How I Treat Series

PLASMA CELL DYSCRASIAS

How I treat AL amyloidosis

Giovanni Palladini1,2 and Giampaolo Merlini1*

Amyloidosis Research and Treatment Center, Foundation “Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo,” Pavia, Italy; and
1
2
Department of Molecular Medicine, University of Pavia, Pavia, Italy

The treatment of patients with systemic light chain (AL) amyloidosis is a challenge to hematologists. Despite its gener-
ally small size, the underlying clone causes a rapidly progressing, often devastating multiorgan dysfunction through the

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

toxic light chains that form amyloid deposits. Clinical manifestations are deceitful and too often recognized at an irre-
versible stage. However, hematologists are in the unique position to diagnose AL amyloidosis at a presymptomatic
stage, checking biomarkers of amyloid organ involvement in patients with monoclonal gammopathies at higher risk to
develop the disease. Adequate technology and expertise are needed for a prompt and correct diagnosis, particularly
for ruling out non-AL amyloidoses that are now also treatable. Therapy should be carefully tailored based on severity of
organ involvement and clonal characteristics, and early and continual monitoring of response is critical. Three recent ran-
domized clinical trials moved AL amyloidosis to evidence-based era. Above all, the daratumumab-bortezomib combina-
tion is a new standard-of-care for newly diagnosed patients, inducing rapid and deep responses that translate into high
rates of organ response. The availability of new effective drugs allows to better personalize the therapy, reduce toxic-
ity, and improve outcomes. Patients should be treated within clinical trials whenever possible.

Introduction undetermined significance (MGUS) or multiple myeloma (MM)

and can be readily detected in serum by mass spectrome-
Systemic immunoglobulin light chain (AL) amyloidosis is caused
try.19,20 These genetic and posttranslational characteristics may
by the conversion of light chains (LCs) from their soluble states
be exploited, possibly through machine learning,21 for detect-
into highly organized fibrillar aggregates that deposit in tissues,
ing patients with plasma cell (PC) dyscrasias at high risk for
resulting in progressive organ damage and dysfunction.1 Rapid
developing AL amyloidosis, facilitating early diagnosis.22
organ deterioration imposes early diagnosis and prompt effec-
tive therapies to halt disease progression and possibly rescue
Several studies have delineated the biologic characteristics of
organ function.2 LCs, LC aggregates, or preceding intermediar-
the B-cell/PC clone that is usually small and indolent.23 Amyloi-
ies may induce proteotoxicity, leading to cell dysfunction and
dogenic PCs are vulnerable to proteasome inhibitors, account-
death, as shown in cardiac cells.3-5 Cardiomyocytes, in ing for improved clinical outcomes after the introduction of
response, produce high levels of natriuretic peptide type-B and bortezomib.24,25 Cytogenetic abnormalities are detected in
its N-terminal fragment (BNP and NT-proBNP, respectively) approximately 80% of patients via fluorescent in situ hybridiza-
that are pivotal for patient management.6 Furthermore, amyloid tion (FISH). t(11;14) is the most frequent (40% to 60% of
fibrils may cause cell damage and distortion of tissue architec- patients) and is associated with poorer hematologic response
ture contributing to organ dysfunction.7 Accordingly, although rates and overall survival with bortezomib and dexamethasone
experimental strategies aiming at reducing amyloid load are with or without cyclophosphamide.26 The BCL-2 inhibitor vene-
being developed, current therapy aims at suppressing the syn- toclax is very effective in patients with t(11;14),27 and larger,
thesis of the amyloid protein while adapting to patient’s frailty. controlled studies of this agent are warranted. Gain(1q21) is
present in 15% to 20% of patients and is associated with poor
Structural features of LCs underlie their amyloidogenicity. response to oral melphalan.28 Compared with MGUS/MM, AL
Approximately 80% are of the l isotype, and a limited pool of amyloidosis shows less intraclonal heterogeneity29 and different
LC variable region genotypes are responsible for the produc- transcriptional programs,30 suggesting that AL amyloidosis may
tion of amyloidogenic free LCs (FLC), consistent with a biased be more amenable to eradication than MM.
selection.8-11 Specific LC germline use can partly explain organ
tropism.11,12 Somatic mutations, acquired during clonal selec-
tion, determine LC higher flexibility, kinetic instability, and a Case 1: a young, asymptomatic man
higher dynamic state that underlie amyloidogenicity and tissue
toxicity.13-16 Studies are ongoing to develop LC stabilizers
with MGUS and increased
expected to inhibit fibril formation and proteotoxicity.17,18 N- cardiac biomarkers
glycosylation of k LCs is more common in patients with AL A 58-year-old, very active man, with low-intermediate risk immu-
amyloidosis than in those with monoclonal gammopathy of noglobulin G (IgG) l MGUS diagnosed 1 year earlier, presented

2918 blood® 12 MAY 2022 | VOLUME 139, NUMBER 19

 Clinical suspicion of amyloidosis

Search for monoclonal protein: SIFE, UIFE, FLC

Monoclonal protein No monoclonal protein

Abdominal fat biopsy* Cardiac involvement

Negative Positive No Yes PYP/DPD/HMDP

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

Strong clinical suspicion Amyloid typing Negative Positive

Organ biopsy Strong clinical suspicion ATTR amyloidosis likely

Organ biopsy Genetic testing

Positive: ATTRv or other

Negative: ATTRwt
cardiac amyloidosis

Figure 1. Diagnostic algorithm in symptomatic patients. Ideally, AL amyloidosis should be diagnosed at a presymptomatic stage. When amyloidosis is suspected,
the first step should be searching for a monoclonal protein with sensitive technology. Patients with suspect cardiac involvement in whom monoclonal components are
not detected may undergo a biopsy-free diagnostic process.58 Scintigraphy with bone-seeking tracers, such as DPD, PYP, and HMDP, can diagnose ATTR amyloidosis
without a biopsy in the absence of a plasma cell dyscrasia, but cardiac uptake can be seen also in patients with AL amyloidosis. In the presence of a monoclonal com-
ponent biopsy-based diagnosis and typing with mass spectrometry,102 or, in highly specialized laboratories, with immunohistochemistry or immuno-electron micros-
copy102 are mandatory. Amyloid deposits can be demonstrated with minimally invasive procedures, such as biopsy of abdominal fat, bone marrow, and minor salivary
glands. Abdominal fat aspirate has excellent feasibility and good sensitivity (85% when associated with bone marrow biopsy) in AL amyloidosis.103 If less invasive biop-
sies are negative, a biopsy of an affected organ will typically be required. Genetic testing allows discrimination between hereditary and wild-type TTR amyloidosis and
identification of rarer hereditary variants. *In patients with a monoclonal protein, amyloid deposits should be searched also in the bone marrow biopsy. DPD, scintigra-
phy with 99mTc 3,3-diphosphono1,2-propanodicarboxylic acid; FLC, circulating free light chains; HMDP, scintigraphy with 99mTc-hydroxymethylene diphosphonate; PYP,
scintigraphy with 99mTc-pyrophosphate; SIFE, serum immunofixation electrophoresis; UIFE, urine immunofixation electrophoresis.

at the second yearly control with normal hematology and bio- immunofixation). Hemopoietic stem cells were harvested
chemistry values. Serum monoclonal spike was stable (8 g/L), as uneventfully. However, 3 months later, NT-proBNP increased to
well as FLC concentration (l, 180 mg/L; k, 20 mg/L; ratio, 0.11), 954 ng/L, and the patient reported unusual fatigue after strenu-
and proteinuria was 220 mg/d with urine immunofixation elec- ous physical exercise while maintaining VGPR. The patient con-
trophoresis showing monoclonal l FLC. Bone marrow biopsy sented to proceed to high-dose melphalan (200 mg/m2). The
showed 8% l typic plasma cells, and FISH analysis showed procedure was uneventful. Three months after ASCT, he
t(11;14) in 35% of interphases. The patient was asymptomatic achieved complete hematologic response (CR), with reduction
and working full time. The finding of a significant increase of of NT-proBNP to 584 ng/L, thus qualifying for cardiac response.
NT-proBNP to 745 ng/L from the previous 114 ng/L raised the Eighteen months after ASCT, the patient is in CR, with negative
suspicion of heart involvement, and an appropriate workup was minimal residual disease (MRD) by next-generation flow cytome-
started. The abdominal fat aspirate showed amyloid deposits try, and NT-proBNP is now 98 ng/L.
that were typed as AL l by mass spectrometry. Echocardiogra-
phy was normal. Cardiac magnetic resonance was consistent Comments about patient 1
with early cardiac amyloidosis. Cardiac troponin I was 0.01 This patient illustrates the possibility to diagnose AL amyloidosis
ng/mL, and the patient was classified as cardiac stage31 II. We at a very early asymptomatic stage and to fully exploit the thera-
thoroughly discussed the opportunity to start anticlone therapy, peutic armamentarium and restore organ function. About 3% to
carefully considering toxicity and benefit balance. The patient 5% of patients with a known precursor PC disorder will progress
decided to start therapy, and because he was eligible for autolo- to AL amyloidosis. However, even in referral centers, it takes a
gous stem cell transplantation (ASCT), we started treatment with median time of almost 1 year to reach the diagnosis, based on
cyclophosphamide, bortezomib, and dexamethasone (CyBorD). signs or symptoms, in patients with preexisting PC dyscrasias.32
During the first course, asymptomatic orthostatic hypotension When symptoms manifest, even a minor delay translates into
(80/50 mm Hg) occurred but resolved spontaneously. After 4 significant shortening of survival.33 For this reason, we advo-
courses, a very good partial response (VGPR) was achieved (l, cated the use of sensitive markers of amyloid organ involvement
48 mg/L; k, 17 mg/L; difference between involved and unin- during the follow-up of individuals with MGUS to facilitate a pre-
volved FLC [dFLC], 31 mg/L; positive serum and urine symptomatic diagnosis.34 In this patient, an increase of

