Critical Reviews in Oncology/Hematology 99 (2016) 249–260

Contents lists available at ScienceDirect

Critical Reviews in Oncology/Hematology

journal homepage: www.elsevier.com/locate/critrevonc

Immunomodulatory drugs in AL amyloidosis

T. Jelinek a,b , Z. Kufova b , R. Hajek a,b,∗
a
Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
b
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
2. Mechanism of action of immunomodulatory drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
2.1. Immunomodulatory effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
2.2. Direct antitumor effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
2.3. Anti-angiogenic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
2.4. Anti-inflammatory effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
2.5. Effects on the bone marrow microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
3. Thalidomide in the treatment of AL amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
4. Lenalidomide in the treatment of AL amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
5. Pomalidomide in the treatment of AL amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
6. Problematics of response assessment with IMiDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
7. Treatment strategies in AL amyloidosis and role of IMiDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

a r t i c l e i n f o a b s t r a c t

Article history: Immunoglobulin light chain amyloidosis (AL amyloidosis) is indeed a rare plasma cell disorder, yet the
Received 25 October 2014 most common of the systemic amyloidoses. The choice of adequate treatment modality is complicated
Received in revised form and depends dominantly on the risk stratification of these fragile patients. Immunomodulatory drugs
20 November 2015
(IMiDs) are currently used in newly diagnosed patients as well as in salvage therapy in relapsed/refractory
Accepted 12 January 2016
patients. IMiDs have a pleiotropic effect on malignant cells and the exact mechanism of their action has
been described recently. Thalidomide is the most ancient representative, effective but toxic. Lenalidomide
Keywords:
seems to be more effective, nevertheless the toxicity remains high, especially in patients with renal
AL amyloidosis
Immunomodulatory drugs
insufficiency. Pomalidomide is the newest IMiD used in this indication with a good balance between
Thalidomide efficacy and tolerable toxicity and represents the most promising compound. This review is focused on
Lenalidomide the evaluation of all three representatives of IMiDs and their roles in the treatment of this malignant
Pomalidomide disorder.
© 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Immunoglobulin light chain amyloidosis (AL amyloidosis, AL) is

a low tumor burden plasma cell disorder characterized by the pres-
ence of a small indolent clone of plasmocytes in bone marrow (BM)
synthesizing misfolded light chains. Instead of conforming to the ␣-
∗ Corresponding author at: Department of Haematooncology University Hospital helical configuration of most proteins, these amyloidogenous light
Ostrava 17, Listopadu 1790, 708 52 Ostrava,Czech Republic. Fax: +420 597 37 2092. chains form a ␤-pleated sheet responsible for formatting insoluble
E-mail addresses: tomas.jelinek.md@gmail.com (T. Jelinek), roman.hajek@fno.cz
fibrils causing damage to vital organs (Bhat et al., 2010). Although
(R. Hajek).

http://dx.doi.org/10.1016/j.critrevonc.2016.01.004
1040-8428/© 2016 Elsevier Ireland Ltd. All rights reserved.
250 T. Jelinek et al. / Critical Reviews in Oncology/Hematology 99 (2016) 249–260
AL is a very rare disease, it is the most common systemic amyloi-
dosis with an incidence of 10 patients per million cases per year,
resulting in approximately 5000 new patients/year in the European
Union (Merlini and Palladini, 2013). Due to the nature of the disease,
patients usually present with multi-organ dysfunction (involving
the cardiac, renal, gastrointestinal, peripheral and autonomic ner-
vous system), which is essential to their prognosis. The presence
and extent of heart involvement is the most important prognostic
determinant, and cardiac dysfunction may be best assessed by the
cardiac biomarkers N-terminal pro-natriuretic peptide type-B (NT-
proBNP), brain natriuretic peptide (BNP) and troponins (Gatt and
Palladini, 2013). A staging system based on these biomarkers was
revised by Kumar et al., (2012a) and allows to discriminate between
low-risk, intermediate-risk and high-risk patients, who have signif-
icantly different prognoses. According to this Mayo Clinic staging
system, the physicians should choose the appropriate treatment
approach based on the fragility of patients.
The goal of the treatment in AL amyloidosis is the rapid elimi-
nation of toxic free light chains and the achievement of complete
hematological remission (Palladini et al., 2012a), which is necessary
for amelioration of organ function (Merlini and Palladini, 2008).
Achieving a maximal hematological response is a crucial factor and
only under these conditions the organ treatment response can be
expected. Reaching organ treatment response may last a long time
(1–2 years) and is especially important in patients with advanced
cardiac involvement (Wechalekar et al., 2013). Disease response
and progression criteria are summarized in Table 1 (Comenzo et al.,
2012; Gertz et al., 2005; Palladini et al., 2012a).
The conventional treatment of AL amyloidosis is based on a
combination of corticosteroids (prednisone, dexamethasone) and
alkylators (melphalan, cyclophosphamide). This combination used
to be a standard treatment option for a long time, first used in 1972
(Jones et al., 1972). The effects of these two groups of compounds
are mutually potentiated. The oral combination of melphalan and
prednisone is well tolerated in patients with AL, but for a bet-
ter treatment response, dexamethasone is usually used instead of
prednisone (Dhodapkar et al., 1997; Kyle et al., 1997; Skinner et al.,
1996). In the clinical trial combining oral melphalan and high-
dose dexamethasone in patients ineligible for autologous stem
cell transplantation (ASCT), median progression-free and overall
survival were 3.8 and 5.1 years, respectively, with an estimated
overall response rate (ORR) of 67% including complete remission
(CR) in 1/3 of patients. Oral combination of melphalan and high
dose dexamethasone has become widely accepted as a first line
treatment option for patients with AL amyloidosis ineligible for
ASCT (Palladini et al., 2007, 2004). Interestingly, the same Italian
group recently reported the results of a large retrospective study
showing that the treatment outcome of this combination is depen-
dent on the fraction of patients with advanced cardiac amyloidosis,
respectively on the doses of dexamethasone they are able to tol-
erate. Hematological response was achieved in 76% (CR in 31%) of
patients who were fit enough to receive melphalan with full-dose
dexamethasone, while only 51% (CR 12%) of patients responded
to melphalan with attenuated dexamethasone (Palladini et al.,
2014a,b).
Autologous stem cell transplantation (ASCT) was described for
the first time in 1998 as an effective treatment modality in AL
amyloidosis (Comenzo et al., 1998). The most commonly used
myeloablative regimen is melphalan 200 mg/m2 , the same as in
multiple myeloma patients, but with frequent dose reductions with
consideration to renal or cardiac insufficiency. Recently, in the
XIVth International Symposium on Amyloidosis, a cohort of 148
patients who had undergone risk adapted ASCT and had received
melphalan 100, 140 and 200 mg/m2 in 14%, 52% and 34% respec-
tively was presented. Interestingly, by multivariate analysis, the
melphalan dose had no impact on overall survival () (p = 0.25)
(Landau et al., 2014). Complete remissions can be expected in
30–40% of cases using this therapeutical approach (Dispenzieri
et al., 2013; Gertz et al., 2004; Sanchorawala et al., 2007a; Skinner
et al., 2004). Only one prospective multicentric randomized clin-
ical trial comparing ASCT with oral melphalan + dexamethasone
was conducted, but the results did not support the superiority of
ASCT. Conversely, median OS was only 22.2 months in the ASCT
group vs. 56.9 months in the melphalan + dexamethasone group
(p = 0.04) (Jaccard et al., 2007). However, these results must be
interpreted very carefully because of high peritransplant mortal-
ity (24%) related to the inappropriate choice of transplant eligible
candidates and some protocol difficulties in the ASCT group.
In 2013 two large retrospective studies supporting the use of
ASCT in suitable patients with AL amyloidosis were published. An
European Group for Blood and Marrow Transplantation (EBMT)
analysis of 1315 patients with AL showed time progress in treat-
ment results and 1 year OS reached 91% in the period between
2009–2010 in comparison to 65% in the period between 1997–1999
(Hegenbart et al., 2013). Another analysis from The Amyloidosis
Center at Boston University with 593 patients with AL treated with
ASCT during last 19 years presented remarkable long-term sur-
vival results with a CR rate of 40%, median OS 6.7 years and 25% of
patients living longer than 19 years after ASCT (Sanchorawala et al.,
2014a). In conclusion, it is possible to state that with appropriate
patient selection and a risk-adapted treatment approach, ASCT is a
safe and effective modality for approximately 30% of patients with
AL. The reported 10 year survival after ASCT is about 43% (Cordes
et al., 2012). The already mentioned adequate selection of patients
with limited cardiac involvement is indeed the most important fac-
tor for the safety of ASCT. Patients who have troponin T > 0.06 ng/ml,
NT-proBNP > 5000 pg/ml and systolic blood pressure < 100 mm Hg
at diagnosis should not be considered for high-dose chemotherapy
(Gatt and Palladini, 2013; Girnius et al., 2014).
Proteasome inhibitors (PIs) represent a very effective group of
drugs used in the treatment of AL amyloidosis. The majority of clini-
cal studies were conducted with bortezomib. Although there are no
available results of any prospective randomized clinical trials, data
coming from ongoing clinical trials phase II are very encouraging. In
patients with monotherapy of bortezomib, 67–69% achieved hema-
tological response and 24–38% achieved CR (Reece et al., 2011).
The combination of bortezomib and dexamethasone achieved a
hematological response in 80–94% of cases (Kastritis et al., 2007).
Incorporating cyclophosphamide with bortezomib and dexam-
ethasone (CVD) proved clinical efficacy with an ORRORR in 81% (CR
42%) of patients, 2 year progression-free survival (PFS) and OS were
67% and 98%, respectively (Venner et al., 2012). These results were
confirmed in many other clinical trials. Rapid treatment response
was also observed (Gatt and Palladini, 2013). Recently, a large ret-
rospective matched control case study of 184 newly diagnosed
patients with AL was published. The authors compared the out-
come of 87 patients treated with bortezomib plus melphalan and
dexamethasone (BMDex) with that of 87 controls treated with
MDex. A higher proportion of complete responses were observed
in the BMDex cohort (42% vs. 19%), and this resulted in a higher
overall hematological response rate (69% vs. 51%), but it did not
result in the survival improvement in the overall population. How-
ever, a significant survival advantage for BMDex was observed in
patients without severe (New York Heart Association class III or IV)
heart failure and with NT-proBNP < 8500 ng/l. Patients treated with
full-dose dexamethasone had similar response rates and survival
whether they received bortezomib or not. So, intermediate-risk
patients who are not fit enough to receive high-dose dexametha-
sone are likely to have the greatest advantage from the addition
of bortezomib to MDex (Palladini et al., 2014a,b). In conclusion, no
phase III or retrospective matched analysis indicates a clear signifi-
cant benefit in the terms of OS/PFS compared to standard treatment
 T. Jelinek et al. / Critical Reviews in Oncology/Hematology 99 (2016) 249–260 251

