Al Hamed et al.

Blood Cancer Journal (2021)11:97

https://doi.org/10.1038/s41408-021-00486-4 Blood Cancer Journal

REVIEW ARTICLE Open Access

Comprehensive Review of AL amyloidosis: some

practical recommendations
Rama Al Hamed1, Abdul Hamid Bazarbachi 1
, Ali Bazarbachi2, Florent Malard 3
, Jean-Luc Harousseau4 and
Mohamad Mohty 3

Abstract
Amyloid light chain (AL) amyloidosis is among the more common and more severe of the amyloidoses usually
involving the slow proliferation of a bone-marrow-residing plasma cell (PC) clone and the secretion of unstable
immunoglobulin-free light chains (FLC) that infiltrate peripheral tissues and result in detrimental end-organ damage.
Disease presentation is rather vague, and the hallmark of treatment is early diagnosis before irreversible end-organ
damage. Once diagnosed, treatment decision is transplant-driven whereby ~20% of patients are eligible for
autologous stem cell transplantation (ASCT) with or without bortezomib-based induction. In the setting of ASCT-
ineligibility, bortezomib plays a central role in upfront treatment with the recent addition of daratumumab to the
current emerging standard of care. In general, management of AL amyloidosis is aimed at achieving deep, durable
responses with very close monitoring for early detection of relapse/refractory disease. This article provides a
comprehensive review of the management of patients with AL amyloidosis including goals of therapy, current
treatment guidelines in the setting of both ASCT-eligibility and ineligibility, treatment response monitoring
recommendations, toxicity management, and treatment of relapse/refractory disease.
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Introduction ultimately, failure. Organs involved usually include kid-

Systemic amyloidoses constitute disorders of diverse neys, heart, gastrointestinal (GI) tract, liver, and nervous
etiologies involving the synthesis and abnormal extra- system whereby undoubtedly cardiac involvement is the
cellular deposition of misfolded proteins in various organs main driver of disease prognosis and mortality2. Given
with resultant damage. Among the different amyloidoses, that more than 69% of patients already have more than
amyloid light chain (AL), previously called “primary”, one organ involved at the time of diagnosis3, it becomes
amyloidosis is among the more common and more severe, vital to not only diagnose AL amyloidosis early, but to also
affecting ~10 per million per year1. Even though rarely effectively control plasma cell dyscrasias and thus halt
due to a nonplasma cell B-cell close, AL amyloidosis is escalating organ damage.
usually a plasma cell (PC) disorder whereby a small, Owing to toxicity, autologous stem cell transplantation
slowly proliferating, bone-marrow-residing PC clone, (ASCT) remains the standard of care and first-line treat-
secretes unstable immunoglobulin light chains. Those ment in a small proportion of patients. Importantly, the
amyloidogenic free light chains (FLCs) can then infiltrate outcome of ASCT-ineligible patients has improved by the
peripheral organs resulting in organ dysfunction and introduction of new first-line agents, specifically borte-
zomib. Currently, active research involving second-line
novel treatments and anti-CD38 antibodies offers new
Correspondence: Mohamad Mohty (mohamad.mohty@inserm.fr) hope. Nonetheless, the main hallmark of management
1
Department of Internal Medicine, Jacobi Medical Center, Albert Einstein remains early recognition and initiation of treatment
College of Medicine, New York, NY, USA
2 before the occurrence of irreversible organ damage.
Department of Internal Medicine, American University of Beirut, Beirut,
Lebanon
Full list of author information is available at the end of the article

© The Author(s) 2021

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It becomes vital to differentiate AL amyloidosis from diagnosis before symptom onset. This includes mono-
transthyretin (TTR) amyloidosis, another disease of clonal gammopathy of undetermined significance
increasing prevalence, due to the difference in manage- (MGUS) patients who would benefit from regular follow-
ment. TTR is a liver-synthesized thyroxine and vitamin A up of markers such as N-terminal pro-brain natriuretic
transporter4,5. Age (wild-type, previously called senile peptide (NT-proBNP) and albuminuria, which could
amyloidosis) or an autosomal dominant amino acid sub- begin to rise before overt HF and nephrotic syndrome
stitution (mutant) result in fibrillogenesis whereby TTR develop8,9 (Fig. 1). Once suspected and a monoclonal
dissociates into intermediates that misassemble into component is confirmed, confirmation requires tissue
amyloid fibrils and deposit in end-organs, most notably biopsy (fat pad, bone marrow (BM), salivary gland,
the heart6. While AL amyloidosis is treated with che- involved organ) and typing (mass spectrometry [current
motherapy and transplant, TTR cardiac amyloidosis is gold standard], immunogold electron microscopy,
treated with targeted therapy such as tafamidis7. immunofluorescence, and immunohistochemistry) fol-
lowed by risk stratification and disease staging9 (Fig. 1).
Diagnostic approach There are four staging models that utilize cardiac
The symptoms and the presentation of amyloidosis soluble biomarkers—Mayo 2004 model, European 2015
depend on the organs involved in the disease and so, modification of Mayo 2004 model, Mayo 2012 model, and
patients can present with a myriad of unspecific symp- Boston University (BU) model10–14 (Table 1). The Mayo
toms that could be easily misinterpreted, thus clouding 2004 model, uses troponin T (TnT) and NT-proBNP and
the diagnosis of amyloidosis and delaying treatment categorizes disease into one of three stages according to
initiation. Common symptom constellations include, but the specified thresholds of TnT <;0.035 microg/L and NT-
are not limited to, heart failure with preserved ejection proBNP < 332 ng/L11. Depending on whether TnT and
fraction (HFpEF), nephrotic range proteinuria, organo- NT-proBNP were both low, only one was high or both
megaly due to amyloid deposition (hepatomegaly, mac- were elevated, disease was classified as stage I, II, or III,
roglossia, enlarged salivary glands etc.), peripheral respectively11. In 2015, a European group proposed a
neuropathy, and constitutional symptoms (weight loss, modification of the Mayo 2004 model, in which patients
fatigue) (Fig. 1). By the time such symptoms surface, classified in stage III of the Mayo model were further
organ damage has already occurred. It thus becomes subclassified into low-risk and high-risk groups, stage IIIA
important to identify high-risk patient populations who and IIIB, using a new threshold for NT-proBNP of
would benefit from regular screening to establish a 8500 ng/L. Patients with an NT-proBNP > 8500 ng/L had

Fig. 1 Monitoring, presenting symptoms, anddiagnosis of AL amyloidosis. MGUS monoclonal gammopathy of undetermined significance,
NT-proBNP N-terminal pro b-type natriuretic peptide.