HOW I TREAT AL AMYLOIDOSIS blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 2919
 NT-proBNP raised suspicion of amyloid cardiac involvement.
A NT-proBNP is a very sensitive marker, but it is not specific (being
100
elevated in other conditions), and heart involvement can be con-
90
firmed by echocardiography or magnetic resonance. Our diag-
80
nostic approach is reported in Figure 1. Once diagnosis is
Survival probability (%)

70 established, it is necessary to assess the risk to carefully balance

Stage I, 247 patients
60 expected benefit and possible treatment toxicity. Cardiac
50 Stage IIIa involvement is the main determinant of frailty and survival. Cur-
40 276 patients
Stage II, 606 patients
rent validated staging systems are reported in Figure 2.31,35-39
30 The patient was cardiac stage II and considering the young age
20
and perfect fit, he was eligible for high-dose melphalan and
Stage IIIb, 249 patients ASCT. Eligibility criteria vary for centers (Figure 3); however, only
10
P<0.001 20% of newly diagnosed patients are eligible for this intensive
0
0 24 48 72 96 120 144 168
treatment. ASCT is safe, with ,3% treatment-related mortality in
referral centers, and highly effective, providing $VGPR in
Time (months)

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

approximately 70% of patients and a median survival . 15 years
B in patients achieving CR.40,41 Induction therapy with
100
bortezomib-based regimens should be considered in all
90
transplant-eligible patients.42,43 Furthermore, the recently con-
80 cluded Andromeda trial, reported an unprecedented high rate
Survival probability (%)

70 of deep hematologic responses ($VGPR in 78.5%) for daratu-

Stage I, 317 patients
60 mumab plus CyBorD, which was recently approved by the US
50 Stage III
Food and Drug Administration and European Medicines Agency
40 372 patients for newly diagnosed AL amyloidosis.44 Daratumumab-CyBorD is
30
Stage II, 331 patients a new standard of care and will become also the preferred
induction therapy before ASCT. Importantly, daratumumab-
20
CyBorD is also effective in patients whose amyloid clones harbor
10 Stage IV, 358 patients the t(11;14) who have poorer outcomes with CyBorD alone.44
P<0.001
0 Because daratumumab was not available in Italy at the time this
0 24 48 72 96 120 144 168
patient was seen, he received CyBorD achieving VGPR after 4
Time (months)
courses. Based on data suggesting that ASCT can be deferred
C to relapse after successful induction, without detrimental effects
100
P<0.001 on overall survival, we elected to postpone ASCT.45-47 This prac-
90 tice is common in Europe. Actually, in a survey including 3064
80 patients treated between 2011 and 2018 in 10 European referral
Progression to dialysis (%)

Stage III, 207 patients

70 centers, ASCT was used as frontline therapy in 6% of patients
60 and as second-line therapy in 10%.48 Although some centers
50 prefer transplant for all eligible patients upfront, we generally
Stage II, 579 patients
40
prefer to defer ASCT in subjects who attain CR and/or organ
response after induction. However, at our center, we proceed to
30
ASCT in patients with MM. In this patient, the appearance of
20
mild symptoms and increase in NT-proBNP suggested that
Stage I, 592 patients
10 attaining VGPR was not sufficient to halt disease progression,
0 and the patient proceeded to ASCT. Approximately 30% of
0 24 48 72 96 120 144 168 patients do not respond to first-line treatment, and they should
Time (months) promptly be switched to another class of drugs. Quality of organ
response is strictly dependent on the depth of hematology
Figure 2. Stratification of 1378 patients with AL amyloidosis according to response, and although in some patients VGPR or even PR is
the validated staging systems. (A) European modification of the Mayo Clinic enough to reach it, in patients with highly toxic LCs, persistence
2004 staging system.31,35 The staging system is based on NT-proBNP and cardiac
of even MRD may be sufficient to hamper amelioration of organ
troponin (cTn). Troponin I was used in this figure. Cutoffs are 332 ng/L for
NT-proBNP and 100, 35, and 54 ng/L for cTnI, cTnT, and high-sensitivity cTnT, function.49 In patients who achieve CR without organ response,
respectively. B-type natriuretic peptide can substitute for NT-proBNP in the MRD evaluation may help decide regarding further therapy. Pro-
staging system (cutoff, 81 ng/L).36 Patients with stage I, II, and III have 0, 1, and 2 posed criteria for grading organ response are now being vali-
markers above the cutoff, respectively. Patients with stage III are classified as
dated.50 The criteria for hematologic and organ response are
stage IIIa or IIIb according to concentration of NT-proBNP below or above 8500
ng/L. (B) Revised Mayo Clinic staging system.37 The staging system is based on reported in Table 1.39,51-54 In this fit patient, stem cell collection
NT-proBNP, cTn, and dFLC. Cutoffs are 1800 ng/L for NT-proBNP and 25 ng/L was uneventful, although the incidence of major complications
for cTnT. Troponin I can substitute for cTnT (cutoff, 70 ng/L)38 and was used in (hypotension, hypoxia, cardiac arrhythmia, and fluid retention)
this figure. Patients with stage I, II, III, and IV have 0, 1, 2, and 3 markers above during stem cell mobilization and collection is approximately
the cutoff, respectively. (C) Renal staging system.39 The staging system is based
on estimated glomerular filtration rate (eGFR) and proteinuria. Cutoffs are 50 mL/
15%. The patient was eligible for full-dose melphalan (200
min per 1.73 m2 for eGFR and 5 g/24 h for proteinuria. Patients with stage I, II, mg/m2), which is important to optimize outcomes, and reached
and III have 0, 1, and 2 markers above the cutoff, respectively. CR and cardiac response.

2920 blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 PALLADINI and MERLINI
 ASCT eligible Not ASCT eligible Stage IIIb

Induction Dara-CyBorD Modified regimens

Dara-CyBorD CyBorD3 Supportive cardiology therapy
2-4 cycles BMDex4 (not if ASCT is planned) Consider cardiac transplant

Stem cell collection CR or VGPR with

organ response
ASCT may be CR/VGPR+OR
postponed to
YES NO Second line
relapse Follow up
1 therapy
Mel200 ASCT

Relapse

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

CR or VGPR with OR

YES NO Second line

2
Follow up therapy

1. For patients with eGFR <30mL/min, Mel140 may be considered 3. If daratumumab is not available
2. For patients with multiple myeloma, consider maintenance 4. For patients with severe neuropathy, MDex can be considered

Figure 3. Upfront treatment algorithm for AL amyloidosis. At our center, the first step in the design of the therapeutic strategy is assessing eligibility for ASCT.
However, the role of ASCT in AL amyloidosis is not supported by controlled trials and is challenged by the availability of very effective treatments like Dara-CyBorD.
Yet, large long-term outcome studies, which are lacking for newer combinations, show that ASCT grants long-lasting responses with a prolonged improvement in sur-
vival.40 At our center, eligibility for stem cell transplant with full dose (200 mg/m2) melphalan requires the following: age ,70 years, Eastern Cooperative Oncology
Group performance status ,2, NT-proBNP ,5000 ng/L, troponin T ,60 ng/L, left ventricular ejection fraction . 45%, New York Heart Association class ,III, systolic
blood pressure $100 mm Hg, glomerular filtration rate .50 mL/min unless on dialysis, bilirubin ,2 mg/dL, and diffusing capacity of the lungs for carbon monoxide
.50%. At some referral centers, including ours, transplant is performed only in patients who are eligible for full-dose melphalan.42 Eligibility can be extended with a
risk-adapted conditioning dose of melphalan (100-140 mg/m2).104 However, there is no evidence that reduced-dose melphalan is better than bortezomib-based chemo-
therapy, and this approach is even more challenged by newer powerful nontransplant regimens.44,105 Induction should be performed with Dara-CyBorD. If daratumu-
mab is not yet available, CyBorD can be used. In subjects who have contraindications to bortezomib (eg, peripheral neuropathy), daratumumab-based induction
without bortezomib may be considered, or ASCT can be performed upfront. In some cases, a satisfactory response (CR or VGPR, accompanied by organ response) can
be achieved after induction alone. In these cases, treatment can be discontinued, and close monitoring initiated to detect hematologic relapse before this causes pro-
gression of organ involvement. This sequential approach reduces treatment-related mortality to less than 1% and allows fully exploiting modern powerful regimens in
transplant-eligible patients.45-47 This approach is adopted at some referral centers, but it is not supported by controlled studies. If patients achieve less than a satisfac-
tory response after ASCT, consolidation with bortezomib may improve the outcome.106 Dara-CyBorD is a new standard of care for patients who do not undergo ASCT.
In patients who are potentially eligible for transplantation, melphalan should be avoided. In elderly individuals, BMDex may be considered. Patients with contraindica-
tions to bortezomib can be treated with MDex. Patients with advanced cardiac involvement (stage IIIb) should start bortezomib based treatment immediately, with
attenuated dosages and under close medical control. Cardiac transplant may be considered. Dara-CyBorD, daratumumab, cyclophosphamide, bortezomib, and dexa-
methasone; OR, organ response.

