamente conservata (FE 55%). Nel corso della degenza è emersa una sindrome nefrosica (9.7 gr/24h), associata a disprotidemia (proteine totali 50 g/L) e si confermava un deterioramento della funzione renale (creatininemia stabile a 1.4 mg/dl). Abbiamo sottoposto il paziente ad una serie di controlli ematochimici, anche in funzione di una valutazione per eventuale biopsia renale, quali il dosaggio dei markers tumorali per escludere sindromi paraneoplastiche con riscontro di rilevante aumento del Ca125 (641 KU/L) e minimo del Ca 15-3 (33 KU/L), e la batteria autoimmunitaria, in cui emergeva esclusivamente un minimo aumento non rilevante del C3 (2.190 g/l) e C4 (0.550 g/l); anche i markers virali risultavano negativi. Era stato dimesso a fine dicembre 2018 con l’intenzione di approfondire a breve il quadro clinico e con una creatininemia sempre intorno a 1.4 mg/dl e GFR stimato (con formula MDRD) di 52 ml/min.

Dal 14 gennaio al 15 febbraio nuovo ricovero in Nefrologia con una creatininemia all’ingresso di 2.36 mg/dl. Visto l’aumento dei markers tumorali e l’anamnesi positiva per pregressa neoplasia, è stato sottoposto, dopo pochi giorni dall’ingresso e previa premedicazione, a Tac stadiante con mdc con riscontro di “multiple formazioni linfonodali sovra e sottodiaframmatiche nel mediastino superiore, anteriormente alla trachea, in sede ilare bilateralmente, nel retroperitoneo superiore, all’altezza dell’origine del tripode celiaco, con diametro massimo 22 mm. Reni in sede, con spessore parenchimale modestamente assottigliato ed effetto parenchimografico simmetrico. Aumentate di dimensioni due alterazioni ossee osteoaddensanti all’ala sacrale di destra ed all’altezza del II metamero sacrale”. Dal punto di vista laboratoristico, un’immunofissazione sierica evidenziava componente monoclonale IgG kappa <1 g/l.

Il 4 febbraio 2019 veniva sottoposto a biopsia renale con diagnosi di amiloidosi AL (colorazione rosso Congo positiva) (Fig. 1); il frustolo di parenchima renale comprendeva 19 glomeruli di cui 2 scleroialini. Tutti i glomeruli erano caratterizzati da espansione della matrice mesangiale con ispessimento della membrana basale capillare per deposizione di materiale debolmente PAS positivo che in alcuni glomeruli assumeva un aspetto nodulare; nell’interstizio erano presenti foci di infiltrato infiammatorio di tipo linfocitario e plasmacellulare e materiale debolmente PAS positivo con focali aree di atrofia tubulare. Il lume dei tubuli era occupato da voluminosi cilindri ed i vasi di medio e piccolo calibro erano ispessiti per la presenza del materiale debolmente PAS positivo”. L’amiloide non è stata tipizzata con l’immunogold o altro.


Fig. 1: A) (Rosso Congo; 40x) La colorazione rosso Congo mette in evidenza depositi di amiloide attorno ai vasi ed all’interno dei glomeruli (frecce). Questi depositi hanno mostrato dicroismo alla luce polarizzata; B) (Colorazione tricromica; 200x) Amiloide (depositi blu) all’interno del glomerulo (asterisco); C) (PAS; 200x) Amiloide (deposito rosa) all’interno del glomerulo (freccia); D: Amiloide (deposito rosa) attorno ai vasi (freccia).

Era stato anche eseguito uno striscio su sangue midollare con presenza di infiltrato plasmacellulare pari al 10% della cellularità totale, in quadro compatibile con mieloma multiplo ed amiloidosi renale (catene Kappa libere: 379 mg/l; catene lambda libere: 32.90 mg/l; rapporto K/L libere di 11.520 ratio; BJ: 210 mg/l). In quell’occasione la creatinina era aumentata a 2.7 mg/dl, NT-proBNP era 5923 pg/ml e la troponina T di 43.41 ng/l; a fine febbraio 2019 veniva ripetuto un’ecocardiogramma che mostrava un ventricolo sinistro lievemente ipertrofico con pareti isoecogene e contrattilita’ globale normale (FE 55%) e dilatazione biatriale.

Dal punto di vista clinico, durante la degenza si è instaurato un quadro di ipotensione ortostatica ingravescente che ha reso necessaria la sospensione della terapia antipertensiva e la prescrizione di midodrina (30 gtt tre volte al giorno).