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Table 1 Amyloidosis staging models.

Model Criteria Points Score Stage

Mayo 2004 Troponin (TnT) > 0.035 microg/L 1 point 0 Stage I

1 Stage II
NT-proBNP > 332 ng/L 1 point 2 Stage III
Mayo 2012 Troponin (TnT) ≥ 0.025 ng/mL 1 point 0 Stage I
1 Stage II
NT-proBNP ≥ 1800 pg/mL 1 point 2 Stage III
dFLC ≥ 18 mg/dL 1 point 3 Stage IV
European 2015 Troponin (TnT) > 0.035 microg/L 1 point 0 Stage I
1 Stage II
NT-proBNP > 332 ng/L 1 point
2 Stage IIIa
NT-proBNP > 8500 ng/L 1 additional point if score = 2
3 Stage IIIb
BU 2019 Troponin (TnI) ≥ 0.1 ng/mL 1 point 0 Stage I
1 Stage II
BNP ≥ 81 pg/mL 1 point
2 Stage III
BNP ≥ 700 pg/mL 1 additional point if score = 2
3 Stage IIIb

higher risk disease and poorer prognosis12. The Mayo Risk-adapted management approach
model was revised in 2012 incorporating different When choosing the appropriate treatment approach,
thresholds for TnT and NT-proBNP and introducing potential organ impairment needs to be considered. While
difference in FLC (dFLC) as an additional marker for the younger and fitter patient can tolerate more intense
disease burden13. One point was attributed to each of therapy, the frailer one has poor treatment tolerance and
TnT ≥ 0.025 ng/mL, NT-proBNP ≥ 1800 pg/mL, and is, as such, at an increased risk of early mortality. The
dFLC ≥ 18 mg/dL, thus classifying disease into four stages, determination of frailty in amyloidosis is not accompanied
I–IV according to a total score of 0–3, respectively13. by specific frailty scores, but short-term survival can be
Recently, the BU group derived a new staging system that used as a surrogate to estimate frailty. Age and the
correlates with the Mayo 2004 system, but utilizes BNP number, type and extent of organ involvement and to a
instead14. A BNP threshold >81 pg/mL best identified lesser extent, pre-existing comorbidities, are the main
cardiac involvement and thus correlated with the Mayo determinants of frailty in this patient population.
2004 staging system (κ = 0.854)14. Three stages were thus The Mayo Clinic investigators looked at the effect of
developed based on a BNP > 81 pg/mL and troponin I age, among other factors, on survival in a cohort of 592
(TnI) > 0.1 ng/mL, whereby disease was classified into patients with mass-spectrometry-verified AL amyloidosis
stages I, II, and III when both markers were lower than between 2008 and 2015. The cohort was followed up for 8
prespecified thresholds, only one was elevated or both years and the median overall survival (OS) was 44 months.
were elevated, respectively14. Furthermore, stage III was Dividing the patients into two age groups, <65 years and
further divided to include stage IIIb in the event of a BNP ≥65 years, it was evident that the younger patients had a
> 700 pg/mL14. This allows for centers without access to much better survival than those aged ≥65 years15.
NT-proBNP or TnT to accurately stage AL amyloidosis. It The effect of the number of organs involved on survival
is evident that the aforementioned models are very suc- was investigated in the same cohort. There was a sig-
cessful in dividing patients into distinct survival groups nificant decrease in survival as the number of organs
when examining the 12-year survival curves for the same involved increased (p < 0.001)15. However, it is not just the
patient dataset10. number of organs involved in the disease, but also the