Table 1
Hematological and organ response and progression criteria.

Criteria Response Progression

Hematological assessment
CR Normal serum free light chain ratio with negative serum Any detectable monoclonal protein or abnormal FLC ratio
and urinary immunofixation (FLC must double)
VGPR The difference in the free light chains (dFLC) less than
40 mg/l
PR A reduction in the dFLC greater than 50% 50% increase in serum M-protein to >0.5 g/dl or 50%
increase of 24 h urine protein to >200 mg/day
NR A less than 50% response in dFLC FLC increase of 50% to >10 mg/dl

Heart
NT-proBNP >30% and >300 ng/l decrease if baseline >30% and >300 ng/l increase
NT-proBNP ≥650 ng/l
cTn ≥33% increase
NYHA class response ≥two-class decrease if baseline NYHA class 3 or 4 EF (≥10% decrease)

Other organs
Kidney 50% decrease (at least 0.5 g/day) of 24 h urine protein 50% increase (at least 1 g/day) of 24 h urine protein to
(pre-treatment urine protein must be >0.5 g/day) >1 g/day
Creatinine and creatinine clearance must not worsen by OR
25% over baseline 25% worsening of serum creatinine or creatinine clearance
Liver 50% decrease in abnormal ALP value Decrease in liver size 50% increase of ALP above the lowest value
radiographically at least 2 cm
Peripheral nervous system Improvement in electromyogram nerve conduction Progressive neuropathy by electromyography or nerve
velocity (rare) conduction velocity

ALP—alkaline phosphatase; cTn—cardiac troponin; dFLC—difference between involved and uninvolved free light chain; EF—ejection fraction; NR—no response; VGPR—very
good partial response.

regimen and there is still no certainty about the role of upfront
bortezomib in the overall patient population with AL amyloidosis
(Dispenzieri, 2014). This question should be answered in the near
future when the results of phase III randomized multicenter clinical
trial EMN03 comparing MDex vs. BMDex (bortezomib, melphalan,
dexamethasone) will be published.
Immunomodulatory drugs are highly effective agents used in
the treatment of multiple myeloma and they have been tested in
other monoclonal gammopathies including AL amyloidosis. This
review is focused on current experiences with three representa-
tives of immunomodulatory agents: thalidomide, lenalidomide and
the most current, pomalidomide (Table 2).
2. Mechanism of action of immunomodulatory drugs
Immunomodulatory drugs (IMiDs) are a group of therapeu-
tic compounds that are analogs of thalidomide, a glutamic acid
derivate. Thalidomide was first synthesized by Chemie Grünenthal
in 1954 and was broadly used as an antiemetic agent for morning
sickness during pregnancy. In early 1960s its teratogenic effect was
recognized and the agent was immediately withdrawn from most
markets (Rajkumar, 2004). Nevertheless, around the same time,
it was serendipitously discovered that thalidomide is effective in
the treatment of erythema nodosum leprosum, a disease charac-
terized by high levels of serum TNF␣ (Iyer et al., 1971). This ability
of thalidomide to inhibit production of TNF␣ by activated human
monocytes was presented in 1991 (Sampaio et al., 1991). Besides
this anti-inflammatory effect, other mechanisms of action were
gradually discovered such as its immunomodulatory effect, direct
antitumor activity, anti-angiogenic activity and its effect on the
bone marrow microenvironment. Its exact mechanism of action,
however, has remained unclear for a long time. Recent discoveries
have brought to light how these drugs exactly work (Krönke et al.,
2014; Lu et al., 2014). All these properties of IMiDs were dominantly
investigated in multiple myeloma, the most common malignant
monoclonal gammopathy (Quach et al., 2010; Sedlarikova et al.,
2012). As AL amyloidosis is also a clonal plasma cell dyscrasia, it is
possible to presume that majority of IMiD’s effects will be identical,
although the intensity of each effect may differ in various plasma
cell disorders (Bartlett et al., 2004).
2.1. Immunomodulatory effects
Survival of malignant plasma cells, as other tumor cells, is par-
tially facilitated by the impaired endogenous immune surveillance
against tumor antigens (Zou, 2005). IMiDs are able to affect the
immune system in several ways that lead to the eradication of
malignant plasma cells.
The first effect is co-stimulation of T cells. T cell activation is
mediated via antigen specific T cell receptor (TCR), but also requires
a co-stimulation signal mostly provided by professional antigen-
presenting cells (APC). IMiDs are able to co-stimulate CD3+ T cells
that have been partially activated either by anti CD3+ or dendritic
cells (DC). The presence of IMiDs abolishes the requirement of the
secondary co-stimulation signal from APCs (Davies et al., 2001).
IMiDs improve proliferation of both CD4+ and CD8+ T cells and
augment the production of Th2 cytokines–interleukin 2 (IL-2) and
interferon ␥ (IFN-␥). The higher production of IL-2 in T cells is due to
the depletion of IKZF1 and IKZF3, but this exact mechanism will be
discussed later (Krönke et al., 2014). Higher levels of IL-2 and IFN-
␥ increase the number of natural killer cells (NK cells), improve
their function and mediate the death of malignant plasma cells
(Sedlarikova et al., 2012).
Natural killer T cells (NKT cells) are T lymphocytes which bear
natural killer cell markers on their surfaces and they possess a
direct tumor cytotoxic effect. NK cells have an irreplaceable role in
innate immunity, in killing both tumor and virus infected cells. The
presence of thalidomide, lenalidomide and pomalidomide enhance
both NKT and NK cells that lead to the death of clonal plasmocytes
(Davies et al., 2001; Quach et al., 2010).
Another possible effect of IMiDs is the inhibition of regulatory
T cells (Tregs) that probably play an important role in establishing
and maintaining immunological unresponsiveness to self-antigens.
Several studies have shown that Tregs are expanded in hema-
tological malignancies and also in solid tumors and that IMiDs
inhibit proliferation of Tregs via decreased FoxP3 mRNA expres-
sion (Muthu Raja et al., 2011; Sedlarikova et al., 2012). However, as
252 T. Jelinek et al. / Critical Reviews in Oncology/Hematology 99 (2016) 249–260