Case 2: a woman with rapidly The scintigraphy showed no cardiac uptake, and the biopsy
showed amyloid deposits that were not further characterized.
worsening dyspnea and NT-proBNP was 10 740 ng/L, and troponin I was 0.44 ng/mL.
peripheral edema The patient was referred to our center 2 months later, more
A 58-year-old woman began to experience exertional dyspnea. than 1 year after the onset of symptoms. She reported fatigue,
Three months later, she was hospitalized because worsening dyspnea for minor exertion, petechiae, and ecchymoses in the
dyspnea and pleural effusion. Echocardiogram reported left ven- upper part of the body. Physical examination revealed mild mac-
tricular hypertrophy with preserved ejection fraction (55%). roglossia, jugular vein distention, pleural effusion, hepatomeg-
Diuresis resolved pleural effusion, and she was discharged. Over aly, distal edema, and hypotension (86/53 mm Hg). Serum and
the next 6 months, symptoms worsened, and cardiac catheteri- urine electrophoresis and immunofixation revealed an IgG k
zation showed normal coronaries. Two months later, the patient spike (28 g/L) with free k LCs and Bence Jones proteinuria.
was seen in another cardiology center because of recurrent car- Serum k FLCs were 303 mg/L (ratio, 25.2; dFLC, 291 mg/L). A
diac syncope and nonsustained ventricular tachycardia. An bone marrow biopsy speciman showed 31% monotypic k PC
implantable cardioverter defibrillator (ICD) was implanted, and with gain1q21 and amyloid deposits. No other myeloma-
oral amiodarone was started. Echocardiography showed dia- defining events were present. Abdominal fat aspirate was posi-
stolic dysfunction and increased wall thickness (posterior wall, tive for amyloid that was typed as AL k by immuno-electron
16 mm; interventricular septum, 15 mm) with reduced ejection microscopy. NT-proBNP was 15 585 ng/L, troponin I was 0.53
fraction (43%). The suspicion of cardiac amyloidosis was raised, ng/mL, and echocardiography confirmed advanced amyloid
and a scintigraphy with 99mTc 3,3-diphosphono1,2-propanodi- involvement. The patient was stage IIIb, and because there was
carboxylic acid and an endomyocardial biopsy were performed. no sign of other organ damage, we started evaluation for

HOW I TREAT AL AMYLOIDOSIS blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 2921
Table 1. Criteria for hematologic and organ response

Hematologic response Criteria

Complete response (CR) Both criteria must be met:
 Absence of amyloidogenic light chains (either free and/or as
part of a complete immunoglobulin) defined by negative
immunofixation electrophoresis of both serum and urine.
 Either a FLC ratio within the reference range or the
uninvolved FLC concentration is greater than involved FLC
concentration with or without an abnormal FLC ratio
Very good partial response (VGPR) dFLC ,40 mg/L
Partial response (PR) dFLC decrease .50%
No response (NR) Less than a partial response

Organ response

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

Cardiac response Decrease of NT-proBNP by .30% and 300 ng/L (if baseline
NT-proBNP .650 ng/L)
Renal response At least 30% decrease in proteinuria or drop below 0.5 g/24 h, in the
absence of renal progression defined as a .25% decrease in eGFR
Hepatic response 50% decrease in abnormal alkaline phosphatase value or decrease in
radiographic liver size by $2 cm

Hematologic, cardiac, and renal response criteria have been validated,39,51 whereas hepatic response criteria have been obtained by consensus.52 A value adequate to measure
hematologic response is deemed to be 50 mg/L. For patients with dFLC between 50 and 20 mg/L, hematologic response other than complete response (ungraded) is reached when
dFLC falls below 10 mg/L.53,54

cardiac transplantation. In the meantime, she started treatment York Heart Association class 4, NT-proBNP .8500 ng/L, and
with CyBorD with reduced bortezomib (1 mg/m2) and dexa- systolic blood pressure ,90 mm Hg) are not appropriate candi-
methasone (20 mg) dosage. After the second cycle, she experi- dates for ICD implantation.59 The patient reported recurrent
enced worsening of heart failure that required hospitalization. purpura, a common finding particularly in advanced stages of
Investigations revealed reduction of the serum monoclonal com- the disease, that is attributed to amyloid infiltration of blood
ponent to 19 g/L and of dFLC to 35 mg/L, qualifying for VGPR, vessels. Coagulation abnormalities are multifactorial, including
whereas NT-proBNP increased to 16 834 ng/L and troponin I to factor x and other factor deficiencies, and occur in a significant
0.63 ng/L. Three days after admission, the patient collapsed and proportion of patients.60 These extremely fragile patients are
died with pulseless electrical activity. very sensitive to treatment toxicity, and we attenuated treatment
dosages. Although early and deep response is associated with
Comments about patient 2 improved survival in patients with stage IIIb,61 in this subject,
This case illustrates the devastating effects of delayed diagnosis: cardiac involvement was likely already too advanced. At present,
in this rapidly progressing disease, “time is life,” and even few there is no treatment capable of improving the outcome of
months can irreversibly compromise any chance to benefit from most patients with stage IIIb. However, subcutaneous daratumu-
effective therapies. Symptoms that should trigger an appropriate mab can induce rapid and deep responses, which makes it a
workup for amyloidosis are listed in Table 2. The diagnosis of valuable option in these patients. A multicenter phase 2 trial of
cardiac amyloidosis can be augmented by machine learning single-agent daratumumab in subjects with stage IIIb is under-
applied to electrocardiographic and echocardiographic data.55 way (NCT04131309). Moreover, removing amyloid deposits with
In the European survey, the percentage of patients presenting antibodies is expected to improve outcomes and is currently
with very advanced cardiac damage (stage IIIb) remained the being tested in clinical trials (Table 3). Young patients with stage
same (15%-16%), and median survival remained disappointingly IIIb with isolated heart involvement should be considered for
low (4.5 months) in the periods 2004 to 2010 and 2011 to cardiac transplantation that is now associated with outcomes
2018.56 A recent survey among US community and academic comparable to nonamyloid cardiomyopathy.62 However, scarcity
hematologists showed that low disease awareness, inadequate of donors frequently renders time on waiting list incompatible
referral practices, and inadequate screening/testing procedures with patient’s needs.
account for a 1- to 1.5-year diagnostic delay.57 Scintigraphy with
bone tracers (PYP or DPD) is used to search for cardiac transthyr-
etin amyloidosis that usually shows strong uptake.58 However, Case 3: a man with rheumatoid
the presence of the monoclonal protein should be ascertained arthritis, proteinuria, smoldering MM,
first, using appropriate methods (Figure 1), because its presence
makes cardiac biopsy mandatory and scintigraphy unnecessary. and bilateral carpal tunnel syndrome
In this case, the cardiologists elected to perform scintigraphy A 70-year-old man with a 1-year history of rheumatoid arthritis
and cardiac biopsy concomitantly. Because of recurrent syncope treated with hydroxychloroquine and prednisone (2.5 mg/d) and
and registered ventricular arrhythmias, an ICD was implanted. of smoldering MM (IgG l; FLC ratio, 0.08; dFLC, 141 mg/L;
Probably, patients with very advanced cardiac amyloidosis (New bone marrow PC infiltrate, 25%; t(11;14) in 25% of interphases)

2922 blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 PALLADINI and MERLINI
Table 2. Presymptomatic hints, symptoms, and signs leading to the diagnosis of AL amyloidosis

Symptomatic

Presymptomatic Organ involved Symptoms Signs

Increased markers of possible Heart Reduced exercise tolerance Lower extremity edema
amyloid organ involvement: Dyspnea at rest or exertion Pleural effusions
Fatigue Jugular vein distension
 Heart: NT-proBNP Syncope Arrhythmia
 Kidney: Albuminuria Angina Thickened ventricular walls and
 Liver: Alkaline phosphatase low voltages on ECG
Monitored during follow-up of
Kidney Loss of appetite Lower extremity edema
MGUS patients and particularly
Fatigue and weakness Anasarca
in those with abnormal FLC
ratio, and LC propensity to
Soft tissues Jaw or buttock claudication Periorbital (upper body) purpura
form amyloid (glycosylated k
Carpal tunnel (often bilateral) Macroglossia

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

LCs, use of LC genes IGLV6-
Dysarthria Nail dystrophy
57, IGLV2-14, IGLV1-44, and
Shoulder pad
LCs identified by machine
Arthropathy
learning algorithm)
Myopathy

Peripheral nervous system Length dependent sensory-motor Orthostatic hypotension

including autonomic nervous neuropathy Intestinal dysmotility
system Lipothymia Erectile dysfunction
Taste alterations Voiding dysfunction
Early satiety

Liver Right upper quadrant tenderness Hepatomegaly

Jaundice Weight loss
Early satiety

Gastrointestinal tract Abdominal discomfort Malabsorption

Gastrointestinal bleeding
Diarrhea
Weight loss

was referred to our center because of bilateral carpal tunnel syn- to chronic phlogosis is caused by deposition of SAA-derived
drome and proteinuria of 1.2 g/d (creatinine, 0.71 mg/dL). There amyloid fibrils and presents with renal damage.63 Treatment is
was no sign of amyloid cardiac involvement (normal echocardi- aimed at controlling the underlying inflammation. Moreover, car-
ography; NT-proBNP, 42 ng/L; troponin I, 0.03 ng/mL). Serum pal tunnel syndrome can be found both in AL and in transthyre-
amyloid A apolipoprotein (SAA) level was normal. Abdominal fat tin amyloidosis. Thus, accurate tissue typing was mandatory.
aspirate was positive, and the amyloid deposits reacted with
anti-l (and not with anti-SAA and anti-transthyretin) antibodies In this patient, bone marrow PC infiltrate was higher than 20%.
at immuno-electron microscopy. A diagnosis of AL amyloidosis This measure of clonal bulk is an additional negative prognostic
with renal and soft tissue involvement was made, and the factor independent of cardiac involvement,64 as well as dFLC
patient was enrolled in the ANDROMEDA trial and randomized level.37,53,54 The patient could be treated with daratumumab-
CyBorD in the ANDROMEDA trial. This regimen is well
to the daratumumab-CyBorD arm. After 2 infusions, treatment
tolerated, but 1 of the most common adverse events with dara-
was interrupted because of a respiratory infection. However, by
tumumab in AL amyloidosis is respiratory infection,65 as
then, a VGPR had been reached (dFLC, 13 mg/L; free light chain
occurred in this subject who was also immunocompromised by
ratio [FLCR], 0.61 ; positive serum immunofixation) with renal
steroid treatment of rheumatoid arthritis. Nevertheless, the
response (proteinuria, 0.5 g/d). Cycle 2 was also interrupted
infection was manageable, and VGPR was reached after only 2
after the second infusion because of a respiratory infection. The
infusions. Prophylaxis of infections may be useful in patients with
following 4 cycles were completed without complications, but AL amyloidosis treated with daratumumab as was shown in
we elected to withhold daratumumab maintenance. The patient MM.66 Besides its high efficacy, the ability of daratumumab to
is currently asymptomatic 2 years after treatment discontinua- induce deep responses after the first infusion67,68 is particularly
tion, and VGPR is maintained (dFLC, 14 mg/L; FLCR, 0.81; posi- relevant in patients with AL amyloidosis who need to reach a
tive serum immunofixation). deep reduction of the amyloid LCs as soon as possible.