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type of organs involved that determine survival. For ASCT (HDM-ASCT) remains the standard of care in low-
instance, comparing survival in patients with isolated risk patients19. Approximately 20% of patients are likely
cardiac involvement to those with cardiac plus multi- eligible for this procedure. For those ineligible, a cautious
organ involvement, yields very similar survival curves approach is necessary, involving standard intensity and,
between the two groups (p = 0.51)15. On the other hand, for the frailer patients, low-intensity therapies (Fig. 2).
comparing survival in patients with isolated renal invol- The eligibility criteria for ASCT have evolved over the
vement to those with renal plus multi-organ involvement, years and with the emergence of novel agents12,20–22.
yields significantly different survival curves (p < 0.001) Typically, potentially reversible contraindications are
whereby isolated renal involvement infers a survival assessed before deeming a patient ineligible for ASCT.
advantage compared to the latter. As such, cardiac Otherwise, the presence of one exclusion criteria, speci-
involvement is therefore the most important prognostic fically pertaining to cardiopulmonary or renal status could
factor in AL amyloidosis whereby when present, irre- suffice in making a patient ASCT-ineligible. The most
spective of other organ involvement, influences survival. common eligibility criteria for ASCT are9:
As previously discussed, several powerful staging models ●
Age < 70 years
build on cardiac involvement to classify disease and aid ●
Eastern Cooperative Oncology Group (ECOG)
treatment decisions. performance status < 2
Another important determinant of outcome and treat- ●
NYHA Class < III (New York Heart Association
ment response is cytogenetic profile. A recent retro- classification of the extent of heart failure)
spective chart review of 140 AL amyloidosis patients ●
Left ventricular ejection fraction (LVEF) > 45%
explored the most frequent cytogenetic abnormalities and ●
Systolic blood pressure (SBP) ≥ 100 mmHg
their impact on survival16. Sixty-one percent of the ●
TnT < 0.06 ng/mL or high-sensitivity (hs)-TnT <
patients harbored a cytogenetic abnormality, the most 75 ng/mL
common of which was translocation t(11;14) accounting ●
NT-proBNP < 5000 ng/L
for 44%, followed by hyperdiploidy (43%)16. A statistically ●
Creatinine clearance (CrCl) > 50 ml/min (unless on
significant relationship was noted between several chronic dialysis)
abnormalities and increased plasma cell (PC) burden, ●
Bilirubin < 2 mg/dL
including gain (+) 5p/5q (p = 0.025), del13q (0.009), ●
Diffusion capacity of the lungs for carbon monoxide
+11q (p < 0.001), and hyperdiploidy (p < 0.001)16. In (DLCO) > 50%
multivariable analysis, hyperdiploidy was confirmed a ●
No more than two organs significantly involved
significant poor prognostic factor16. In the setting of The choice of therapy for ASCT-eligible patients has
cardiac involvement, hyperdiploidy was also associated evolved over time and has been a matter of perspective for
with worsening progression-free survival (PFS) (p = many years. The advantages of stem cell transplantation
0.0497) and OS (p = 0.006)16. Similarly, del13q was are high response rate and response durability whereas the
associated with cardiac involvement but did not appear to disadvantages are the short-term morbidity and mortality
impact survival16. In addition, the overall presence of associated with it, which can be quite significant, and the
t(11;14) did not carry any prognostic value in terms of PFS fact that this therapy can only be offered to a minority of
and OS, although on further stratification, patients har- select patients. Nonetheless, complete response (CR) rates
boring isolated t(11; 14) had relatively worse PFS relative achieved with ASCT remain higher than those possible
to those without any cytogenetic abnormalities16. Con- with any other treatment regimen but data from two major
versely, the absence of any cytogenetic abnormalities was groups show that CR rates after ASCT are conditioning-
associated with improved PFS and OS (p = 0.042 and dose dependent23,24. A study carried out between July
0.019, respectively)16. This becomes important as well 1994 and December 2008 compared HDM (200 mg/m2) to
when choosing therapy. For instance, patients with +1q a reduced dose (100–140 mg/m2) in 421 AL amyloidosis
were found to have a better response to treatment with patients. The results demonstrated a significantly higher
daratumumab, a monoclonal receiving increased atten- CR rate in the high-dose group (43% versus 24%, p <
tion in the field16. As will be further discussed, patients 0.001)24. Similarly, between January 2000 and August
harboring t(11;14) are more likely to have disease resistant 2015, a study of 457 patients using the same melphalan
to bortezomib-based regimens and are more likely to conditioning-dose levels, showed a significantly higher CR
respond to venetoclax17,18. rate in the high-dose group (53% versus 37%, p = 0.003)23.
In both studies, high-dose melphalan was associated with
Treatment of ASCT-eligible patients lower transplant-related mortality (TRM) (9% versus 14%,
The first question to answer upon considering a treat- p = 0.12; 2% versus 6%, p = 0.01)23,24. The median PFS and
ment plan for a patient is whether or not the patient is OS were also significantly longer in the high-dose groups
eligible for ASCT. High-dose melphalan with subsequent in both studies.

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Fig. 2 Treatment algorithm for AL amyloidosis. ASCT autologous stem cell transplantation, ECOG Eastern Cooperative Oncology Group, NYHA
New York Heart Association classification of the extent of heart failure, LVEF left ventricular ejection fraction, SBP systolic blood pressure, TnT troponin
T, CrCl creatinine clearance, DLCO diffusion capacity of the lungs for carbon monoxide, BMPC bone marrow plasmacytosis, IMiD immunomodulatory
imide drugs, PI proteosome inhibitors, OS overall survival, G-CSF granulocyte colony-stimulating factor, CR complete remission, PFS progression-free
survival, ESRD end-stage renal disease, ORR overall response rate.

Despite the deeper responses achieved with ASCT ASCT as a treatment strategy, thus contributing to the
compared to other treatment modalities, it is important to study’s limitation. In addition, patient selection criteria
assess the durability of such a response. A recent study were not well established. For example, of the 50 patients
looking into the need for subsequent or second-line randomized to the HDM-ASCT arm, only 37 (74%) went
therapy after ASCT in 186 patients highlighted that in on to receive ASCT. This translated into a high day + 100
those who had survived for at least 10 years post diag- TRM of 24% in this group26. Most of the remaining
nosis, 47% remained treatment-free25. When categorized patients went on to have an early death26. Along the same
according to initial treatment modality, ASCT treatment lines, a systematic review of 12 studies also found no
versus standard-intensity therapies, 58% of ASCT patients advantage of ASCT over conventional chemotherapy in
were treatment-free at 10 years compared with only 36% improving OS in AL amyloidosis27. However, the evidence
in the non-ASCT group (Δ 22%)25. As such, long‐term was weak, and the authors cautioned that further research
survivors are increasingly seen in AL amyloidosis and was needed27.
ASCT is associated with a more durable response com- In North America between 1995 and 2012, a randomized,
pared with standard-intensity therapies. multicenter study of 1536 AL amyloidosis patients at 134
That said, a randomized controlled trial in 100 patients centers, demonstrated that the rate of early mortality after
performed between 2000 and 2005 by the Intergroupe ASCT at 30 days and 100 days progressively declined over
Francophone du Myélome (IFM) reported evidence that successive time periods (1995–2000, 2001–2006, and
argued against ASCT for AL amyloidosis26. It compared 2007–2012)28. At 30 days, the TRM rates were 10%, 7%, and
high-dose standard-intensity therapy (melphalan + dex- 4% for these time periods, respectively, and at 100 days 19%,
amethasone) with HDM and ASCT rescue. The non- 11%, and 4%, respectively, (p < 0.01)28. Also, centers per-
ASCT arm had an improved survival (p = 0.04)26. forming more than four transplantations per year for AL
Although HDM followed by ASCT had been in use for amyloidosis had superior survival outcomes28. This data
more than a decade by then, some of the participating highlight the importance of center experience in achieving
centers in the study had just started adopting HDM- better outcomes in this patient population but also explain