there are many contradictory results, a conclusion cannot be drawn

at this moment.

2.2. Direct antitumor effects

approvala
EMA/FDA

NO/NO

NO/NO

NO/NO
Immunomodulatory drugs also possess a direct anti-
proliferative effect via the inhibition of the cyclin-dependent

Pomalyst, Imnovid
kinase (CDK) pathway, downregulation of anti-apoptotic proteins
Thalomid, Myrin
Talidex, Talizer,

and activation of FAS-mediated cell death. The IMiD-induced cell

Inmunoprin,
Trade name

cycle arrest of malignant plasmocytes in G1 phase is mediated

Revlimid via increased levels of the p21WAF-1 protein through epigenetic
modifications (Hideshima et al., 2000; Sedlarikova et al., 2012).
Clonal plasma cells are protected against apoptosis by anti-
Prophylaxis of VTE

apoptotic proteins regulated via NF-␬B transcription factor (Wang

et al., 1998). It was demonstrated that treatment with IMiDs
downregulated the activity of this transcription factor in clonal
plasmocytes (Chu et al., 1997).
The exact mechanism of the antitumor activity of IMiDs has been
YES

YES

YES

recently described by several groups of investigators (Krönke et al.,

thrombocytopenia,

thrombocytopenia,

2014; Lu et al., 2014). It seems that IKZF1 (Ikaros) and IKZF3 (Aio-
VTE, fatigue, skin
VTE, obstipation,
polyneuropathy,

los), two lymphoid transcription factors playing central roles in the

Frequent AEs

Neutropenia,

Neutropenia,

biology of B and T cells, are responsible for the antitumor effect

drowsiness
Peripheral

of lenalidomide and all immunomodulatory agents. It was shown

anemia,

that lenalidomide causes selective ubiquitination and degradation

rash

VTE

of these two transcription factors by the CRBN-CRL4 (cereblon-

cullin4A-RING) E3 ubiquitin ligase. IKZF1 and IKZF3 are essential
transcription factors for terminal differentiation of B and T cell lin-
eages. Lenalidomide causes increased binding of IKZF1 and IKZF3
Neuropathy

to cereblon (CRBN) and promotes their ubiquitination and degra-

dation. It seems that CRBN is essential for lenalidomide activity in
+++

multiple myeloma. So, in aggregate it was shown that lenalidomide

+

acts via a previously unknown mechanism of action-enforced bind-

ing of the substrate receptor CRBN to IKZF1 and IKZF3, which results
Teratogenicity

in the degradation and depletion of IKZF1 and IKZF3 (Krönke et al.,

2014; Licht et al., 2014; Lu et al., 2014).
+++

+++

+++

2.3. Anti-angiogenic activity

Chemical formula

All IMiDs possess an anti-angiogenic effect, although it is gen-

erally considered that this activity prevails in thalidomide whereas
C13 H10 N2 O4

C13 H13 N3 O3

C13 H11 N3 O4

lenalidomide and pomalidomide have far greater immune enhanc-

ing effects (Dredge et al., 2002). This property of thalidomide is
probably dominantly responsible for the development of malfor-
mations in children in the late 1950s and early 1960s. It appears
that IMiDs modulate chemotactic factors affecting endothelial cell
migration such as TNF␣, VEGF and ␤FGF secreted by bone marrow
stromal cells (Dredge et al., 2002). It seems that PI3 K/Akt-signalling
pathway plays a key role in anti-angiogenic activity of IMiDs
because immunomodulatory drugs reduce Akt phosphorylation,
thus they affect the expression of these chemotactical factors and
therefore restrain angiogenesis (Dredge et al., 2005; Sedlarikova
et al., 2012).

2.4. Anti-inflammatory effects

The relative contribution of anti-inflammatory properties of

VTE —venous thromboembolism.

IMiDs toward their anti myeloma activity is uncertain (Quach et al.,

In AL amyloidosis indication.
Basic characteristics of IMiDs.

2010). Cyclooxygenase 2 (COX-2), which catalyzes the conversion

Structure

of arachidonic acid to various prostaglandins (PG), is involved in

the pathogenesis of several malignancies including plasma cell
dyscrasias (Masferrer et al., 2000). For instance, PG-E2 promotes
Pomalidomide

tumor induced angiogenesis, production of IL-6 and, of course,

Lenalidomide
Thalidomide

inflammation (Hinson et al., 1996). Thalidomide, lenalidomide and

pomalidomide are able to inhibit the expression of COX-2 via the
Table 2

Drug

shortening of the half life of COX-2 mRNA in a dose dependent

a

manner (Payvandi et al., 2004).