Comments on patient 3 The role of maintenance has not been adequately explored in
In this patient, symptoms were recognized early, and the diag- patients with AL amyloidosis. In the ANDROMEDA study, treat-
nosis was made when he was still renal stage I. However, this ment with daratumumab could be continued for up to 2 years if
subject had a chronic inflammation (rheumatoid arthritis) that well tolerated, but there was no control arm for maintenance. In
can give rise to AA (reactive) amyloidosis. Amyloidosis reactive our patient, who was prone to infections, we elected to withhold

HOW I TREAT AL AMYLOIDOSIS blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 2923
Table 3. Antiamyloid therapies currently under development for AL amyloidosis

Agent Target Comments

CAEL-101 Amyloid fibrils  Targets amyloid deposits in vivo as assessed by imaging studies
 Promising results in preliminary uncontrolled studies94
 Phase 3 trials comparing CyBorD vs CyBorD plus CAEL-101 in stage IIIa
(NCT04512235) and IIIb (NCT04504825) subjects are ongoing

Birtamimab Amyloid fibrils  Post hoc analysis of the phase 3 study of birtamimab vs placebo plus
bortezomib-based upfront therapy suggests survival benefit in Mayo Clinic 2012
stage IV patients
 A trial is now planned in Mayo Clinic 2012 stage IV patients

Doxycycline Amyloid deposits  Reduces LC proteotoxicity and inhibits the formation of and disrupts amyloid
Amyloid light chains fibrils in animal models95,96
 Two retrospective controlled studies reported a survival advantage with
doxycycline97,98

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

 A phase 2 trial of doxycycline in conjunction with bortezomib-based chemotherapy
showed low early mortality rates99
 An international randomized phase 3 trial of bortezomib-based therapy with or
without doxycycline is ongoing (NCT03474458)
 A Chinese randomized phase 3 trial of CyBorD with or without doxycycline
showed no improvement of progression free survival (NCT03401372)100

maintenance. Controlled studies are warranted to ascertain of worsening hypotension. During the first BMDex course, fluid
whether maintenance has a role in AL amyloidosis. At our center retention worsened again. By the end of cycle 1, fluid retention
and at the Mayo Clinic,69 maintenance is considered in patients and hypotension resolved and did not recur during subsequent
with large clones (eg, fulfilling the SLiM CRAB criteria) and/or cycles. After 3 cycles, a partial response was reached, and VGPR
high-risk cytogenetics. was attained after 6 cycles and maintained at the completion of
cycle 8 (positive urine immunofixation; dFLC, 33 mg/L; ratio,
0.30), with cardiac (NT-proBNP 686 ng/L), renal (proteinuria 1.4
Case 4: an older man with g/d), and liver (alkaline phosphatase 150 U/L) response, and
macroglossia, peripheral edema, and treatment was discontinued. The patient was followed every 6
months for 5 years, when an increase in dFLC was observed
dysautonomia (141 mg/L; ratio, 0.06) with stable NT-proBNP (767 ng/L) and
A 72-year-old man developed worsening speech difficulty proteinuria (1.6 g/d). The only symptoms were mild fatigue and
caused by slowly progressing macroglossia. After 18 months, persistent involvement of soft tissues. Rescue treatment with ixa-
foamy urine, peripheral edema, impotence, and symptomatic zomib, lenalidomide, and dexamethasone was started. After 2
postural hypotension with occasional syncope ensued, and the cycles, partial hematologic response was achieved (dFLC, 61
patient sought medical advice. Proteinuria was present and mg/L; ratio, 0.16) with stable symptoms, increased NT-proBNP
the general practitioner suspected amyloidosis and referred the (3835 ng/L), stable proteinuria (1.4 g/d), and an increase in
patient to our center. He presented with typical macroglossia serum creatinine (from 0.77 to 1.4 mg/dL). Treatment was con-
and submandibular gland swelling, nephrotic syndrome (protein- tinued for 4 more cycles with stable hematologic and organ
uria, 5.9 g/d; normal creatinine), symptomatic orthostatic hypo- parameters. After lenalidomide discontinuation, NT-proBNP
tension, and hepatomegaly (8 cm below costal margin). level decreased to 480 ng/L. Eighteen months later, a new rise
Echocardiography revealed amyloid heart involvement, in dFLC was documented (169 mg/L; ratio, 0.09) that was associ-
NT-proBNP was 5500 ng/L, and cardiac troponin I was ated with stable NT-proBNP (576 ng/L), proteinuria (1.5 g/d),
0.05 ng/L. Alkaline phosphatase was elevated (480 U/L; upper and creatinine (1.5 mg/dL). Rescue treatment with pomalido-
reference limit, 150 U/L) with normal bilirubin and aminotransfer- mide and dexamethasone was started. A VGPR was
ases. Immunofixation electrophoresis showed monoclonal l FLC re-established after 3 cycles (dFLC, 21 mg/L; ratio, 0.48; persis-
in serum and urine, and circulating l FLC concentration was 849 tent positive urine immunofixation). A suspected pomalidomide-
mg/L (ratio, 85; dFLC, 840 mg/L). Bone marrow plasma cell infil- related increase in NT-proBNP was observed during therapy (up
trate was 16%, with no chromosomal abnormalities by inter- to 3057 ng/L) while renal involvement remained stable (protein-
phase fluorescence in situ hybridization (iFISH). Abdominal fat uria, 1.3 g/d; creatinine, 1.3 mg/dL). The patient is now 81 years
aspirate showed amyloid deposits characterized as AL-l type by old, and he is enjoying an active life despite persistent macro-
immuno-electron microscopy. A diagnosis of AL amyloidosis glossia, with resolution of symptoms of heart and renal involve-
with cardiac, renal, liver, soft tissue, and autonomic nervous sys- ment and of hypotension.
tem involvement was made, and the patient was enrolled in a
clinical trial comparing melphalan and dexamethasone (MDex) Comments on patient 4
with MDex plus bortezomib (BMDex). The patient was random- Symptoms of AL amyloidosis depend on organ involvement and
ized to the BMDex arm. The use of fitted elastic leotards was can be often mistaken for manifestations of more common dis-
recommended. Diuretic therapy was initiated before chemother- eases. However, typical soft tissue involvement and combination
apy with furosemide 25 mg/d, and the patient lost 2 kg in 1 of signs of simultaneous involvement of different organs can be
week. Higher doses of furosemide were not tolerated because a clue to diagnosis as in this patient. Yet, multiorgan

2924 blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 PALLADINI and MERLINI
Table 4. Supportive therapy in AL amyloidosis

Condition Supportive measures

Fluid retention  Salt restriction
 Careful administration of diuretics (furosemide or torasemide, spironolactone)
Liberal use can worsen hypotension and reduce pre-load which can exacerbate cardiac dysfunction

Hypotension  Fitted elastic stockings

 Midodrine, droxidopa, and pyridostigmine

Neuropathy  Gabapentin and pregabalin

 Serotonin-norepinephrine reuptake inhibitors (duloxetine and venlafaxine)

Diarrhea  Loperamide
 Octreotide in patients who are refractory to loperamide

Malnutrition  Nutritional counseling and support

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

End-stage renal disease  Dialysis
 Renal transplant in eligible patients with adequate hematologic response (CR/VGPR)101

Heart failure  Beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium
channel blockers should be used with great caution in cardiac amyloidosis
 Heart transplant in eligible young patients with severe heart damage and with minimal or no
extracardiac involvement. This should be followed by effective chemotherapy. Risk-adapted
chemotherapy while on transplant list is recommended under intensive monitoring