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one of the potential limitations of the IFM study—relatively induction followed by ASCT. Given the morbidity and
earlier time of investigation. mortality associated with transplantation, it is probably
best to wait and observe rather than proceed to ASCT in a
Induction chemotherapy patient who has achieved CR in response to induction
Another controversial aspect of ASCT in AL amyloi- chemotherapy. At this point though, stem cells could be
dosis is whether or not induction chemotherapy is collected for future ASCT. On the other hand, in patients
required. Hwa et al. investigated the impact of induction who achieve CR with induction chemotherapy but have a
chemotherapy on the response following transplant29. All higher chance of early relapse, proceeding to ASCT may
patients (n = 415) who received ASCT within 12 months be the better option if they are eligible for it. These may be
of diagnosis were included and were divided according to patients who have high-risk fluorescence in situ hybridi-
baseline bone marrow plasmacytosis (BMPC) level into zation (FISH) genetics (uncommon in amyloidosis
two groups (>10%, n = 116 versus ≤10%, n = 299)29. patients), such as those previously discussed, or patients
Patients with a low tumor burden (BMPC ≤ 10%) did not with very high BMPC at diagnosis, which resembles
show any difference in response rate irrespective of multiple myeloma (MM) with amyloidosis.
induction chemotherapy29. For patients with BMPC > Given the rapid progression of amyloidosis and the fact
10%, the results were very different though, whereby the that diagnosis and subsequent treatment are a race against
overall response rate (ORR) was significantly better with a the clock, it is imperative that patients do not suffer fur-
near doubling of the complete response (CR) rate in ther deterioration in organ function. As such, induction
patients who had received induction therapy pre-ASCT chemotherapy with bortezomib-based regimen should be
(34% versus 18%, p = 0.048)29. Afrough et al. highlighted considered for stem cell eligible patients, particularly with
the improved survival with pre-ASCT induction as well in BMPC > 10% or in the event of a foreseeable delay of
128 patients comparing conventional induction with >1 month in ASCT9.
melphalan or steroids to novel agents such as the thali-
domide-analogues, the immunomodulatory imide drugs ASCT-associated toxicity
(IMiDs), and proteosome inhibitors (PI) whereby hema- The first stage in the management of toxicity in relation
tological, but not organ response, was significantly higher to ASCT is during stem cell mobilization and collection
with IMiD/PI-based regimens30. Induction with IMiD/PI- whereby low serum albumin, elevated NT-proBNP and
based regimens was also found to be a significant positive increased septal thickening were found to be important
predictor of OS30. risk factors for toxicity34,35 During stem cell mobilization,
Multiple clinical trials have also looked into the role of patients can experience various toxicities including
bortezomib or bortezomib-based regimens in both tachyarrhythmias, thromboembolic events, weight gain
induction and conditioning. A prospective, single-arm (due to fluid retention), bleeding, acute kidney injury,
trial (NCT01083316) used bortezomib-dexamethasone hypertensive crises, or hypotension. To minimize risk of
(Vd) for induction followed by bortezomib-HDM for toxicity, it is recommended to use granulocyte-colony-
conditioning whereby 100% (n = 27) achieved hematolo- stimulating factor (G-CSF) without cyclophosphamide
gical response (HR) with 63% CR and 37% very good given the increased cardiac morbidity, significantly higher
partial response (VGPR) 6 months post-ASCT31. The number of apheresis required, increased hospitalizations
cohort of patients was followed up for an extended and increased toxicity associated with the latter36. The
median of 77 months whereby renal and cardiac respon- recommended dose of G-CSF is 10–16 μg/kg/day, either
ses occurred in 65% and 88%, respectively, at 5-years post- as one dose or divided into two doses, 3 days before stem
ASCT31. Median OS and PFS were not yet reached cell collection for an optimal total of at least 5 × 106 CD34+
highlighting the durability of response with the incor- cells/kg37. The general recommendation though, is to split
poration of bortezomib32. The phase II HOVON 104 trial the dose. If patients fail stem cell mobilization, plerixafor
(NTR3220) investigated the use of four cycles of Vd is a well-tolerated adjuvant36.
induction treatment, followed by HDM-ASCT33. The The major ASCT toxicities remain cardiac arrhythmias,
overall HR after induction was 80% including 20% CR and worsening HF, syncope, and end-stage renal disease
38% VGPR with improvement 6 months post-ASCT to (ESRD). Twenty-five percent of patients who have had
overall HR of 86% with 46% CR and 26% VGPR. The trial pretransplant 24-h Holter monitoring will have evidence
confirmed the efficacy of Vd and demonstrated the of nonsustained ventricular tachycardia (NSVT), a con-
amplified outcome post-ASCT. However, due to dition associated with an inferior short-term (6 months)
treatment-related toxicity and disease characteristics, survival38. On adjustment for cardiac (Mayo) stage, NSVT
primary endpoint could not be reached33. was actually not found to impact peritransplant mortality
It remains relatively unclear whether CR in response to and pretransplant NSVT is therefore not an exclusion
induction alone is comparative to CR in response to criterion13,38. As such, ~50% of patients will experience