 T. Jelinek et al. / Critical Reviews in Oncology/Hematology 99 (2016) 249–260
Another mechanism of the anti-inflammatory action of IMiDs
is their inhibitory effect on TNF␣ (an inflammatory cytokine pro-
duced by monocytes and macrophages), which is mediated via the
degradation of TNF␣ mRNA (Sampaio et al., 1991). In compari-
son with thalidomide, inhibition of TNF␣ was 2000× more potent
with lenalidomide and 20,000× more potent with pomalidomide
(Muller et al., 1999). Therefore, immunomodulatory agents may
have a therapeutical potential not only in multiple myeloma or
other malignancies, but also in inflammatory conditions such as
Crohn’s disease or rheumatoid arthritis (Akobeng and Stokkers,
2009; Quach et al., 2010).
2.5. Effects on the bone marrow microenvironment
Osteolytic lesions and back pain are usually the first symptoms
that force patients with multiple myeloma to visit their physicians.
Immunomodulatory drugs possess many properties influencing the
bone marrow microenvironment and interactions between malig-
nant plasma cells, including the inhibition of osteoclastogenesis
(Breitkreutz et al., 2008) or changes in the expression of adhesive
molecules important for the proliferation and migration of plas-
mocytes (Geitz et al., 1996). In AL amyloidosis, however, osteolytic
lesions are extremely rare, so the the detailed description of these
mechanisms will not be mentioned in this part.
3. Thalidomide in the treatment of AL amyloidosis
Thalidomide is the first and principal drug of the immunomod-
ulatory agents group. In biochemical nomenclature it is called
2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C13 H10 N2 O4 ), a
synthetic derivate of glutamic acid. Thalidomide exists as a racemic
mixture of two optically active enantiomers, S and R, wherein the S
enantiomer is responsible for the teratogenic and anti-tumor effect,
while the R enantiomer possesses a sedative effect (Rajkumar,
2004).
Low dose thalidomide used as monotherapy in the treatment
of AL amyloidosis is not very efficient (Dispenzieri et al., 2003;
Seldin et al., 2003). On the contrary, high doses of thalidomide
are not well tolerated in this fragile group of patients (Dispenzieri
et al., 2003) either. The combination of thalidomide and dexam-
ethasone achieved 48% of hematological responses and 19% of
hematological complete remissions in the group of patients with
relapsed/refractory AL (Palladini et al., 2005). The use of thalido-
mide and dexamethasone as adjuvant chemotherapy after ASCT in
patients with newly diagnosed AL, who had not obtained CR after
ASCT, was also investigated. The benefits of adjuvant therapy were
seen in 42% (13/31) of patients who had an improvement in hema-
tological response at 12 months post-SCT, including seven who
achieved a CR after having stable disease (SD) or partial remission
(PR) initially (Cohen et al., 2007). Patients with advanced cardiac AL
amyloidosis (NYHA IV), who received a combination of oral mel-
phalan, thalidomide and dexamethasone, reached hematological
response in 36%, but 27% of them died during treatment (Palladini
et al., 2009). The combination of another alkylator, cyclophos-
phamide, with thalidomide and dexamethasone (regimen CTD)
was used in 75 transplant ineligible patients with advanced AL
amyloidosis, including 44 patients (56.6%) with clonal relapse to
prior therapy. Hematological response occurred in 48 out of 65
(74%) evaluable patients, including a complete response in 14 (21%)
patients. The median estimated OS from commencement of treat-
ment was 41 months (Wechalekar et al., 2007). The ALChemy
trial, one of the largest prospective observational studies in AL
amyloidosis worldwide, is currently being conducted at the UK
Amyloidosis Centre in London. Recently, the update of this study
was presented in the XIVth International Symposium on Amy-
253
loidosis. The data of 500 enrolled patients showed that 58% of
patients were treated with a thalidomide-based regimen (mainly
CTD), 51% of all patients reached a hematological response with
a complete response in 14%. The estimated survival at 12, 36 and
48 months was 67%, 56% and 51%, respectively. Toxicity grade 3
or higher was seen in 59% of all patients (Gillmore et al., 2012;
Wechalekar et al., 2014). These results show that the toxicity of this
regimen remains high and in the UK bortezomib-based regimens
are being used increasingly. A retrospective matched comparison of
cyclophosphamide, bortezomib and dexamethasone (CVD) vs. risk-
adapted cyclophosphamide, thalidomide and dexamethasone was
published recently by the same London group. The overall response
rates were 71.0% vs. 79.7% in the CVD and CTD arms, respectively,
(p = 0.32). A higher CR rate was observed in the CVD arm (40.5%) vs.
CTD (24.6%), (p = 0.046). 1 year OS was 65.2% and 66.7% for CVD and
CTD, (p = 0.87) and the median PFS was 28.0 and 14.0 months for
CVD and CTD, respectively (p = 0.039). In summary, CVD correlated
with improved depth of response and superior PFS thus supporting
its use in the frontline setting, but there was no difference in the
terms of OS (Venner et al., 2014).
The toxicity of thalidomide containing regimens is not negli-
gible. Toxicities of grade 3 and higher were present in more than
50% of treated patients practically in all published studies. Fluid
retention, symptomatic bradycardia, peripheral neuropathy and
progression of renal failure are the most common (Gillmore et al.,
2012; Palladini et al., 2005; Seldin et al., 2003). Thalidomide in com-
bination with other drugs shows clinical effectivity but its toxicity
is limiting. These combinations represent the treatment modality
for patients refractory to bortezomib or for patients who tolerate
thalidomide’s toxic effects.
4. Lenalidomide in the treatment of AL amyloidosis
Lenalidomide,3-(4-amino-l-oxo-l,3-dihydro-2H-isoindol-2-
yl)piperidine-2,6-dione (C13 H13 N3 O3 ), has a preserved chiral
center and occurs as a racemate, in a mixture of two optically
active enantiomers, S and R, similar to thalidomide (Kotla et al.,
2009). Lenalidomide (Revlimid, formerly CC-5013) is ranked
among thalidomide’s analogs (Celgene’s class of immunomodula-
tory compounds) with a more favorable toxic profile and increased
efficacy. This second generation IMiD showed approximately
50–2000× higher effectivity depending on the type of “in vitro”
test compared to thalidomide. Unfortunately, its teratogenic
potential is preserved (Quach et al., 2010; Sedlarikova et al., 2012).
Lenalidomide in monotherapy is not an appropriate treatment
modality for patients with AL amyloidosis because of low efficacy
and inadequate toxicity, especially in patients with renal insuffi-
ciency. Initial doses of lenalidomide should not exceed 15 mg/day
(Adam et al., 2013; Dispenzieri et al., 2007). In 2007, two phase-
II studies with a combination of lenalidomide and dexamethasone
(Len/Dex) were conducted mostly in relapsed/refractory patients
with AL. The hematological overall response rates ranged from 41%
to 67% (Dispenzieri et al., 2007; Sanchorawala et al., 2007b). The
most common treatment-related adverse event (AE) was myelo-
suppression in 45% and 35% of patients, respectively. Fatigue, skin
rash and thromboembolic complications represent other frequent
side effects. Another study with Len/Dex was published in 2012 by
Palladini et al., in which this combination was used as salvage ther-
apy for 24 patients refractory to bortezomib, melphalan and in 79%
also to thalidomide. Hematological response was observed in 41%
of patients, but 50% of patients experienced severe adverse events
(Palladini et al., 2012b). The most recent study with Len/Dex was
conducted in 84 AL amyloidosis patients with relapsed/refractory
clonal disease following prior treatment with thalidomide (76%)
and/or bortezomib (68%). The overall hematological response rate
254 T. Jelinek et al. / Critical Reviews in Oncology/Hematology 99 (2016) 249–260
was 61%, including 20% of complete responses. While the median
OS has not been reached, the 2 year OS and PFS rates were 84% and