See Cibeira et all.70

involvement makes these patients frail and difficult to treat different referral centers to start treatment when early, relatively
intensively. Supportive measures to manage fluid retention, small increases in FLC (approximately 40% of baseline value) are
hypotension, and malnutrition should be started early, possibly detected.78,79 Small increases in FLC should be regarded cau-
before initiation of chemotherapy (Table 4).70 Dexamethasone tiously particularly in patients who presented with advanced car-
can exacerbate fluid retention and arrhythmias and should be diac involvement. Rescue therapy is discussed in Figure 4. This
used at lower dosage (#20 mg) in patients with advanced heart patient was rescued with a combination of ixazomib and lenali-
involvement (New York Heart Association class III or IV, cardiac domide,80 and pomalidomide at first and second relapse,
stage IIIb, repetitive ventricular arrhythmias).71 At diagnosis, this before progression became symptomatic. Although he never
patient was cardiac stage II and renal stage II, and he was not a reached CR, his disease was controlled for 10 years, with a
candidate for stem cell transplantation because of age, heart good quality of life.
involvement, and hypotension, qualifying as intermediate risk.
Bortezomib is the most used agent in upfront therapy, based on The optimal goal of therapy is yet to be established and possi-
retrospective uncontrolled studies.35,72 Running controlled clini- bly varies during follow-up. In patients with this rapidly progress-
cal trials has been difficult in AL amyloidosis because of the rela- ing disease, it is necessary to closely monitor (every 2 cycles) the
tive rarity of this condition and the easy access to drugs licensed outcome of therapy to promptly switch regimen and avoid fur-
for MM. This patient was enrolled in the AC-004-EU/EMN-03
ther organ deterioration.61,81 A deep reduction of FLCs should
trial comparing MDex and BMDex (NCT01277016). This aca-
be achieved very early,81 but ideal timing and depth vary based
demic, investigator-initiated study showed that BMDex grants
on disease severity and treatment regimen. With daratumumab,
higher hematologic response rates than MDex (81% vs 57%;
FLCs usually drop after the first administration.67 In patients with
VGPR/CR, 64% vs 39%) and was the only study to demonstrate
advanced cardiac involvement, an earlier (after 1 cycle) assess-
an overall survival advantage for the experimental arm in AL
ment of response is advisable to allow a rapid shift in nonres-
amyloidosis.73 BMDex is well tolerated and relatively inexpen-
ponders. This can be particularly relevant in subjects receiving
sive. Moreover, it can potentially overcome the effect of the 2
daratumumab. At the end of frontline therapy, either CR or
most common chromosomal abnormalities found in this disease:
t(11;14) and gain 1q(21).26,28 In this patient, BMDex induced organ response should be reached, and the recently validated
VGPR with cardiac, renal, and liver response that lasted 5 years. composite hematologic and organ response criteria can offer
It has recently been shown that restaging discriminates survival guidance in this assessment.82 However, in patients with an
even after upfront therapy.74 The patient had asymptomatic aggressive underlying clone (eg, with SLiM CRAB or high-risk
hematologic relapse and was rescued when he still was cardiac myeloma cytogenetics) CR might be more obstinately pursued,
stage II. There are no validated criteria for hematologic progres- as recently suggested by the Mayo Clinic group.69 In the longer
sion in AL amyloidosis, and there is disagreement on when term, biomarkers of organ involvement should progressively
treatment should be started at relapse.75-77 This is relevant not decrease and normalize, indicating amyloid FLC concentration is
only for individual patient management but also for the lack of kept at a level that does not prevent recovery of organ dysfunc-
validated definition of progression-free survival in clinical trials. tion.50 In fit patients who fail to attain organ response despite
However, it is generally agreed that organ progression should CR, MRD assessment can be useful, and further therapy can be
not be awaited, because this is associated with shorter survival considered if MRD is detected.49 The role of MRD as an end
and time to dialysis.39,51 Indeed, it is common practice at point in AL amyloidosis should be explored in future studies.

HOW I TREAT AL AMYLOIDOSIS blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 2925
 ASCT eligible Not ASCT eligible

ASCT Consider regimens used

upfront

No previous dara Previous exposure to

and/or bortezomib dara and/or bortezomib

• Clinical trials • Clinical trials

• Dara/bort/dex • Len/dex

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

• Dara/len/dex • Pom/dex
• Dara single agent • Ixa/dex
• CyBorD or BMDex • MDex
• Bort/Dex • Venetoclax in patients with
• MDex t(11;14)
according to access to the • Bendamustine/rituximab in
different therapeutic agents IgM-AL amyloidosis
according to access to the
different therapeutic agents

Figure 4. Rescue treatment algorithm for AL amyloidosis. Relapsed/refractory patients should be enrolled in clinical trials whenever possible. Treating relapsed
patients with a different class of agents than that used in upfront therapy is associated with prolonged PFS but has no impact on OS.107 Thus, if response to the
previous line of therapy lasted at least 12 to 18 months, retreatment with the same drugs can be considered. Eligible patients who did not perform ASCT can
be transplanted at relapse. At present, many relapsing patients have not been exposed to daratumumab, and this agent alone or combined with bortezomib or
lenalidomide can be used safely and effectively at relapse.65,67,108 Immune modulatory drugs are commonly used in the treatment of relapsed/refractory patients with
AL amyloidosis. Lenalidomide and pomalidomide grant hematologic response in approximately 50% of patients with generally low (15%) CR rates and can rescue
patients who are refractory to alkylators, proteasome inhibitors, and other immunomodulatory drugs.109,110 Immunomodulatory drugs cause an increase in
cardiac biomarkers that interferes with the assessment of cardiac response, and lenalidomide may worsen renal function in subjects with elevated proteinuria.111 The
second-generation, orally available proteasome inhibitor ixazomib is active in patients previously exposed to bortezomib.92,112 Recent studies reported high CR/VGPR
rates (80%) in relapsed/refractory patients with t(11;14) treated with venetoclax.27 Bendamustine can be considered in patients with IgM-AL amyloidosis. Dara,
daratumumab; Dex, Dexamethasone; Ixa, Ixazomib; Len, lenalidomide; OS; overall survival; PFS, progression-free survival; Pom, pomalidomide.

Case 5: an older woman with bendamustine, rituximab, and dexamethasone, which was
well tolerated, and after 4 cycles, a low dFLC response was
lymphadenopathy and an IgM reached (dFLC, 4 mg/L; ratio, 0.63; monoclonal component,
monoclonal protein 10 g/L). Two more cycles were performed without improve-
ment of hematologic response while alkaline phosphatase
A 77-year-old woman was referred to a hematologist
normalized. The patient is hematologically and clinically sta-
because of bilateral enlarged cervical lymph nodes. Subse-
ble 1 year after treatment discontinuation.
quent investigations showed mediastinal and retroperito-
neal lymphadenopathy (,2 cm). An IgMl monoclonal
Comments on patient 5
component was detected. Blood tests were all normal. A
IgM-related AL amyloidosis is a distinct clinical entity that
lymph node biopsy showed amyloid deposits. No clonal
accounts for 6% to 10% of all AL amyloidosis cases.83,84 Local-
lymphocytes or plasma cells were detected in her bone
ized amyloid deposits are more common, as well as lymph
marrow. The patient was followed closely without therapy.
nodes, peripheral nervous system, and lung involvement, and
After 2 years, bilateral, symmetrical, ascending, sensitive,
amyloid FLC levels tend to be lower. The level of cardiac bio-
peripheral neuropathy appeared, and the patient was
markers is prognostic, but liver involvement and peripheral neu-
referred to our center. The concentration of the monoclonal ropathy also predict a poor outcome and were incorporated in a
protein was 25 g/L, l FLC level was 40 mg/L (dFLC, 24 mg/ staging system specific for IgM-AL amyloidosis.84 Peripheral
L; ratio, 0.40), hemoglobin level was 11.5 g/dL, and alkaline neuropathy is frequently symptomatic, but it is not detected by
phosphatase level was 360 U/L (upper reference limit, 150 nerve conduction studies. Having both peripheral nervous sys-
U/L) with normal bilirubin and aminotransferases. Testing for tem and liver involvement, this patient classified stage III despite
anti-myelin–associated glycoprotein and anti-ganglioside normal cardiac biomarkers.
antibodies was negative. Nerve conduction studies showed
a purely axonal pattern. There were no signs of amyloid car- In most patients with IgM-AL amyloidosis, the clone can be
diac or renal involvement. We repeated a bone marrow detected in the bone marrow at diagnosis. The underlying clone
biopsy that showed a 7% clonal, CD20-positive lymphoplas- can be a pure PC (in 25% of cases) or a lymphoplasmacytic
macytic infiltrate. The clone harbored both the MYD88L265P neoplasm (in 65% of cases) as in the present case, and this is
and the CXCR4 mutations. The patient was treated with relevant for the choice of treatment.85 Lymphoplasmacytic

2926 blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 PALLADINI and MERLINI
clones harbor the MYD88 (95%-97%), CXCR4 (30%-40%), in these patients. New therapies are emerging, and more
ARID1A (17%), and CD79B (8%-15%) mutations. Patients with than 20 interventional trials are now recruiting. Immuno-
IgM-AL amyloidosis caused by pure plasma cell clones should therapies showing promise in MM will hopefully be
be treated like patients with non–IgM-AL amyloidosis, whereas offered to patients with AL amyloidosis. The anti-CD38
patients with lymphoplasmacytic clones are generally treated antibody isatuximab showed encouraging results in a
with rituximab-containing regimens, based on treatments devel- recent phase 2 clinical trial in relapsed/refractory patients
oped in Waldenstr€ om macroglobulinemia. Rituximab can be (NCT03499808).93 Chimeric antigen receptor T cells, and
combined with dexamethasone and cyclophosphamide, borte- bispecific T-cell engager antibodies and antibody–drug
zomib, or bendamustine.86-88 Patients with IgM-AL amyloidosis conjugates, such as belantamab mafodotin that is being
can also successfully undergo autologous stem cell transplant.89 evaluated in a European trial (NCT04617925), will allow tar-
Ibrutinib can be an option in patients with favorable mutational geting additional PC antigens. Finally, the continuous, stim-
pattern, but a first report highlighted a rather poor tolerability ulating progress in basic and translational research are
and scarce efficacy of this drug.90 Patients with IgM-AL amyloid- offering new insights in the mechanisms of disease, and
osis have lower response rates and shorter survival than other there is hope that new treatment targets will eventually be
patients with AL amyloidosis when adjusted to stage.85 made available.