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arrhythmias following ASCT, most of which will be low In summary, HDM-ASCT is a durable and reliable
grade but with grade 3/5 arrhythmias accounting for treatment option that allows for deep and sustainable
~10%39. It remains unclear whether primary AICD responses in a minority of select, eligible patients which
(Automatic Implantable Cardioverter Defibrillator) could be preceded by bortezomib-based induction ther-
implantation will be of benefit, even among those who are apy when BMPC > 10% or a foreseeable delay in ASCT is
at high-risk of sudden cardiac death and so, decisions expected. Despite its consistent results, treatment with
should be case specific. ASCT is associated with a handful of detrimental adverse
Worsening heart failure is another toxicity that may be events including arrhythmias, worsening HF and pro-
encountered during transplantation and about 5% of gression to ESRD, with the introduction of novel agents,
patients will have a reduction in EF of >10%, which such as bortezomib, resulting in improved results and
increases the 100-day mortality40. Multiple factors con- offering an alternate treatment modality.
tribute to the heart failure risk during peritransplant in
this population including electrolyte imbalance, medica- Treatment of ASCT-ineligible patients
tions, fluid overload, arrhythmia, temporary cessation of The survival pattern for transplant ineligible patients
cardiac medications, sepsis, and exacerbation of organ has been improving over time. Trends in presentation,
dysfunction during transplant. It is worth noting that management and outcome among 1551 newly diagnosed
standard heart failure treatments such as beta blockers, AL amyloidosis patients between 2000 and 2014 were
calcium channel blockers and/or ACE inhibitors, cannot evaluated and when stratified into three eras (2000–2004,
be used for worsening heart failure management in this 2005–2009, and 2010–2014), survival improved sig-
patient population and so should be avoided41. nificantly over time with OS rates of 25%, 46%, and 47%,
Another important toxicity that could complicate ASCT respectively, (p < 0.001)43.
is ESRD. In a study examining the association between The main first-line options for treatment of transplant
acute renal failure and mortality in AL amyloidosis during ineligible patients are (1) bortezomib-based regimens: Vd,
ASCT, the medical records of 408 ASCT patients between cyclophosphamide–bortezomib–dexamethasone (CyBorD),
1996 and 2010 were examined42. Dialysis was required by and bortezomib-melphalan-dexamethasone (BMDex), or (2)
72 (18%) patients. Eight patients started dialysis >30 days melphalan-dexamethasone (MDex) (Fig. 2). MDex was the
prior to ASCT (Group II), 36 started ±30 days after ASCT first standard-intensity regimen to produce a meaningful HR
(Group III) and 28 initiated dialysis >1 month after ASCT and was the reason for the aforementioned improved sur-
(Group IV) whereby patients who were never dialyzed vival from 2000 to 2014. The non-ASCT first-line regimen
were assigned to Group I42. Median OS was not reached changed over time with 65% of patients in 2010–2014
in Groups I and II but was 7 months in Group III and receiving bortezomib-based therapy, 79% of patients in
48.5 months in Group IV (p < 0.001)42. TRM was 2005–2009 receiving MDex, and 64% of patients in
observed in 44.4% of the patients in Group III, 6-fold 2000–2004 receiving melphalan-prednisone43. The rate of
higher than the next highest group with a TRM of only better than VGPR was higher in more recent periods (66% vs
3.6% (p < 0.001)42. The most common causes of TRM 58% vs 51%; p = 0.001), a change largely driven by improved
were cardiac and sepsis. In the multivariate analysis, only VGPR rates in the non-ASCT population43. In one study by
hypoalbuminemia (<2.5 g/dL, p < 0.001) and estimated Palladini et al., 0.22 mg/kg of melphalan plus 40 mg/day of
glomerular filtration rate (eGFR) <40 mL/min/1.73 m2 dexamethasone were given on days 1–4 in a 28-day cycle44.
(p < 0.001) were independently associated with starting The study proved that this combination resulted in high
dialysis within 30 days of ASCT42. The risk of dialysis response rates, with a 67% HR including 33% CR. Responses
increased exponentially with increasing the number of were durable, and the median time to response was
risk factors present. If none or 1 factor was present, risk of 4.5 months44. This makes MDex an effective regimen, which
dialysis was 2% and 10%, respectively42. Nonetheless, the can be used when bortezomib is contraindicated or is una-
presence of both, hypoalbuminemia and eGFR <40 mL/min vailable. However, when dealing with elderly patients or
resulted in a 44% risk of dialysis. As such, screening with those with pre-existing severe renal or cardiac involvement, a
serum albumin and eGFR may reduce the risk42. Unfor- lower dose of dexamethasone should be considered (i.e.,
tunately, these two risk factors are also risk factors for 20 mg on days 1–4) due to the toxicities and increased fluid
progression to ESRD as part of the natural progression of retention associated with dexamethasone.
AL amyloidosis. Thus, the decision on whether to proceed Multiple studies have looked into the use of
to ASCT is a difficult one. It is important to note though, bortezomib-based regimens upfront44–46. Three studies,
that patients are likely to experience improved renal which highlight the durable HR associated with
function as the disease burden decreases post induction, bortezomib-based regimens, are the European CyBorD
then making them eligible for subsequent treatment collaboration study of 230 patients between 2013 and
with ASCT. 201644, a prospective observational study by the UK