73%, respectively. 16% of patients achieved an organ response at 6
months, with a marked improvement in organ responses in patients
on long term therapy (median duration 11 months) and 55% achiev-
ing renal responses by 18 months. The rate of renal responses
among patients who received prolonged treatment was unexpect-
edly high, raising the possibility that immunomodulatory effects
of lenalidomide therapy might enhance the otherwise slow natural
regression of amyloid deposits (Mahmood et al., 2014b). The combi-
nation of Len/Dex showed clinical activity in the pre-treated group
of patients with AL amyloidosis and represent a valuable option as
salvage therapy, but the treatment is accompanied by significant
toxicity (Gatt and Palladini, 2013; Palladini et al., 2012b).
The complete response rate remained low (0–29%) with the
Len/Dex regimen, therefore a number of phase II studies have
focused on the addition of an alkylator to this combination. Three
independent clinical trials with incorporated cyclophospamide
were conducted (regimen CLD) (Kastritis et al., 2012; Kumar et al.,
2012a; Palladini et al., 2013). The hematological response rates
ranged from 55% to 62% and CR rates remained low—approximately
10%. The toxicity was prominent in all these studies with more than
60% of patients reporting severe adverse events, including mainly
hematological toxicity in approximately 40% of cases. Fluid reten-
tion, fatigue, skin rash and gastrointestinal problems rank among
other frequent side effects. Results from another clinical trial with
CLD regimen in 28 newly diagnosed AL amyloidosis patients not
eligible for ASCT were recently presented by Cibeira et al. The
treatment schedule consists of 12 cycles of CLD followed by main-
tentance with low-dose lenalidomide (10 mg) and dexamethasone
until intolerance or disease progression. The overall hematological
response rate was 46%, including complete response in 14%. The
organ response rate was 32%. Serious adverse events were reported
in 25% of cases (Cibeira et al., 2014).
The addition of melphalan to lenalidomide and dexamethasone
(regimen MLD) is other logical combination considering that the
regimen Mel/Dex has been the golden standard of the treatment
of AL amyloidosis to date. In the study published by Moreau et al.,
26 patients with newly diagnosed AL were treated with the MLD
regimen, hematological response was observed in 58% of patients
with CR in 23%. The maximum tolerated dose of lenalidomide was
15 mg/day and the dose of melphalan was 0.18 mg/kg/day (Moreau
et al., 2010). In another study with MLD in a more pre-treated group
of patients, hematological partial and complete responses were
achieved by 43% and 7% of patients, respectively. Grade 3/4 tox-
icities were experienced by 88% patients, with myelosuppression
being the most common (Sanchorawala et al., 2013).
The largest phase II clinical study using lenalidomide in AL amy-
loidosis was presented at ASH 2013 by Schönland and his colleagues
from Heidelberg (Bochtler et al., 2013). 50 patients with newly diag-
nosed AL amyloidosis ineligible for HDM-ASCT were enrolled in this
prospective single center trial. The treatment schedule was 6 cycles
of oral treatment with lenalidomide 10 mg/day, days 1–21, melpha-
lan 0.15 mg/kg/day, days 1–4 and dexamethasone 20 mg/day, days
1–4, every four weeks. Hematological response was achieved in 78%
of patients: CR in 9 (20%) and PR in 26 (58%) of 45 evaluable patients,
respectively. Organ response was observed in 5 (10%) patients at
the end of the study (6 months after the end of treatment). In
comparison to the historical Mel/Dex group from the same cen-
ter (patients with the same inclusion and exclusion criteria), there
was a significantly higher hematological response rate in the MLD
group (78% vs. 58%, p = 0.06) and the improvement was also seen in
median OS (not reached vs. 26 months, p = 0.03). Overall, toxicity
was manageable in most patients, the most common being hema-
tological toxicity (neutropenia in 76% patients). The most common
non-hematological AE was the worsening of cardiac function or
symptoms of autonomic neuropathy (14 patients) and infection (8
patients). Treatment with MLD was effective and feasible in this
cohort of mostly elderly patients including patients with advanced
cardiac involvement (Bochtler et al., 2013).
The use of lenalidomide in combination with an alkylator in
these pre-treated groups of patients with AL amyloidosis was
frequently associated with toxicities grade 3/4, dominantly with
hematological toxicity and fatigue (Bochtler et al., 2013; Kastritis
et al., 2012; Kumar et al., 2012a; Palladini et al., 2013; Sanchorawala
et al., 2013). The higher frequency of severe adverse events is
expectable considering the fragility of this population of patients
and the fact that these chemotherapeutical regimens have not been
optimized yet. The results of the recent clinical trial conducted by
Schönland et al. show that lenalidomide possesses a high therapeu-
tic potential in patients with AL amyloidosis. Accompanied toxicity
may be associated with a different metabolic pathway of lenalido-
mide in comparison with thalidomide and pomalidomide. The
pharmacokinetics of lenalidomide is connected with renal func-
tion, because the excretion of the drug is provided dominantly by
the kidneys. The regimens containing lenalidomide may be a good
treatment alternative for patients refractory to bortezomib or for
patients with polyneuropathy.
The use of lenalidomide in the first line treatment in AL amy-
loidosis should be investigated and its use should be optimized in
clinical trials, especially in patients with no renal insufficiency.
5. Pomalidomide in the treatment of AL amyloidosis
Pomalidomide (CC-4047, Actimid, Imnovid, Pomalyst) is the
third immunomodulatory agent used in clinical practice. The
chemical formula of pomalidomide is 4-amino-2-(2,6-dioxo-3-
piperidyl)isoindoline-1,3-dione (C13 H11 N3 O4 ). This compound is
derived from thalidomide by adding an amino group to position
4 of the phthaloyl ring and exists in two forms, enantiomers S and
R (Sedlarikova et al., 2012). This thalidomide analogue possesses
pleiotropic effects on myeloma cells. Most of these mechanisms
are probably effective also on clonal plasmocytes in AL amyloidosis
(Quach et al., 2010). Pomalidomide inhibits angiogenesis, induces
apoptosis of multiple myeloma cells, has strong immunomodula-
tory abilities and is the most effective in TNF-mRNA degradation in
comparison to thalidomide and lenalidomide (Dredge et al., 2002;
Muller et al., 1999).
Pomalidomide is the newest immunomodulatory agent used in
the treatment of AL amyloidosis. Pomalidomide and dexametha-
sone (regimen Pom/Dex) were investigated in the treatment of
this disease, but only in a limited number of patients. A phase II
clinical trial with 33 patients with refractory/relapsed AL amyloi-
dosis was conducted by investigators from Mayo Clinic Rochester
(Dispenzieri et al., 2012). Patients were treated with pomalidomide
2 mg/day for 28 days (1 cycle) along with orally administered dex-
amethasone 40 mg/week. A majority (82%) of patients had cardiac
involvement, 25% had Mayo cardiac stage III disease. The hema-
tological response was rapid (median 1.9 months) and was seen
in 48% of patients with 3% of complete response, organ treatment
response was achieved in 18% of patients. Remarkably, hematolog-
ical responses to pomalidomide were seen in 40–50% of patients
pre-treated with lenalidomide or bortezomib. The median overall
survival rate was 27.9 months with a 1year OS rate of 76%. Median
and 3 year PFS were 14.1 months and 17%, respectively. The toxicity
profile of the regimen was manageable, although grade 3 or higher
AEs at least possibly related to treatment were reported in 52%
(non-hematological) and 91% (hematological) (Dispenzieri et al.,
2014, 2012). The NT-proBNP reduction did not follow the hema-
tological response similar to what has been seen in other studies
 T. Jelinek et al. / Critical Reviews in Oncology/Hematology 99 (2016) 249–260 255