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

Neuropathy was the main reason to start treatment in this sub-
ject. The differential diagnosis of monoclonal gammopathies of Acknowledgments
neurologic significance is challenging.91 In this patient, age was The authors received research support by a grant from CARIPLO
considered a contraindication to ASCT, and we preferred a “Harnessing the plasma cell secretory capacity against systemic
light chain amyloidosis” (grant 2018-0257), a grant from the Italian
bortezomib-free combination because of neuropathy. The vali- Ministry of Health “Towards effective, patient-tailored anti-plasma
dated response criteria of the International Society of Amyloid- cell therapies in AL amyloidosis: predicting drug response and
osis consistently predict survival and can be used in IgM-AL overcoming drug resistance” (grant GR-2018-12368387), and by a
amyloidosis.84 grant from Cancer Research United Kingdom, Fundaci on Cientıfica
Asociaci
on Espa~nola Contra el Cancer, and Associazione Italiana per
la Ricerca sul Cancro under the Accelerator Award 2017 Program
“Early detection and intervention: understanding the mechanisms of
Conclusion transformation and hidden resistance of incurable haematological
After many years of empirical treatment, the therapy of malignancies.”
patients with AL amyloidosis has now entered the realm of
evidence-based medicine, with 3 international clinical trials
completed in the last 2 years.44,73,92 We should now further Authorship
exploit these achievements with new controlled trials based Contribution: G.P. and G.M. wrote the manuscript.
on validated end points. However, our evidence-based
Conflict-of-interest disclosure: G.P. reports honoraria for lectures from
knowledge only covers a small part of the management of
and membership on advisory boards with Janssen and honoraria for lec-
patients with AL amyloidosis. Daratumumab-bortezomib tures from Pfizer and Siemens. G.M. declares no competing financial
combinations can be used as frontline therapy in almost all interests.
patients, and the key eligibility criteria to safely proceed to
ASCT are now shared by referral centers. However, impor- ORCID profiles: G.P., 0000-0001-5994-5138; G.M., 0000-0001-7680-
tant questions, such as best treatment at relapse, role of 3254.
maintenance, and the most cost-effective approach in
patients with specific chromosomal abnormalities still need Correspondence: Giampaolo Merlini, Amyloidosis Research and Treat-
ment Center, Foundation IRCCS Policlinico San Matteo, Viale Golgi,
to be answered in controlled studies. For these reasons,
19, 27100 Pavia, Italy; e-mail: gmerlini@unipv.it.
patients should still be referred to specialized centers and
treated within clinical trials whenever possible. With a grow-
ing therapeutic armamentarium, survival has more than tri- Footnotes
pled; however, no progress was made in patients with Submitted 21 June 2021; accepted 18 August 2021; prepublished
stage IIIb. Amyloid-directed therapy is an appealing oppor- online on Blood First Edition 13 September 2021. DOI 10.1182/
tunity to accelerate recovery of organ function, particularly blood.2020008737.

REFERENCES increase in cellular oxidant stress. Circ Res. 6. Merlini G, Lousada I, Ando Y, et al.
1. Merlini G, Dispenzieri A, Sanchorawala V, et 2004;94(8):1008-1010. Rationale, application and clinical
al. Systemic immunoglobulin light chain qualification for NT-proBNP as a surrogate
4. Lavatelli F, Imperlini E, Orr
u S, et al. Novel end point in pivotal clinical trials in patients
amyloidosis. Nat Rev Dis Primers. 2018;
mitochondrial protein interactors of with AL amyloidosis. Leukemia. 2016;
4(1):38.
immunoglobulin light chains causing heart 30(10):1979-1986.
2. Palladini G, Milani P, Merlini G. amyloidosis. FASEB J. 2015;
Management of AL amyloidosis in 29(11):4614-4628. 7. Marin-Argany M, Lin Y, Misra P, et al. Cell
2020. Hematology (Am Soc Hematol damage in light chain amyloidosis: fibril
5. Shi J, Guan J, Jiang B, et al. internalization, toxicity and cell-mediated
Educ Program). 2020;
2020(1):363-371. Amyloidogenic light chains induce seeding. J Biol Chem. 2016;
cardiomyocyte contractile dysfunction and 291(38):19813-19825.
3. Brenner DA, Jain M, Pimentel DR, et al. apoptosis via a non-canonical p38alpha
Human amyloidogenic light chains directly MAPK pathway. Proc Natl Acad Sci USA. 8. Comenzo RL, Zhang Y. Ig V-L germline gene
impair cardiomyocyte function through an 2010;107(9):4188-4193. use and plasma cell burden in AL amyloidosis

HOW I TREAT AL AMYLOIDOSIS blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 2927
 (AL) contribute to the tropism of organ- 21. Garofalo M, Piccoli L, Romeo M, et al. 35. Palladini G, Sachchithanantham S, Milani P,
system involvement. Blood. 2000; Machine learning analyses of antibody et al. A European collaborative study of
96(11):154A. somatic mutations predict immunoglobulin cyclophosphamide, bortezomib, and
light chain toxicity. Nat Commun. 2021; dexamethasone in upfront treatment of
9. Perfetti V, Palladini G, Casarini S, et al. The 12(1):3532. systemic AL amyloidosis. Blood. 2015;
repertoire of l light chains causing 126(5):612-615.
predominant amyloid heart involvement 22. Zhou P, Kugelmass A, Toskic D, et al.
and identification of a preferentially Seeking light-chain amyloidosis very early: 36. Lilleness B, Ruberg FL, Mussinelli R, Doros
involved germline gene, IGLV1-44. Blood. the SAVE trial identifying clonal lambda G, Sanchorawala V. Development and
2012;119(1):144-150. light chain genes in patients with MGUS or validation of a survival staging system
smoldering multiple myeloma. J Clin incorporating BNP in patients with light
10. Abraham RS, Geyer SM, Price-Troska TL, et Oncol. 2019;37(15):8010. chain amyloidosis. Blood. 2019;
al. Immunoglobulin light chain variable (V) 133(3):215-223.
region genes influence clinical presentation 23. Merlini G, Stone MJ. Dangerous small
and outcome in light chain-associated amy- B-cell clones. Blood. 2006; 37. Kumar S, Dispenzieri A, Lacy MQ, et al.
loidosis (AL). Blood. 2003;101(10):3801-3808. 108(8):2520-2530. Revised prognostic staging system for light
chain amyloidosis incorporating cardiac
11. Kourelis TV, Dasari S, Theis JD, et al. 24. Oliva L, Orfanelli U, Resnati M, et al. The biomarkers and serum free light chain
Clarifying immunoglobulin gene usage amyloidogenic light chain is a stressor that measurements. J Clin Oncol. 2012;
in systemic and localized sensitizes plasma cells to proteasome 30(9):989-995.