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National Amyloidosis Center of 915 patients between CAEL-101 in AL amyloidosis to provide a recommended
2010 and 201745, and a phase III trial of MDex versus dose of CAEL-101 to be given in combination with
BMDex between 2011 and 201646. Across these studies CyBorD for a planned randomized study in Mayo stage
the CR rates on intention-to-treat (ITT) analysis ranged IIIa and IIIb patients48. CAEL-101 is an AL amyloid fibril
from 21 to 25%44–46. Cardiac response varied from 17 to reactive IgG1 antibody aimed at potentially clearing
38% and renal response, 15 to 44%44–46. The median OS amyloid deposits48. The study enrolled 13 patients (7
across these studies was >4 years and the median follow-up heart, 3 kidney, 3 both) in a 3 + 3 dose escalation safety
period ranged from 25 to 32 months44–46. The phase III study whereby the maximum dose tolerated was 1000 mg/m2
trial (NCT01277016) comparing MDex to BMDex in newly weekly for 4 weeks and then every other week. Patients
diagnosed AL patients reported very exciting data in 109 were receiving CyBorD in tandem48. Of the six patients
patients recruited in Europe and Australia (56 in MDex receiving the maximum dose, it was well tolerated with
arm, 53 in BMDex arm)46. Although there was no differ- the exception of three significant adverse events (recur-
ence in the CR and partial response (PR) rates, or in cardiac rent atrial fibrillation, Clostridium difficile infection and
and renal response rates, at the end of treatment after a enlarged pleural effusion)48. Seven patients were evaluated
median of five cycles, the overall HR rate was significantly for organ response and 2 met criteria in the 500 mg/m2
better in the BMDex arm compared with the MDex arm cohort48. Given the potential for early organ response,
(79% versus 52%, p = 0.002) whereas VGPR or CR was CAEL-101 could prove groundbreaking, awaiting two
achieved in 64% of the patients on the BMDex arm versus recently initiated phase III trials employing the maximum
39% of those on the MDex arm46. This translated into dose of CAEL-101 at 1000 mg/m2.
improvements with BMDex over MDex in PFS and OS with
a 2-fold decrease in mortality (HR 0.5, [0.27–0.90])46. Assessing treatment response
With respect to toxicity management, it is important to Palladini et al. identified the criteria for both, hemato-
avoid bortezomib in the setting of pre-existing neuropathy logical and cardiac responses to treatment offering sur-
or to opt for an attenuated dose regimen. Subcutaneous rogate end points for clinical trials49 (Fig. 3). The analysis
administration is recommended at weekly dosing; twice of a multicenter cohort of 816 patients demonstrated the
weekly dosing is not recommended and is likely to result in strong correlation between the extent of FLC reduction
termination of therapy. Because bortezomib can be cardi- and survival improvement, as early as 3 months post-
otoxic to this patient population, initiating at a lower dose treatment initiation49. Four levels of response/survival
(0.7–1.0 mg/m2) and uptitrating as tolerable can be con- were identified: CR with negative serum protein electro-
sidered when dealing with patients with cardiac involve- phoresis and immunofixation (SPEP/IFE), negative urine
ment. Patients should be monitored carefully for side effects protein electrophoresis and immunofixation (UPEP/IFE)
and symptoms including regular monitoring for cardiac and normal FLC ratio (FLCr); VGPR with a dFLC <40 mg/L;
biomarkers, especially in the setting of high-risk disease. In PR with dFLC decrease >50%; and no response (NR) with
the emergence of neuropathy or other major toxicity, the a dFLC less than that achieved in PR49. With the avail-
dose of bortezomib can be reduced or discontinued. ability of highly effective antiplasma cell therapy, the cri-
The recent ANDROMEDA phase III trial (NCT03201965) teria requirement of normal FLCr was further clarified to
compared CyBorD to daratumumab-CyBorD in patients include abnormal FLCr inverted in favor of the non-
with newly diagnosed AL amyloidosis. Patients received amyloidogenic FLC50. As such, an abnormal FLCr does
weekly daratumumab in cycles 1 and 2, every 2 weeks in not preclude achieving CR when the uninvolved (uFLC) is
cycles 3–6, and every 4 weeks thereafter up to 2 years. The greater than the involved FLC (iFLC)50.
safety run-in of the study showed an overall HR rate of 96% In assessing treatment effectiveness, the target response for
without any new safety concerns beyond that already most patients should be at least a VGPR. In those with a low
demonstrated for daratumumab in multiple myeloma (MM) presenting dFLC of 20–50 mg/L, a target response should be
and CyBorD47. The primary results of the recently com- a dFLC <10 mg/L. If a patient has a serum M-spike (true for
pleted trial indicated that the addition of daratumumab ~50% of patients), this can help in assessing response,
results in higher HR (92% versus 77%) and VGPR/CR (79% especially in those with a low level of circulating light chains
versus 49%) with better cardiac (42% versus 22%) and renal where assessing response becomes very challenging. A ret-
(54% versus 27%) responses and prolonged PFS. Thus, the rospective analysis of 716 patients, 73% of which had a
study concluded that the addition of daratumumab to measurable M-spike before ASCT, found a measurable M-
CyBorD results in both, deeper and more rapid, HR47. The spike prior to ASCT an independent negative predictor of
preliminary ANDROMEDA results are thus promising and OS and PFS51. In patients with renal failure where the free
favorably comparable to ASCT. light chains are cleared by the kidneys, it is sometimes hard
A phase II, open-label, dose selection study to assess the response and a bone marrow biopsy may help
(NCT04304144) evaluated the safety and tolerability of to see if a deep remission has been achieved.

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Al Hamed et al. Blood Cancer Journal (2021)11:97 Page 9 of 13

Fig. 3 Criteria for hematologic and organ response in amyloidosis. SPEP/IFE serum protein electrophoresis and immunofixation, UPEP/IFE urine
protein electrophoresis and immunofixation, dFLC delta free light chain, uFLC uninvolved free light chain, eGFR estimated glomerular filtration rate,
CHOR composite hematologic/organ response model. Response criteria were derived from Palladini et al. J. Clin. Oncol 2012; Comenzo et al.
Leukemia 2012; and Palladini et al. Blood 2014. a: New BNP-based cardiac criteria were derived from Lilleness et al. BJH 2020. CHOR scoring model
derived from Sidana et al. Blood Cancer Journal 2020.

That said, it is empirical to determine when a shift in level of dFLC, and was 38 and 13 months in the
gears and initiation of new therapy is warranted. There 10–40 mg/L and >40 mg/L groups, respectively (log-rank
are three occasions when this should be considered: (1) if p < 0.0001)45. Cardiac responses were better in those with
there is no change in serum iFLC after the first cycle, (2) stringent dFLC responses (61%) compared with lesser
if a patient does not achieve a PR after 2–3 cycles, and (3) responses (45%; p = 0.005)45. The authors concluded that
if treatment is not tolerated. a stringent dFLC response predicted prolonged TNT and
Increasing data are emerging about the depth of impressive organ responses45. Similarly, in another study
response irrespective of the HR criteria. The UK pro- of patients who achieved at least a VGPR, an iFLC <
spective study on upfront bortezomib therapy reported 20 mg/L was associated with significantly better OS and
outcomes in the largest AL amyloidosis cohort treated PFS (p < 0.001)52. Using a more stringent dFLC of 5 mg/L,
with upfront bortezomib and explored the impact of post- there appeared to be a further significant improvement in
treatment dFLC < 10 mg/L (“stringent dFLC response”) PFS (p < 0.001) but not in OS (p = 0.11)52. In summary, as
and portrayed that patients with stringent dFLC responses well as using the HR criteria, a further understanding of
had significantly better OS and time-to-next treatment the depth of response in a patient is possible if low levels
(TNT) compared to those with weaker responses45. The of iFLC and dFLC are achieved.
study looked at three levels of dFLC (<10 mg/L, It is important to emphasize that complete HR does not
10–40 mg/L, and >40 mg/L)45. The median OS was not necessarily translate into organ response. As such,
reached in patients with the first two levels and was increasing attention is now being channeled to minimal
53 months in those with dFLC of >40 mg/L (log-rank p < residual disease (MRD). Sidana et al. evaluated MRD in 44
0.0001)45. The median TNT was not reached in the lowest AL amyloidosis patients using MRD by next-generation