Table 3
Results of clinical trials including IMiDs in AL amyloidosi.

Regimen Number of patients Hematologic Organ response (%) The most common Median OS (months) or
(%—newly response (%) (CR adverse events grade 1–3 year survival (%)
diagnosed) [%]) 3/4 (%)

Thalidomide containing regimens

Thalidomide Seldin et al., 2003 16 (0%) 25% (0%) 0% Overall 50% Not specified
Fatigue/sedation 38%
Thal/Dex Palladini et al., 2005 31 (0%) 48% (19%) 26% Overall 65% Not specified
Symptomatic bradycardia (26%)
CTD Wechalekar et al., 2007 75 (41%) 74% (21%) 33% Overall 32% 41
MTD Palladini et al., 2009 22 (73%) 36% (5%) 18% Overall 27% 5.3
CTD Venner et al., 2014 69 (100%) 80 (25%) 27% Not specified 67% (1 year OS)

Lenalidomide containing regimens

Len/Dex Dispenzieri et al., 2007 22 (41%) 41% (not specified) 23% Overall 86% Not specified
Neutropenia 45%
Len/Dex Sanchorawala et al., 2007b 34 (9%) 67% (29%) 41% Myelosuppression 35% Not specified
Fatigue 35%
Len/Dex Palladini et al., 2012b 24 (0%) 41% (0%) 4% Overall 50% 14
Thrombocytopenia 17%
Len/Dex Mahmood et al., 2014 84 (0%) 61% (20%) Not specified Not specified 84% (2 year OS)
CLD Kumar et al., 2012b 35 (69%) 60% (11%) 31% Overall 74% 37.8
Neutropenia 40%
CLD Palladini et al., 2013 21 (0%) 62% (5%) 19% Overall 57% 36
CLD Kastritis et al., 2012 37 (65%) 55% (8%) 22% Neutropenia 34% 41% (2 year OS)
CLD Cibeira et al., 2015 28 (100%) 46% (14%) 32% Overall 25% Not specified (study ongoing)
MLD Moreau et al., 2010 26 (100%) 58% (23%) 50% Overall 81% 81% (2 year OS)
Neutropenia 11%
MLD Bochtler et al., 2013 50 (100%) 78% (20%) 10% (at six months) Neutropenia 76% Not achieved
MLD Sanchorawala et al., 2013 16 (69%) 50% (7%) 11% Overall 88% Not achieved
Myelosuppression 57%

Pomalidomide containing regimens

Pom/Dex Dispenzieri et al., 2012 33 (0%) 48% (3%) 15% Hematologic 91% 27.9
Non-hematologic 52%
Pom/Dex Milani et al., 2013 27 (0%) 67% (18%—VGPR) (short-term follow-up) Overall 67% (short-term follow-up)
Neutropenia 30%
Pom/Dex Sanchorawala et al., 2014b 12 (0%) Not specified (22%) Not specified Overall 50% Not specified (study ongoing)

of patients with AL amyloidosis taking immunomodulatory drugs
(Dispenzieri et al., 2010; Gibbs et al., 2009; Tapan et al., 2010).
A second clinical trial with high dose (4 mg/day) pomalidomide
and oral dexamethasone (40 mg/week) was conducted by Milani
et al. and its preliminary results were presented at ASH 2013. 27
patients with relapsed/refractory AL previously exposed to an alky-
lator or bortezomib were enrolled in the trial and 41% had also
received an immunomodulatory agent. Overall, 18 patients (67%)
achieved a hematological response, with 5 (18%) very good par-
tial responses. Moreover, of the 7 patients previously exposed to
lenalidomide, 5 responded to pomalidomide and the 3 patients
who were refractory to ixazomib responded as well, indicating that
pomalidomide can overcome resistance to other immunomodula-
tory drugs and a second-generation proteasome inhibitor. Overall,
18 patients (67%) experienced severe (grade 3–4) adverse events:
neutropenia (n = 8, 30%), fluid retention (n = 7, 26%, all with heart
involvement), infection (n = 3, 11%), less common were neuropathy
and rash. As previously reported with other immunomodulatory
drugs, pomalidomide was associated with an increase in NT-
proBNP during cycle 1 (Milani et al., 2013).
The preliminary data of the most recent clinical trial with
Pom/Dex in 12 patients with relapsed AL were presented at the
XIVth International Symposium on Amyloidosis by Sanchorawala
et al. Hematological complete response was observed in 2 of 9
evaluable patients (22%), toxicity grade 3 or higher was reported
in 6 cases (50%). Other data were not specified but the trial is still
ongoing (Sanchorawala et al., 2014b).
These results show good efficacy of pomalidomide and dex-
amethasone in patients with refractory AL amyloidosis previously
exposed also to other IMiDs. Further studies to optimize this potent
rescue regimen are warranted.
6. Problematics of response assessment with IMiDs
NT-proBNP and BNP are important and useful biomarkers of car-
diac involvement, especially of heart failure. The prognostic value
of these biomarkers in AL amyloidosis is indisputable, but they also
serve to assess the organ (cardiac) treatment response. Neverthe-
less, the use of immunomodulatory agents may cause an elevation
of cardiac biomarkers in a significant proportion of patients usu-
ally during the first cycle of chemotherapy. This phenomenon may
complicate the assessment of organ treatment response in patients
treated with IMiDs.
Gibbs et al. described this phenomenon in 51 patients who
achieved complete hematological response measured by the
decrease of serum free light chains (FLC). Overall, 42 patients were
treated with a regimen based on thalidomide (CTD) and 9 patients
were treated with melphalan and dexamethasone (Mel/Dex). An
increase in NT-proBNP from baseline was seen in 36 (71%) patients
at 6 months. A subsequent fall in their NT-proBNP levels was seen
at 12 months in 33 (92%) of these patients. There was no signifi-
cant rise in creatinine serum level at 6 months, suggesting that the
rise in NT-proBNP was not due to a change in the renal function.
Importantly, there was no difference in the rate of NT-proBNP rise
when comparing the CTD regimen to Mel/Dex. It is clearly shown
that NT-proBNP values can rise transiently in the immediate post
chemotherapy period in nearly three quarters of patients with a
complete FLC response in this analysis. The exact mechanism of
this phenomenon has remained unclear and it has not impacted
the rate of clonal relapse or overall survival (Gibbs et al., 2009).
Tapan et al. described the rise of BNP level (> 30% increase from
baseline) in 86% of patients treated with lenalidomide and dexam-
ethasone (Len/Dex). In 68% of patients the increase occured during
the first cycle of chemotherapy. All the patients with an increase
 256
Table 4
Ongoing clinical trials with IMiDs in AL amyloidosis.

Title Regimens Condition Estimated enrollment Identifier

Experimental arm Active comparator

A phase I/II clinical trial of pomalidomide Pomalidomide orally 1 mg/day, days X Untreated systemic AL 54 patients NCT01807286
with melphalan and dexamethasone in 1–21; amyloidosis
patients with newly diagnosed untreated Melphalan orally 9 mg/m2 /day days
systemic AL amyloidosis 1–4;
Dexamethasone orally 40 mg/day days
1–4;
28 days long cycle
An open-label, phase II study of Pomalidomide orally 2–4 mg/day days X Primary amyloidosis of 28 patients NCT01510613
pomalidomide and dexamethasone (PDex) 1–28; light chain type