Dopo confronto multidisciplinare con oncologo ed ematologo del nostro nosocomio e con il centro di riferimento dell’amiloidosi di Pavia, non sono stati presi in considerazione ulteriori accertamenti strumentali (RMN cardiaca, PET-TAC, biopsia linfonodale) e si è deciso di iniziare, dall’11 febbraio 2019, terapia farmacologica di prima linea, secondo lo schema Vel-Dex: bortezomib (1 mg/m2 sottocute settimanale) e desametasone 10 mg per 2 giorni settimanali, con un ciclo completo eseguito nell’arco di quattro settimane. A questi farmaci abbiamo associato anche l’aciclovir 200 mg due volte al giorno per il noto rischio di riattivazione di herpes zooster. Alla dimissione la funzione renale era ulteriormente peggiorata con una creatininemia di 5.3 mg/dl.

Nel corso del terzo ricovero in Nefrologia, dal 20 febbraio al 29 marzo 2019, si iniziava trattamento emodialitico sostitutivo con emodiafiltrazione [1718] per ulteriore peggioramento della funzione renale (azotemia 160 mg/dl, creatininemia 6.9 mg/dl) ed oligoanuria.

A fine marzo 2019, dopo il primo ciclo di trattamento con Vel/Dex, si assisteva ad un significativo aumento dell’NT-proBNP (2176 pg/ml); peggiorava anche il profilo delle FLC con catene Kappa libere: 627 mg/l; catene lambda libere: 48.40 mg/l; rapporto K/L libere di 12.960 ratio.

Era ancora molto evidente, inoltre, il quadro di ipotensione ortostatica, ulteriormente aggravato dalla terapia con bortezomib, il cui dosaggio, anche in accordo con il centro di riferimento di Pavia, veniva ridotto a 0.7 mg/m2.

Dal punto di vista laboratoristico si manifestava aumento dei valori delle FLC con catene Kappa libere di 771 mg/l, catene lambda libere di 81.8 mg/l ed un rapporto K/L libere di 14.210 ratio.

Durante tutto il decorso della malattia non si sono registrati miglioramenti nei livelli dei biomarkers misurati (pro-BNP, troponina T, catene leggere libere circolanti) (Tabella 1).


  GENNAIO 2019 MARZO 2019 APRILE 2019
pro-BNP (v.n. <100 pg/ml) 5923 21176 20267
S-Kappa lib. (v.n. 3,30 – 19,40 mg/l) 379 627 771
S-Lambda lib. (v.n. 5,71 – 26,30 mg/l) 32.9 48.4 81.8
S-rapporto K/L lib. (v.n. 0,300 – 1,200 ratio) 11.520 12.960 14.200
S-TnT (v.n. 0,00 – 14,00 ng/l) 43.41 80 190
Tabella 1: Andamento temporale livelli ematici biomarcatori di Amiloidosi AL

Concluso il primo ciclo di Vel/Dex, su indicazione dello specialista ematologo, si sospendeva il trattamento con bortezomib, già a dosi ridotte, e si intraprendeva trattamento con lenalidomide 5 mg/die, associato al desametasone. Dopo una settimana dall’inizio della terapia con lenalidomide il paziente è deceduto per arresto cardio-circolatorio, a distanza di quattro mesi dall’esordio di malattia.



L’amiloidosi AL fa parte di un gruppo eterogeneo di patologie caratterizzate dall’accumulo di materiale proteico fibrillare, definito amiloide. È una malattia rara e difficile da diagnosticare perché spesso si presenta con sintomi aspecifici e, a differenza del mieloma multiplo, del quale condivide alcuni schemi terapeutici, non è solo una neoplasia ematologica ma può presentare un danno funzionale multiorgano che espone i pazienti ad una maggiore tossicità delle terapie farmacologiche [1921].

L’obiettivo principale della terapia dell’amiloidosi AL è quello di rallentare o arrestare la produzione della proteina che causa il danno degli organi coinvolti; sulla prognosi della malattia incide non soltanto il tipo di terapia utilizzata ma anche il monitoraggio di biomarcatori (proBNP, FLC, cTn) che possano rendere il più precoce possibile la diagnosi e contribuire positivamente all’outcome stesso.

La terapia farmacologica dell’amiloidosi AL si avvale di varie strategie che tengono conto anche della stratificazione dei pazienti affetti da amiloidosi a seconda del basso, medio ed alto rischio (Tabella 2) [22]; il trapianto autologo di cellule staminali periferiche, associato ad alte dosi di melphalan, è considerato il trattamento più efficace nei pazienti a basso rischio, con età inferiore a 65 anni, con normale troponina cardiaca, frazione di eiezione ventricolare > 45%, PAS >90 mmHg, clearance della creatinina > 50 ml/min [23].