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Al Hamed et al. Blood Cancer Journal (2021)11:97 Page 10 of 13

flow-cytometry (NGF) at a minimum sensitivity of 10-553. about half of them60, and (2) a rise in NT-proBNP/BNP.
The MRD negative rate among patients in CR was 75% To avoid or manage this type of toxicity, we recommend a
relative to 50% in patients achieving VGPR. Patients with low starting dose of lenalidomide of 5–15 mg/day with the
MRD-negativity were more likely to have achieve cardiac lower dose reserved for elderly patients or patients with
response (67% vs 22%, p = 0.04) and improved 1-year PFS baseline cardiac involvement or elevated creatinine. The
after a median follow-up of 14 months (100% vs 64%, p = dose can then be adjusted according to tolerability. One
0.006)53. Similarly, Palladini et al. evaluated MRD by NGF should observe carefully for fluid retention by weighing
at a minimum sensitivity of 10−5 in 92 AL amyloidosis patients daily and measuring cardiac biomarkers as well as
patients who have achieved CR54. Fifty-four percent had monitoring kidney function.
detectable MRD. Undetectable MRD was associated with Pomalidomide is slightly better tolerated than lenali-
higher rates of renal and cardiac responses (90% vs 62%, domide and several studies have demonstrated rapid
p = 0.006 and 95% vs 75%, p = 0.023, respectively)54. Even responses (median 1–3 months) and improved survival
more importantly, hematological progression was more with pom-dex. A study of 33 patients with a median
frequent in the setting of persistent MRD (0% vs 25% at 1 follow-up of 28 months highlighted the activity of the
year, p = 0.001), highlighting an important population pom-dex combination even in the setting of having failed
who would benefit from further treatment54. lenalidomide and bortezomib whereby the confirmed
overall HR rate and PFS were 48% and 14%, respectively61.
Treatment of relapsed/refractory AL amyloidosis Median time to response was 1.9 months and the median
Upon recognizing patients who were not able to attain a duration of response was 19 months (95% CI, 8.3 to not
satisfactory response, it becomes vital to initiate second- attained [NA])61. Similarly, a phase 1/2 trial of pom-dex
line therapy as soon as possible. Currently, the recom- reported an ORR of 50% in 24 evaluable patients62. The
mendation for second-line therapy for relapsed/refractory median time to best ORR was three cycles, and median
AL amyloidosis (RRAL) is daratumumab or duration of ORR was 15 months62. With a median follow-
daratumumab-based therapy (Fig. 2). This is due to its up of 17.1 months, median OS had not yet been reached,
association with an excellent ORR ranging from 63 to and median event-free survival (EFS) was 17.8 months62.
100% whereby most responses were at least VGPR with a A phase 2 trial of pom-dex rescue treatment in 28 patients
median time to HR of 1 week and a 2-year OS rate of previously exposed to alkylators, PIs, and lenalidomide
74%51,55–58. In a recent French study including 15 patients demonstrated a hematological ORR in 68% and a VGPR/
(median age 60 years) treated with daratumumab, ORR CR in 29%, as well as improved survival with median time
was 86% including 43% CR and 14% VGPR59. The most to response of 1 month63. Hematologic ORRs were also
common side effect was infections due to induced hypo- rapid, with half of responding patients doing so within
globulinemia59. Thus, daratumumab has proven an 2 months63. Pomalidomide dose reduction was required
excellent agent for AL amyloidosis resulting in deep in two out of three of those studies due to toxicity
remissions, high response rates and low toxicity. None- whereby patients experienced grade 3–4 myelosuppres-
theless, the long-term results of daratumumab treatment sion (26–45%), fatigue (18%), pneumonia (11–21%), renal
and length of remission are not yet known. failure (3–7.5%), and arrhythmias (0–21%)61,63. It is
Beyond daratumumab, the recommendations for third- important to note that AL amyloidosis patients treated
line treatment of RRAL depend on whether the patient with pomalidomide frequently experience increases in
had a hematological relapse ≥2 years since the last ther- proBNP/BNP without clinical congestive heart failure.
apy, in which case, the physician should consider PIs other than bortezomib also play a role. A few studies
repeating the original therapy. If the patient is not bor- have looked at treatment of AL amyloidosis with the
tezomib refractory, then a bortezomib-based regimen is second-generation PIs, ixazomib and carfilzomib. The
the preferred choice (CyBorD, BMDex, or Vd). On the phase III randomized controlled trial TOURMALINE-
other hand, if the patient is bortezomib refractory, then AL1 (NCT01659658) has recently published its results. It
pomalidomide-dexamethasone (pom-dex) or compared the combination of ixazomib and dex-
lenalidomide-dexamethasone (len-dex) can be used. amethasone (ixa-dex, n = 85) to physician choice (n = 83:
Importantly, ASCT can be considered in the relapsed len-dex, n = 47; melphalan-dex, n = 24; cyclopho-
setting, either as first ASCT or as a second transplant. sphamide-dex, n = 10; thalidomide-dex, n = 2)64.
IMiDs are generally not well tolerated by AL amyloi- TOURMALINE-AL1 is the first phase III trial in patients
dosis patients. Whereby thalidomide is known for its high with RRAL to show a significant clinical outcome
toxicity, lenalidomide comes with concerns too. The two improvement. Despite the trial not meeting the first pri-
main toxicity concerns with lenalidomide are (1) mary endpoint of hematologic ORR, treatment with ixa-
lenalidomide-related renal deterioration which, in a study dex resulted in an improved CR rate (26% versus 19%) and
of 41 patients, occurred in 66% and was only reversible in duration of overall HR (46.5 months versus 20.2 months)