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

immunoglobulin light-chain amyloidosis inhibitor toxicity. Blood. 2017;
by mass spectrometry. Blood. 2017; 129(15):2132-2142. 38. Palladini G, Milani P, Foli A, et al. Oral
129(3):299-306. melphalan and dexamethasone grants
25. Merlini G. CyBorD: stellar response rates in
extended survival with minimal toxicity in
12. Perfetti V, Casarini S, Palladini G, et al. AL amyloidosis. Blood. 2012;
AL amyloidosis: long-term results of a risk-
Analysis of V(lambda)-J(lambda) expression 119(19):4343-4345.
adapted approach. Haematologica. 2014;
in plasma cells from primary (AL) 99(4):743-750.
amyloidosis and normal bone marrow 26. Bochtler T, Hegenbart U, Kunz C, et al.
identifies 3r (lambdaIII) as a new amyloid- Translocation t(11;14) is associated with
39. Palladini G, Hegenbart U, Milani P, et al. A
adverse outcome in patients with newly
associated germline gene segment. Blood. staging system for renal outcome and early
diagnosed AL amyloidosis when treated
2002;100(3):948-953. markers of renal response to chemotherapy
with bortezomib-based regimens. J Clin
in AL amyloidosis. Blood. 2014;
13. Oberti L, Rognoni P, Barbiroli A, et al. Oncol. 2015;33(12):1371-1378.
124(15):2325-2332.
Concurrent structural and biophysical traits
27. Premkumar VJ, Lentzsch S, Pan S, et al.
link with immunoglobulin light chains 40. Sanchorawala V, Sun F, Quillen K, Sloan
Venetoclax induces deep hematologic
amyloid propensity. Sci Rep. 2017; JM, Berk JL, Seldin DC. Long-term
remissions in t(11;14) relapsed/refractory
7(1):16809. outcome of patients with AL amyloidosis
AL amyloidosis. Blood Cancer J. 2021;
treated with high-dose melphalan and stem
14. Morgan GJ, Kelly JW. The kinetic 11(1):10.
cell transplantation: 20-year experience.
stability of a full-length antibody light Blood. 2015;126(20):2345-2347.
28. Bochtler T, Hegenbart U, Kunz C, et al.
chain dimer determines whether endo-
Gain of chromosome 1q21 is an
proteolysis can release amyloidogenic 41. Sidiqi MH, Aljama MA, Buadi FK, et al.
independent adverse prognostic factor in
variable domains. J Mol Biol. 2016; Stem cell transplantation for light chain
light chain amyloidosis patients treated
428(21):4280-4297. amyloidosis: decreased early mortality over
with melphalan/dexamethasone. Amyloid.
2014;21(1):9-17. time. J Clin Oncol. 2018;36(13):1323-1329.
15. Blancas-Mejıa LM, Tischer A, Thompson JR,
et al. Kinetic control in protein folding for 29. Bochtler T, Merz M, Hielscher T, et al. 42. Gertz MA, Schonland S. Stem cell
light chain amyloidosis and the differential Cytogenetic intraclonal heterogeneity of mobilization and autologous transplant for
effects of somatic mutations. J Mol Biol. plasma cell dyscrasia in AL amyloidosis as immunoglobulin light-chain amyloidosis.
2014;426(2):347-361. compared with multiple myeloma. Blood Hematol Oncol Clin North Am. 2020;
Adv. 2018;2(20):2607-2618. 34(6):1133-1144.
16. Maritan M, Romeo M, Oberti L, et al.
inherent biophysical properties modulate 30. Alameda D, Goicoechea I, Vicari M, et al. 43. Cornell RF, Fraser R, Costa L, et al.
the toxicity of soluble amyloidogenic light Tumor cells in light-chain amyloidosis and Bortezomib-based induction is associated
chains. J Mol Biol. 2020;432(4):845-860. myeloma show different transcriptional with superior outcomes in light chain
rewiring of normal plasma cell develop- amyloidosis patients treated with
17. Morgan GJ, Yan NL, Mortenson DE, et al. autologous hematopoietic cell
ment. Blood. 2021;blood.2020009754.
Stabilization of amyloidogenic transplantation regardless of plasma cell
immunoglobulin light chains by small 31. Dispenzieri A, Gertz MA, Kyle RA, et al. burden. Transplant Cell Ther. 2021;
molecules. Proc Natl Acad Sci USA. 2019; Serum cardiac troponins and N-terminal 27(3):264.
116(17):8360-8369. pro-brain natriuretic peptide: a staging sys-
tem for primary systemic amyloidosis. 44. Kastritis E, Palladini G, Minnema MC, et al;
18. Yan NL, Santos-Martins D, Nair R, et al. ANDROMEDA Trial Investigators.
J Clin Oncol. 2004;22(18):3751-3757.
Discovery of potent coumarin-based kinetic Daratumumab-based treatment for
stabilizers of amyloidogenic immunoglobu- 32. Kourelis TV, Kumar SK, Go RS, et al. immunoglobulin light-chain amyloidosis. N
lin light chains using structure-based Immunoglobulin light chain amyloidosis is Engl J Med. 2021;385(1):46-58.
design. J Med Chem. 2021; diagnosed late in patients with preexisting
64(9):6273-6299. plasma cell dyscrasias. Am J Hematol. 45. Abdallah N, Sidana S, Dispenzieri A, et al.
2014;89(11):1051-1054. Outcomes with early vs. deferred stem cell
19. Kumar S, Murray D, Dasari S, et al. Assay to transplantation in light chain amyloidosis.
rapidly screen for immunoglobulin light 33. Schulman A, Connors LH, Weinberg J, et Bone Marrow Transplant. 2020;
chain glycosylation: a potential path to al. Patient outcomes in light chain (AL) 55(7):1297-1304.
earlier AL diagnosis for a subset of patients amyloidosis: The clock is ticking from
[correction published in Leukemia. symptoms to diagnosis. Eur J Haematol. 46. Basset M, Milani P, Nuvolone M, et al.
2019;33:1060]. Leukemia. 2019; 2020;105(4):495-501. Sequential response-driven bortezomib-
33(1):254-257. based therapy followed by autologous
34. Merlini G, Palladini G. Differential diagnosis stem cell transplant in AL amyloidosis.
20. Milani P, Murray DL, Barnidge DR, et al. of monoclonal gammopathy of Blood Adv. 2020;4(17):4175-4179.
The utility of MASS-FIX to detect and moni- undetermined significance. Hematology
tor monoclonal proteins in the clinic. Am J (Am Soc Hematol Educ Program). 2012; 47. Manwani R, Hegenbart U, Mahmood S, et
Hematol. 2017;92(8):772-779. 2012(1):595-603. al. Deferred autologous stem cell

2928 blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 PALLADINI and MERLINI
 transplantation in systemic AL amyloidosis. immunoglobulin light chain amyloidosis. Br treated with upfront bortezomib. Blood.
Blood Cancer J. 2018;8(11):101. J Haematol. 2018;182(1):145-148. 2019;134(25):2271-2280.

48. Palladini G, Sch€

onland S, Merlini G, et al. 60. Abdallah N, Muchtar E, Dispenzieri A, et al. 73. Kastritis E, Leleu X, Arnulf B, et al.
Real-world data on patient characteristics Coagulation abnormalities in light chain Bortezomib, melphalan, and
and treatment patterns for 3000 patients amyloidosis. Mayo Clin Proc. 2021; dexamethasone for light-chain amyloidosis.
with systemic AL amyloidosis in Europe 96(2):377-387. J Clin Oncol. 2020;38(28):3252-3260.
between 2011 and 2018: a retrospective
study by the European Myeloma Network. 61. Manwani R, Foard D, Mahmood S, et al. 74. Abdallah N, Dispenzieri A, Muchtar E, et al.
EHA Library. 2021;8:324734. Rapid hematologic responses improve Prognostic restaging after treatment
outcomes in patients with very advanced initiation in patients with AL amyloidosis.
49. Palladini G, Paiva B, Wechalekar A, et al. (stage IIIb) cardiac immunoglobulin light Blood Adv. 2021;5(4):1029-1036.
Minimal residual disease negativity by next- chain amyloidosis. Haematologica. 2018;
generation flow cytometry is associated 103(4):e165-e168. 75. Milani P, Gertz MA, Merlini G, Dispenzieri
with improved organ response in AL amy- A. Attitudes about when and how to treat
loidosis. Blood Cancer J. 2021;11(2):34. 62. Kristen AV, Kreusser MM, Blum P, et al. patients with AL amyloidosis: an
Improved outcomes after heart international survey [correction published in
50. Muchtar E, Dispenzieri A, Leung N, et al. transplantation for cardiac amyloidosis in Amyloid. 2017;24(4):256]. Amyloid. 2017;
Depth of organ response in AL amyloidosis the modern era. J Heart Lung Transplant. 24(4):213-216.
is associated with improved survival: 2018;37(5):611-618.

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

grading the organ response criteria. 76. Sanchorawala V. Delay treatment of AL
Leukemia. 2018;32(10):2240-2249. 63. Papa R, Lachmann HJ. Secondary, AA, amyloidosis at relapse until symptomatic:
amyloidosis. Rheum Dis Clin North Am. devil is in the details. Blood Adv. 2019;
51. Palladini G, Dispenzieri A, Gertz MA, et al. 2018;44(4):585-603. 3(2):216-218.
New criteria for response to treatment in
immunoglobulin light chain amyloidosis 64. Muchtar E, Gertz MA, Kourelis TV, et al. 77. Palladini G, Merlini G. When should
based on free light chain measurement and Bone marrow plasma cells 20% or greater treatment of AL amyloidosis start at
cardiac biomarkers: impact on survival discriminate presentation, response, and relapse? Early, to prevent organ
outcomes. J Clin Oncol. 2012; survival in AL amyloidosis [correction progression. Blood Adv. 2019;3(2):212-215.
30(36):4541-4549. published in Leukemia. 2020;34:2819].
Leukemia. 2020;34(4):1135-1143. 78. Hwa YL, Warsame R, Gertz MA, et al.
52. Gertz MA, Comenzo R, Falk RH, et al. Delineation of the timing of second-line
Definition of organ involvement and 65. Kimmich CR, Terzer T, Benner A, et al. therapy post-autologous stem cell trans-
treatment response in immunoglobulin Daratumumab for systemic AL amyloidosis: plant in patients with AL amyloidosis.
light chain amyloidosis (AL): a consensus prognostic factors and adverse outcome
Blood. 2017;130(13):1578-1584.
opinion from the 10th International with nephrotic-range albuminuria. Blood.
Symposium on Amyloid and Amyloidosis, 2020;135(18):1517-1530. 79. Palladini G, Milani P, Foli A, et al.
Tours, France, 18-22 April 2004. Am Presentation and outcome with second-line
J Hematol. 2005;79(4):319-328. 66. Drayson MT, Bowcock S, Planche T, et al;
treatment in AL amyloidosis previously sen-
TEAMM Trial Management Group and
sitive to nontransplant therapies. Blood.
53. Milani P, Basset M, Russo F, Foli A, Merlini Trial Investigators. Levofloxacin
2018;131(5):525-532.
G, Palladini G. Patients with light-chain prophylaxis in patients with newly
amyloidosis and low free light-chain burden diagnosed myeloma (TEAMM): a 80. Cohen OC, Sharpley F, Gillmore JD, et al.
have distinct clinical features and outcome. multicentre, double-blind, placebo-con- Use of ixazomib, lenalidomide and
Blood. 2017;130(5):625-631. trolled, randomised, phase 3 trial. Lancet dexamethasone in patients with relapsed
Oncol. 2019;20(12):1760-1772. amyloid light-chain amyloidosis. Br J Hae-
54. Dittrich T, Bochtler T, Kimmich C, et al. AL
matol. 2020;189(4):643-649.
amyloidosis patients with low 67. Roussel M, Merlini G, Chevret S, et al. A
amyloidogenic free light chain levels at first prospective phase 2 trial of daratumumab 81. Kastritis E, Fotiou D, Theodorakakou F, et
diagnosis have an excellent prognosis. in patients with previously treated systemic al. Timing and impact of a deep response
Blood. 2017;130(5):632-642. light-chain amyloidosis. Blood. 2020;
in the outcome of patients with systemic
135(18):1531-1540.
light chain (AL) amyloidosis. Amyloid. 2021;
55. Goto S, Mahara K, Beussink-Nelson L, et al.
68. Palladini G, Kastritis E, Maurer MS, et al. 28(1):3-11.
Artificial intelligence-enabled fully auto-
mated detection of cardiac amyloidosis Daratumumab plus CyBorD for patients
82. Sidana S, Milani P, Binder M, et al. A
using electrocardiograms and echocardio- with newly diagnosed AL amyloidosis:
validated composite organ and
grams. Nat Commun. 2021;12(1):2726. safety run-in results of ANDROMEDA.
hematologic response model for early
Blood. 2020;136(1):71-80.
56. Palladini G, Sch€
onland S, Merlini G, et al. assessment of treatment outcomes in light
First glimpse on real-world efficacy out- 69. Muchtar E, Dispenzieri A, Gertz MA, et al. chain amyloidosis. Blood Cancer J. 2020;
comes for 2000 patients with systemic light Treatment of AL amyloidosis: Mayo 10(4):41.
chain amyloidosis in europe: a retrospec- stratification of myeloma and risk-adapted
83. Palladini G, Russo P, Bosoni T, et al. AL
tive observational multicenter study by the therapy (mSMART) consensus statement
amyloidosis associated with IgM
European Myeloma Network. Blood. 2020; 2020 update. Mayo Clin Proc. 2021;
monoclonal protein: a distinct clinical
136(suppl 1):50-51. 96(6):1546-1577.
entity. Clin Lymphoma Myeloma. 2009;
57. D’Souza A, Osman K, Costa Chase C, 70. Cibeira MT, Ortiz-P
erez JT, Quintana LF, 9(1):80-83.
Borham A, Bruno M. The hematologist’s Fern
adez de Larrea C, Tovar N, Blade J.
Supportive care in AL amyloidosis. Acta 84. Sachchithanantham S, Roussel M, Palladini
role in amyloidosis management: disease
awareness, diagnostic workup, and practice Haematol. 2020;143(4):335-342. G, et al. European Collaborative Study
patterns. Blood. 2020; defining clinical profile outcomes and novel
136(Supplement 1):28-29. 71. Le Bras F, Molinier-Frenkel V, Guellich A, et prognostic criteria in monoclonal
al. Sequential cyclophosphamide- immunoglobulin M-Related light chain
58. Gillmore JD, Maurer MS, Falk RH, et al. bortezomib-dexamethasone unmasks the amyloidosis. J Clin Oncol. 2016;
Nonbiopsy diagnosis of cardiac harmful cardiac effect of dexamethasone in 34(17):2037-2045.
transthyretin amyloidosis. Circulation. 2016; primary light-chain cardiac amyloidosis. Eur
133(24):2404-2412. J Cancer. 2017;76:183-187. 85. Sidana S, Larson DP, Greipp PT, et al. IgM
AL amyloidosis: delineating disease
59. Rezk T, Whelan CJ, Lachmann HJ, et al. 72. Manwani R, Cohen O, Sharpley F, et al. A biology and outcomes with clinical,
Role of implantable intracardiac prospective observational study of 915 genomic and bone marrow morphological
defibrillators in patients with cardiac patients with systemic AL amyloidosis features. Leukemia. 2020;34(5):1373-1382.