Tabella 2: Stratificazione del rischio clinico nei pazienti con amiloidosi AL (relative al centro di riferimento nazionale delle amiloidosi di Pavia) [20]

L’associazione di melphalan e desametasone (MDex) o la combinazione di ciclofosfamide, thalidomide e desametasone (CTD) ha mostrato gli stessi risultati del protocollo precedente ma con una tossicità minore.

I pazienti con malattia avanzata, e ad alto rischio, possono giovarsi di un trattamento di prima scelta definito dalla combinazione dell’inibitore del proteosoma, bortezomib, con il  desametasone (Vel/Dex), protocollo che migliora la sopravvivenza dei pazienti con insufficienza cardiaca sintomatica [2426], come confermato da una metanalisi del 2019, in cui veniva posto l’accento sull’efficacia, tra le varie associazioni di terapie, del protocollo Vel/Dex sulla remissione completa [27].

I farmaci appartenenti alla categoria degli IMiDs (immunomodulatori) hanno trovato un loro spazio come rescue therapy nell’amiloidosi AL. A questa categoria appartengono la thalidomide, lenalidomide e pomalidomide; essi vengono riservati ai pazienti con recidiva di malattia e che non possono essere nuovamente sottoposti a terapie di primo livello. Questi farmaci sono in grado di superare le resistenze agli alchilanti ed all’inibitore del proteasoma e garantiscono, a seconda degli studi, una risposta ematologica tra il 40 ed il 60% [2829].



L’amiloidosi AL rappresenta una patologia che può ancora oggi avere un’evoluzione clinica verso l’exitus. Nella prognosi gioca un ruolo importante sia la diagnosi precoce che l’eventuale interessamento multiorgano.

Nel caso clinico in questione il paziente ha presentato già all’esordio sintomi di interessamento multiorgano (sindrome nefrosica ed insufficienza renale) con successiva insufficienza renale ingravescente richiedente trattamento dialitico; i livelli aumentati di NT- ProBNP, patognomonici di interessamento cardiaco da amilodosi, non correlavano con il dato ecocardiografico e sono rimasti stabilmente elevati anche durante la chemioterapia. L’inizio della terapia con bortezomib e desametasone (schema Vel-Dex) non ha sortito gli effetti sperati ma ha complicato sintomi clinici già presenti, come l’ipotensione ortostatica ingravescente, ed il profilo delle FLC all’immunofissazione sierica è progressivamente peggiorato. L’evoluzione verso l’exitus è stata quasi fulminante, considerando che, in quattro mesi dall’esordio della sindrome, il decesso è arrivato dopo la conclusione del primo ciclo di Vel-Dex e l’inizio della terapia alternativa con lenalidomide.