T. Jelinek et al. / Critical Reviews in Oncology/Hematology 99 (2016) 249–260

for previously treated patients with AL Dexamethasone orally 20–40 mg, days
amyloidosis 1,8,15,22;
28 days long cycle, until progression or
unacceptable toxicity
Phase I study of pomalidomide, Pomalidomide orally days 1–21; X Primary systemic 36 patients NCT01728259
bortezomib, and dexamethasone (PVD) as Bortezomib iv. days 1,8,15; amyloidosis
first-line treatment of AL amyloidosis or Dexamethasone orally 1,8,15,22;
light chain deposition disease 28 days long cycle, until progression or
unacceptable toxicity
A phase 3, randomized, controlled, MLN9708 4 mg orally days 1,8,15; Physician’s choice Relapsed or refractory 248 patients NCT01659658
open-label, multicenter, safety and systemic light chain
efficacy study of dexamethasone plus amyloidosis
MLN9708 or physician’s choice of
treatment administered to patients with
relapsed or refractory systemic light chain Dexamethasone 20 mg/day orally days
(AL) amyloidosis 1,8,15,22;
28 days long cycle
A phase I/II trial of pomalidomide and Pomalidomide orally 2–4 mg/day, days X Previously-treated AL amyloidosis 35 patients NCT01570387
dexamethasone in subjects with 1–28;
previously-treated AL amyloidosis Dexamethasone orally 10–20 mg, days
1,8,15,22;
28 days long cycle, until progression or
unacceptable toxicity
A phase II trial of mrd (melphalan, Dexamethasone 20 mg/day orally days X Primary systemic 35 patients NCT00679367
lenalidomide and dexamethasone) for 1,8,15,22; amyloidosis
patients with AL amyloidosis Lenalidomide 10 mg/day, days 1–21;
Melphalan orally 5 mg/m2 /day days
1–4;
A phase I/II trial of lenalidomide combined Lenalidomide 5–25 mg/day orally, days X Primary (AL) systemic 37 patients NCT00981708
with cyclophosphamide and intermediate 1–21; amyloidosis
dose dexamethasone in patients with Dexamethasone 20 mg/day days 1–4;
primary (AL) systemic amyloidosis Cyclophosphamide 50–100 mg/day
orally days 1–10;
28 days long cycle
A multicentric, phase II trial of Lenalidomide 15 mg/day, day 1–21; X Primary systemic 30 patients NCT01194791
lenalidomide, cyclophosphamide and Cyclophosphamide 300 mg/m2 days amyloidosis (AL) newly
dexamethasone in patients with primary 1,8; diagnosed
systemic amyloidosis (AL) newly Dexamethasone 20 mg/day orally days
diagnosed, not candidates for 1–4 and 9–12;
hematopoietic stem cell transplantation 28 days long cycle, 6 cycles
 T. Jelinek et al. / Critical Reviews in Oncology/Hematology 99 (2016) 249–260
in BNP were asymptomatic without association of modification in
NYHA class congestive heart failure (Tapan et al., 2010). Similarly,
the results of clinical trials with pomalidomide showed the discrep-
ancy between an increase of cardiac biomarkers and hematological
response (Dispenzieri et al., 2012; Palladini et al., 2013).
Even though this phenomenon is transient, it complicates the
assessment and interpretation of treatment organ response in AL.
It is useful to evaluate the dynamics of FLC levels and levels of
cardiac biomarkers. Patients with AL amyloidosis receiving IMiDs
whose cardiac biomarkers rise should not be assumed to be fail-
ing therapy without other signs of disease progression, but should
be monitored closely. Clinical hematologist-oncologists must care-
fully consider how to evaluate the organ treatment response,
dominantly when the decision of changing therapy is about to be
made. Further data is needed for non-thalidomide based regimens
to assess if this has an effect to the same extent.
7. Treatment strategies in AL amyloidosis and role of IMiDs
There is no consensus of optimal therapy for patients with
newly diagnosed AL amyloidosis, because there is minimum data
available from randomized clinical trials, because of the rarity of
this disease and the small number of patients possibly enrolled.
Often, the treatment strategy is based on expert opinions at a
national, European or global level. None of the 3 published ran-
domized clinical trials include novel agents such as proteasome
inhibitors or immunomodulatory agents. Thus, the most evident
benefit of novel agents is increased flexibility of our treatment strat-
egy in newly diagnosed patients, because we can switch from a
thalidomide-based to bortezomib-based regimen if not tolerated
and/or effective. Moreover, we have now got several effective treat-
ment options in a relapse setting.
The treatment strategy in patients with AL amyloidosis is shaped
by background factors including performance status, age, comor-
bidities, contraindications to drugs and also patient preference.
Risk stratification adopted from the Mayo Clinic staging system is
crucial in the choice of treatment strategy and may be a helpful
instrument for physicians as many of the patients are very fragile.
According to this risk adapted staging system based on the level of
cardiac biomarkers (NT-proBNP and Troponin T), patients with AL
are divided into three groups (Dispenzieri et al., 2004; Kumar et al.,
2012a). ASCT should always be considered as a part of front-line
therapy in low-risk patients with AL amyloidosis. These patients
can be also treated with a combined bortezomib based regimen
which allows the safe harvest of peripheral stem cells and leaves
the performance of ASCT only in the case of not achieving complete
remission (Mikhael et al., 2012; Venner et al., 2012). Approximately
50% of patients with newly diagnosed AL are in the intermediate
risk group, these patients are not suitable for undertaking ASCT
as front line treatment. According to two recently published ret-
rospective case control studies, there is still no certainty about
the best treatment option for this group of patients. Bortezomib-
based regimens yielded higher complete response rates, and these
responses were rapidly achieved, but there was no clear improve-
ment in overall survival. It was only in an Italian study where one
subgroup of patients with New York Heart Association class of <3
and NT-proBNP of ≤8500 ng/l, who were not fit enough to recieve
high dose dexamethasone, had a superior OS when bortezomib was
added to Mel/Dex (Palladini et al., 2014a,b; Venner et al., 2014). The
results of the randomized phase III trial are still awaited. The last
interim analysis from ASH 2014 indicates that the addition of borte-
zomib to Mel/Dex grants more profound hematologic responses
that should be balanced with a relative increase in toxicity (Merlini
et al., 2014). Nevertheless, also thalidomide based regimens may be
successfuly used in a selected cohort of patients. A high-risk group
257
of patients has a poor prognosis dominantly because of exten-
sive organ involvement and their treatment remains problematic
with the use of low-dose corticosteroids in combination with novel
agents (Mahmood et al., 2014a). According to recent data pub-
lished by Wechalekar et al. at EHA 2014, it seems that thalidomide
based regimens (TMD) are slightly beneficial compared to borte-
zomib based regimens with an estimated survival rate of 75% vs.
61% at four months for patients with a high-risk Mayo Clinic stage
(Wechalekar et al., 2014).
Immunomodulatory agents showed good efficacy in the treat-
ment of AL and they may be used mainly in patients with
relapsed/refractory disease but also as a part of first-line ther-
apy. The optimization of the regimen reflecting its toxicity plays
an important role. Due to the lack of randomized clinical trials,
it is difficult to decide which immunomodulatory drug is better.
Pomalidomide may be a representative agent of this group with
a good balance between high effectivity and tolerable toxicity.
The summary of practically all published clinical trials containing
immunomodulatory agents is in Table 3.
Thalidomide in combination with other drugs showed good clin-
ical activity in the treatment of AL, but its use is accompanied by
significant toxicity. This IMiD may be a treatment alternative for
patients refractory to bortezomib or may be used also as a first
line treatment if well tolerated. Lenalidomide may be used also in