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Al Hamed et al. Blood Cancer Journal (2021)11:97 Page 11 of 13

when compared to physician’s choice of treatment64. two reasons: t(11;14) is present in ~50% of AL amyloidosis
Although there was no difference between OS and overall patients17, and patients with this translocation are less likely
PFS, treatment with ixa-dex increased hematologic/vital to respond to a bortezomib-based regimen17,18. There is
organ PFS and decreased time to vital organ deteriora- limited experience with venetoclax in AL amyloidosis but in
tion/death, time to treatment failure, and time to sub- 2018, Leung et al. reported on perhaps the first patient with
sequent therapy64. Considering that the duration of AL amyloidosis to be successfully treated with venetoclax
treatment in the ixa-dex arm was twice that of the phy- after his disease markers plateaued on CyBorD18. Sidiqi
sician’s choice arm (median 11.7 months versus et al. have recently demonstrated efficacy and safety of
4.9 months), continuous ixa-dex was generally well tol- venetoclax in 12 RRAL patients treated with venetoclax
erated64. When stratified by prior PI exposure, hemato- between January 2017 and May 201968. Patients had a
logic ORR was 63% versus 50% for Ixa-dex versus median of two prior lines and all but 1 had t(11;14)68. The
physician choice in PI-naïve patients and 41% versus 51% dose used was 400–800 mg/d; 7 in combination with dex-
in PI-exposed65. Thus, ORR was higher for Ixa-dex versus amethasone68. Eight patients were evaluable for response
physician choice in PI-naïve patients and lower in PI- and the response rate was 87% comprising 3 with CR and 4
exposed (though not statistically significant)65. Based on with VGPR68. The median time to best response was
these results, ixa-dex may be considered a new option for 3.4 months and median follow-up was 11.5 months, but two
patients with RRAL, given sensitivity to bortezomib. Ixa- patients progressed at 4 and 5 months from initiation of
zomib was also studied in the all-oral combination, ixa- therapy68. Toxicity was minimal and there were no reports
zomib, cyclophosphamide, and dexamethasone in a phase of tumor lysis syndrome. Notably, in this cohort no deaths
II trial66. The study included 35 patients with newly have been observed so far. Albeit a retrospective case series
diagnosed, biopsy-proven AL amyloidosis but excluded with a small sample size, this study suggests high efficacy
patients with severe organ involvement (alkaline phos- and good tolerability of venetoclax monotherapy and
phatase > 750 U/L, CrCl < 30 mL/min, or NT-proBNP ≥ combination therapy in patients harboring t(11;14).
7500 ng/dL)66. The overall HR was 57% including CR in Bendamustine is another agent to consider although the
4%, VGPR in 26%, and PR in 17%66. Median PFS and OS response rates are not very high in the AL amyloidosis
have not been reached, four patients had disease pro- population. However, for those with an IgM amyloidosis
gression and six have died66. Thus far, this points to or a lymphoplasmacytic histology, in combination with
modest activity in the all-oral regimen awaiting further rituximab, response rates are much better, and survival is
results. improved even in heavily pretreated patients. This is
On the other hand, carfilzomib is a challenging agent highlighted by three recently published studies69–71.
due to the high incidence of cardiac involvement with AL Milani et al. reported on 122 patients, 36 of whom had
amyloidosis. It is known that up to 10% of MM patients IgM amyloidosis69. With a median time to response of
treated with carfilzomib experience cardiac toxicity. It is 3 months, the ORR to bendamustine in the whole cohort
also an intravenous infusion and patients require hydration, was 35%69. In the 12 patients with IgM-AL amyloidosis,
which can aggravate patients predisposed to congestive this was achieved in 58% of subjects (21% with ≥VGPR)69.
heart failure. Results of an investigator-initiated, multi- The median follow-up of living patients was 31 months
center, phase I/II study of carfilzomib in AL amyloidosis (IQR, 17–46) and severe adverse effects were observed in
(NCT01789242) showed that carfilzomib monotherapy was 26%69. Lentzsch et al. conducted a phase II, multicenter
feasible and effective in 28 RRAL patients67. The dose trial (NCT01222260) to assess the efficacy and safety of
escalating phase identified a maximum tolerated dose of 20/ bendamustine with dexamethasone in 31 patients with
36 mg/m2 (which is lower than that for MM)67. HR rates persistent or progressive AL amyloidosis after ≥1 prior
were promising in this bortezomib-exposed population, therapy70. Dose reduction occurred in 31% of patients and
including PI-refractory patients. The ORR and ≥VGPR were 57% of patients achieved a PR or better (11% CR, 18%
54% and 39%, respectively, and although these are VGPR)70. The median OS was 18.2 months and the
encouraging results, cardiac toxicity was experienced by median PFS was 11.3 months70. Side effects were com-
36% (including major toxicities such as ventricular monly myelosuppression, fatigue, and nausea/vomiting70.
tachyarrhythmia, decrease in EF, and hypoxemia)67. Manwani et al. reported outcomes in 27 patients identi-
Venetoclax is an oral, small-molecule B-cell lymphoma 2 fied from the UK National Amyloidosis Centre database
(BCL-2) inhibitor that induces cellular apoptosis, with (5 of which were RRAL) treated with bendamustine and
encouraging activity in chronic lymphoid leukemia (CLL), rituximab showing an ORR of 59% (11% CR, 37% VGPR,
non-Hodgkin lymphoma (NHL), acute myeloid leukemia and 11% PR)71. The median follow-up was 18 months and
(AML), and a subset of MM patients whose clonal plasma the median PFS was 34 months. Side effects comprised:
cells harbor t(11;14) and/or overexpress BCL-2. Venetoclax GI symptoms, fatigue, cytopenias, and neutropenic
may be useful in the management of AL amyloidosis for fever71.

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Al Hamed et al. Blood Cancer Journal (2021)11:97 Page 12 of 13

Finally, another anti-CD38 monoclonal antibody, isa- Conflict of interest

tuximab is an IgG1k monoclonal antibody with high- The authors declare no competing interests.

affinity binding to CD38 expressed on plasma cells, which

Publisher’s note
has proven efficacious in MM as a single agent or in Springer Nature remains neutral with regard to jurisdictional claims in
combination. The phase II trial SWOG S1702 published maps and institutional affiliations.
(NCT03499808) investigates the role of isatuximab. It
included 36 patients with RRAL who have received at Received: 23 February 2021 Revised: 11 April 2021 Accepted: 27 April 2021

least one previous line of therapy72. The median age was

70 and prior therapies included PI (89%), high-dose
therapy followed by ASCT (47%), IMiDs (28%) and an
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