  1. Comenzo RL. Current and emerging views and treatments of systemic immunoglobulin light-chain (Al) amyloidosis. Contrib Nephrol 2007; 153:195-210.
  2.  Li G, Han D, Wei S, Wang H, Chen L. Multiorgan involvement by amyloid light chain amyloidosis. J Int Med Res 2019 Apr; 47(4):1778-86.
  3. Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal response to chemotherapyin AL amyloidosis. Blood 2014; 124:2325-32.
  4. Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac bio and serum free light chains measurements markers. J Clin Oncol 2012; 30(9):989-95.
  5. Adams D, Suhr OB, Hund E, et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol 2016; 29(S1):S14-S26.
  6. Adams D, Théaudin M, Cauquil C, et al. FAP neuropathy and emerging treatments. Curr Neurol Neurosci Rep 2014; 14(3):435.
  7. Lalande S, Johnson BD. Diastolic dysfunction: a link between hypertension and heart failure. Drugs Today (Barc) 2008; 44(7):503-13.
  8. Rapezzi C, Longhi S, Milandri A, et al. Cardiac involvement in hereditary-transthyretin related amyloidosis. Amyloid 2012; 19(S1):16-21.
  9. Szigeti K, Lupski JR. Charcot-Marie-Tooth disease. Eur J Hum Genet 2009; 17(6):703-10.
  10. Varga C, Titus SE, Toskic D, Comenzo RL. Use of novel therapies in the treatment of light chain amyloidosis. Blood Rev 2019; 37.
  11. Miyazaki K, Suzuki K. Autologous Hematopoietic Cell Transplantation Versus Chemotherapy Alone for Immunoglobulin Light Chain Amyloidosis: A Retrospective Study. Clin Lymphoma Myeloma Leuk 2019 Jul; 19(7):413-22.
  12. Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, et al. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol 2010; 28:1031-37.
  13. Palladini G, Milani P, Foli A, et al. Melphalan and dexamethasone with or without bortezomib in newly diagnosed AL amyloidosis: a matched case-control study on 174 patients. Leukemia 2014; 28:2311-16.
  14. Reece DE, Hegenbart U, Sanchorawala V, et al. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood 2011; 118:865-73.
  15. Venner CP, Gillmore JD, Sachchithanantham S, et al. A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis. Leukemia 2014; 28:2304-10.
  16. Kastritis E, Gavriatopoulou M, Roussou M, et al. Addition of cyclophosphamide and higher doses of dexamethasone do not improve outcomes of patients with AL amyloidosis treated with bortezomib. Blood Cancer J 2017; 7:e570.
  17.  Hutchison CA, Cockwell P, Moroz V, Bradwell AR, Fifer L, et al. High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial. Lancet Haematol 2019 Apr; 6(4):e217-e228.
  18. Machiguchi T, Tamura T, Yoshida H. Efficacy of haemodiafiltration treatment with PEPA dialysis membranes in plasma free light chain removal in a patient with primary amyloidosis. Nephrol Dial Transplant 2002 Sep; 17(9):1689-91.
  19. Palladini G, Merlini G. Current treatment of AL amyloidosis. Haematologica 2009; 94:1044-48.
  20. Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol 2011; 29:1924-33.
  21. Merlini G, Palladini G. Amyloidosis: is a cure possible? Ann Oncol 2008;19(S4):iv63-6.
  22. Palladini G, Merlini G. What in new in the diagnosis and management of light chain amyloidosis? Blood 2016; 128:159-67.
  23. Sanchorawala V, Sun F, Quillen K, et al. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation: 20-year experience. Blood 2015; 126:2345-47.
  24. Brett Sperry, et al. Efficacy of Chemotherapy for Light-Chain Amyloidosis in Patients Presenting With Symptomatic Heart Failure. Am Coll Cardiol 2016; 67(25):2941-48.
  25. Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, et al. Bortezomib with or without dexamethasone in primary sistemi (light chain) amyloidosis. J Clin Oncol 2010; 28:1031-37.
  26. Jiang F, Chen J, Liu H, Li L, Lu W, Fu R. The effect and safety of bortezomib in the treatment of AL amyloidosis: a systematic review and meta-analysis. Indian J Hematol Blood Transfus 2018; 34:216-26.
  27. Yuwen Cai, Shizhang Xu, Na Li, Song Li, and Gaosi Xu. Efficacy of Chemotherapies and stem cell transplantation for systemic AL amyloidosis: a network meta-analysis. Front Pharmacol 2019; 10:1601.
  28. Dispenzieri A, Lacy M, Zeldenrust S, et al. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood 2007; 109:465-70.
  29. Kastritis E, Gavriatopoulou M, Roussou M, Bagratuni T, Migkou M, et al. Efficacy of lenalidomide as salvage therapy for patients with AL amyloidosis. Amyloid 2018 Dec; 25(4):234-41.

Efficacy of SUPRA HFR in the treatment of acute renal damage during multiple myeloma


Acute Kidney Injury (AKI) is a frequent complication of multiple myeloma (MM) with unfavorable prognostic significance.

Light chains removal, combined with hematological therapy (CT) seems to offer significant benefits to renal function recovery (RFR).

The SUPRA HFR, through the combination of high cut-off membrane without albumin loss and adsorbent cartridge, represents one of the “emerging” light chain removal methods. We report our multicentric retrospective experience with SUPRA HFR in 7 MM patients.

At the end of the treatment with SUPRA HFR a significant reduction in serum free light chains compared to baseline was observed (min 24%; max 90%; median 74%). Despite a not always early start of the treatment, all patients recovered renal function with withdrawal from dialysis in 6/7 cases.

Our preliminary experience of a combination of SUPRA HFR treatment with CT in 7 MM patients with AKI showed a significative renale functional recovery, with favourable cost/benefit ratio and a simple treatment schedule. These encouraging data suggest to further extend such treatment option, waiting for larger studies in this field.



Acute Kidney Injury, haemodiafiltration, multiple myeloma

Sorry, this entry is only available in Italian.


Il coinvolgimento renale è una complicanza frequente del mieloma multiplo (40-50% dei casi) e può essere di entità estremamente variabile sino a richiedere il trattamento dialitico sostitutivo in circa l’8-10% dei casi (1, 2).  

La visualizzazione dell’intero documento è riservata a Soci attivi, devi essere registrato e aver eseguito la Login con utente e password.