HOW I TREAT AL AMYLOIDOSIS blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 2929
86. Palladini G, Foli A, Russo P, et al. transgenic mouse model of AL amyloidosis. 105. Manwani R, Cohen O, Sharpley F, et al. A
Treatment of IgM-associated AL amyloid- Blood. 2011;118(25):6610-6617. prospective observational study of 915
osis with the combination of rituximab, bor- patients with systemic AL amyloidosis
tezomib, and dexamethasone. Clin 96. Diomede L, Rognoni P, Lavatelli F, et al. A
treated with upfront bortezomib. Blood.
Lymphoma Myeloma Leuk. 2011; Caenorhabditis elegans-based assay
2019;134(25):2271-2280.
11(1):143-145. recognizes immunoglobulin light chains
causing heart amyloidosis. Blood. 2014; 106. Landau H, Hassoun H, Rosenzweig MA, et
87. Milani P, Sch€
onland S, Merlini G, et al. 123(23):3543-3552. al. Bortezomib and dexamethasone
Treatment of AL amyloidosis with
consolidation following risk-adapted mel-
bendamustine: a study of 122 patients. 97. Kumar SK, Dispenzieri A, Lacy MQ, et al.
Blood. 2018;132(18):1988-1991. phalan and stem cell transplantation for
Doxycycline used as post transplant
antibacterial prophylaxis improves survival patients with newly diagnosed light-chain
88. Lentzsch S, Lagos GG, Comenzo RL, et al. in patients with light chain amyloidosis amyloidosis. Leukemia. 2013;27(4):823-828.
Bendamustine with dexamethasone in undergoing autologous stem cell
relapsed/refractory systemic light-chain 107. Tandon N, Sidana S, Gertz MA, et al.
transplantation. Blood. 2012;120(21):3138. Treatment patterns and outcome following
amyloidosis: results of a phase II study.
J Clin Oncol. 2020;38(13):1455-1462. 98. Wechalekar AD, Whelan C. Encouraging initial relapse or refractory disease in
impact of doxycycline on early mortality in patients with systemic light chain
89. Sidiqi MH, Buadi FK, Dispenzieri A, et al. amyloidosis. Am J Hematol. 2017;
cardiac light chain (AL) amyloidosis. Blood
Autologous stem cell transplant for IgM- 92(6):549-554.

Downloaded from http://ashpublications.org/blood/article-pdf/139/19/2918/1896535/bloodbld2020008737c.pdf by guest on 20 August 2024

associated amyloid light-chain amyloidosis. Cancer J. 2017;7(3):e546.
Biol Blood Marrow Transplant. 2019; 108. Sanchorawala V, Sarosiek S, Schulman A, et
99. D’Souza A, Szabo A, Flynn KE, et al.
25(3):e108-e111. al. Safety, tolerability, and response rates
Adjuvant doxycycline to enhance anti-
amyloid effects: Results from the dual of daratumumab in relapsed AL
90. Pika T, Hegenbart U, Flodrova P, Maier B,
Kimmich C, Sch€ onland SO. First report of phase 2 trial. EClinicalMedicine. 2020; amyloidosis: results of a phase 2 study.
ibrutinib in IgM-related amyloidosis: few 23:100361. Blood. 2020;135(18):1541-1547.
responses, poor tolerability, and short sur-
100. Shen KN, Fu WJ, Wu Y, et al. Doxycycline 109. Mahmood S, Venner CP,
vival. Blood. 2018;131(3):368-371.
Combined With Bortezomib- Sachchithanantham S, et al. Lenalidomide
91. Castillo JJ, Callander NS, Baljevic M, Cyclophosphamide-Dexamethasone and dexamethasone for systemic AL
Sborov DW, Kumar S. The evaluation and Chemotherapy for Newly Diagnosed amyloidosis following prior treatment with
management of monoclonal gammopathy Cardiac Light-Chain Amyloidosis: A thalidomide or bortezomib regimens. Br J
of renal significance and monoclonal Multicenter Randomized Controlled Trial. Haematol. 2014;166(6):842-848.
gammopathy of neurological significance. Circulation. 2021 [Epub ahead of print].
Am J Hematol. 2021;96(7):846-853. 110. Milani P, Sharpley F, Sch€
onland SO, et al.
101. Law S, Cohen O, Lachmann HJ, et al. Renal Pomalidomide and dexamethasone
92. Dispenzieri A, Kastritis E, Wechalekar AD, transplant outcomes in amyloidosis. grant rapid haematologic responses in
et al. A randomized phase 3 study of Nephrol Dial Transplant. 2021; patients with relapsed and refractory AL
ixazomib-dexamethasone versus physician’s 36(2):355-365. amyloidosis: a European retrospective
choice in relapsed or refractory AL amyloid-
osis. Leukemia. 2021. series of 153 patients. Amyloid. 2020;
102. Dasari S, Theis JD, Vrana JA, et al. Amyloid
27(4):231-236.
typing by mass spectrometry in clinical
93. Parker T, Rosenthal A, Sanchorawala V, et
practice: a comprehensive review of 16,175 111. Specter R, Sanchorawala V, Seldin DC, et
al. A phase II study of isatuximab
samples. Mayo Clin Proc. 2020; al. Kidney dysfunction during lenalidomide
(SAR650984) (NSC-795145) for patients
with previously treated AL amyloidosis 95(9):1852-1864. treatment for AL amyloidosis. Nephrol
(SWOG S1702; NCT#03499808). Blood. Dial Transplant. 2011;26(3):881-886.
103. Fernandez de Larrea C, Verga L, Morbini P,
2020;136(suppl 1):20-21.
et al. A practical approach to the diagnosis 112. Sanchorawala V, Palladini G, Kukreti V, et
94. Edwards CV, Rao N, Bhutani D, et al. Phase of systemic amyloidoses. Blood. 2015; al. A phase 1/2 study of the oral
1a/b study of monoclonal antibody CAEL- 125(14):2239-2244. proteasome inhibitor ixazomib in relapsed
101 (11-1F4) in patients with AL or refractory AL amyloidosis [correction
104. Nguyen VP, Landau H, Quillen K, et al.
amyloidosis [published online ahead of published in Blood. 2020:135(13):1071].
print 14 September 2021]. Blood. 2021 Modified high-dose melphalan and autolo-
gous stem cell transplantation for immuno- Blood. 2017;130(5):597-605.
95. Ward JE, Ren R, Toraldo G, et al. globulin light chain amyloidosis. Biol Blood
Doxycycline reduces fibril formation in a Marrow Transplant. 2018;24(9):1823-1827. © 2022 by The American Society of Hematology

2930 blood® 12 MAY 2022 | VOLUME 139, NUMBER 19 PALLADINI and MERLINI