patients refractory to bortezomib or in patients with neuropathy.
The toxicity of lenalidomide-containing regimens may be a prob-
lem, especially for patients with renal insufficiency. Pomalidomide
proved to have high efficacy in pilot studies and the lowest toxicity
of all immonomodulatory agents and seems to be a very promis-
ing drug in the treatment of AL. The appropriate dosage of IMiDs
is important and it is possible to recommend 50–100 mg/day of
thalidomide, 10–15 mg/day of lenalidomide, 2 mg/day or 4 mg/day
of pomalidomide (based on available results of clinical studies).
Concerning pomalidomide, it is not possible to decide which dose
level is better, because only two clinical trials have been conducted
to date. Combinations of immunomodulatory drugs and a corti-
costeroid well tolerated in multiple myeloma may represent an
appropriate treatment option also in AL amyloidosis.
8. Conclusion
Immunoglobulin light chain amyloidosis is a rare disease, but
the most common of the systemic amyloidoses. Patients are often
diagnosed in an advanced stage with multiorgan involvement and
their prognosis remains poor. Nevertheless, recently published
data suggests that overall survival of patients eligible for ASCT
with preserved cardiac function is surprisingly long and with a
life expectancy much longer than in multiple myeloma patients.
The combination of melphalan and dexamethasone is still a very
good treatment option for transplant ineligible patients, but novel
agents may offer some benefits. Proteasome inhibitors and mainly
combined bortezomib based regimens seem to be a good choice in
front-line therapy. However, thalidomide based regimens may be
used in this setting as well, if well tolerated. Any data of randomized
clinical trials, which would support the use of one or another group
of agents are still not available. Recent trials with immunomodula-
tory agents, on which this review is focused, show a good clinical
efficacy, but the toxicity remains significant in this fragile group
of patients. Pomalidomide seems to be a very promising drug with
preserved high effectivity and favorable toxic profile in patients
with renal insufficiency as well. The development of a new gen-
eration of proteasome inhibitors, e.g. oral ixazomib (MLN9708),
gives physicians more options in the decision making process of
adequate treatment approach. As AL amyloidosis is a very uncom-
mon disorder, most patients should be treated within the clinical
258 T. Jelinek et al. / Critical Reviews in Oncology/Hematology 99 (2016) 249–260
trials. Active clinical trials with immunomodulatory drugs in AL
amyloidosis are summarized in Table 4. Also, novel therapies tar-
geted directly on amyloid and not on pre-existing malignant clone
of plasmocytes may play a role in the future. Recently, the clini-
cal trial phase III with NEOD001 has been initialized. NEOD001 is a
monoclonal antibody that targets the amyloid that affects both AL
and AA amyloidosis. Finally, what seems to be the most important
issue in clinical practise is an increasing awareness of this rare dis-
ease among physicians—dominantly cardiologists, nephrologists
and also hematologists.
Conflict of interest
The authors have no conflict of interest to be disclosed.
Acknowledgements
TJ—wrote the paper
ZK—proofread the paper
RH—concept, overall proofread, work coordination
This work was supported by the Moravian-Silesian Region
grants MSK 02680/2014/RRC and MSK 02692/2014/RRC; grants
by MH CZ-DRO-FNOs/2014; by The Ministry of Education, Youth
and Sports (Institutional Development Plan of University of
Ostrava in 2015); projects SGS01/LF/2014-2015, SGS02/LF/2014-
2015, SGS03/LF/2015-2016 and by grant IGA of The Ministry of
Health15-29667A. The authors want to give special thanks to Eva
Jarosova for administrative support.
References
Adam, Z., Sčudla, V., Krejčí, M., Cermáková, Z., Pour, L., Král, Z., 2013. Treatment of
AL amyloidosis in 2012; the benefit of new drugs (bortezomib, thalidomide,
and lenalidomide). Summary of published clinical trials. Vnitr˘ní Lékar˘ství 59,
37–58.
Akobeng, A.K., Stokkers, P.C., 2009. Thalidomide and thalidomide analogues for
maintenance of remission in Crohn’s disease. Cochrane Database Syst. Rev.,
http://dx.doi.org/10.1002/14651858.CD007351.pub2, CD007351.
Bartlett, J.B., Dredge, K., Dalgleish, A.G., 2004. The evolution of thalidomide and its
IMiD derivatives as anticancer agents. Nat. Rev. Cancer 4, 314–322, http://dx.
doi.org/10.1038/nrc1323.
Bhat, A., Selmi, C., Naguwa, S.M., Cheema, G.S., Gershwin, M.E., 2010. Currents
concepts on the immunopathology of amyloidosis. Clin. Rev. Allergy Immunol.
38, 97–106, http://dx.doi.org/10.1007/s12016-009-8163-9.
Bochtler, T., Benner, A., Gawlik, M., Kimmich, C., Kristen, A.V., Beimler, J., Ho, A.D.,
Hegenbart, U., 2013. Lenalidomide/melphalan/dexamethasone chemotherapy
in 50 patients with newly diagnosed amyloid light chain amyloidosis: first
results of a prospective single center phase 2 study (Leomex). Blood 122,
1993–1993.
Breitkreutz, I., Raab, M.S., Vallet, S., Hideshima, T., Raje, N., Mitsiades, C., Chauhan,
D., Okawa, Y., Munshi, N.C., Richardson, P.G., Anderson, K.C., 2008.
Lenalidomide inhibits osteoclastogenesis, survival factors and
bone-remodeling markers in multiple myeloma. Leukemia 22, 1925–1932,
http://dx.doi.org/10.1038/leu.2008.174.
Chu, Z.L., McKinsey, T.A., Liu, L., Gentry, J.J., Malim, M.H., Ballard, D.W., 1997. 1997:
Suppression of tumor necrosis factor-induced cell death by inhibitor of
apoptosis c-IAP2 is under NF-kappaB control. Proc. Natl. Acad. Sci. U. S. A. 94,
10057–10062.
Cibeira, M.T., Oriol, A., Lahuerta, J.J., Mateos, M.V., de la Rubia, J., Hernández, M.T.,
Granell, M., Fernández de Larrea, C., San Miguel, J.F., Bladé, J., 2014. Phase II
trial of lenalidomide, dexamethasone and cyclophosphamide (LENDEXAL) for
previously untreated patients with light-chain amyloidosis. Presented at the
XIVth International Symposium on Amyloidosis, Indianapolis.
Cohen, A.D., Zhou, P., Chou, J., Teruya-Feldstein, J., Reich, L., Hassoun, H., Levine, B.,
Filippa, D.A., Riedel, E., Kewalramani, T., Stubblefield, M.D., Fleisher, M., Nimer,
S., Comenzo, R.L., 2007. Risk-adapted autologous stem cell transplantation
with adjuvant dexamethasone + —thalidomide for systemic light-chain
amyloidosis: results of a phase II trial. Br. J. Haematol. 139, 224–233, http://dx.
doi.org/10.1111/j.1365-2141.2007.06783.x.
Comenzo, R.L., Reece, D., Palladini, G., Seldin, D., Sanchorawala, V., Landau, H., Falk,
R., Wells, K., Solomon, A., Wechalekar, A., Zonder, J., Dispenzieri, A., Gertz, M.,
Streicher, H., Skinner, M., Kyle, R.A., Merlini, G., 2012. Consensus guidelines for
the conduct and reporting of clinical trials in systemic light-chain amyloidosis.
Leukemia 26, 2317–2325, http://dx.doi.org/10.1038/leu.2012.100.
Comenzo, R.L., Vosburgh, E., Falk, R.H., Sanchorawala, V., Reisinger, J., Dubrey, S.,
Dember, L.M., Berk, J.L., Akpek, G., LaValley, M., O’hara, C., Arkin, C.F., Wright,
D.G., Skinner, M., 1998. Dose-intensive melphalan with blood stem-cell
support for the treatment of AL (amyloid light-chain) amyloidosis: survival
and responses in 25 patients. Blood 91, 3662–3670.
Cordes, S., Dispenzieri, A., Lacy, M.Q., Hayman, S.R., Buadi, F.K., Dingli, D., Kumar,
S.K., Hogan, W.J., Gertz, M.A., 2012. Ten-year survival after autologous stem
cell transplantation for immunoglobulin light chain amyloidosis. Cancer 118,
6105–6109, http://dx.doi.org/10.1002/cncr.27660.
Davies, F.E., Raje, N., Hideshima, T., Lentzsch, S., Young, G., Tai, Y.T., Lin, B., Podar,
K., Gupta, D., Chauhan, D., Treon, S.P., Richardson, P.G., Schlossman, R.L.,
Morgan, G.J., Muller, G.W., Stirling, D.I., Anderson, K.C., 2001. Thalidomide and
immunomodulatory derivatives augment natural killer cell cytotoxicity in
multiple myeloma. Blood 98, 210–216.
Dhodapkar, M.V., Jagannath, S., Vesole, D., Munshi, N., Naucke, S., Tricot, G.,
Barlogie, B., 1997. Treatment of AL-amyloidosis with dexamethasone plus
alpha interferon. Leuk. Lymphoma 27, 351–356, http://dx.doi.org/10.3109/
10428199709059690.
Dispenzieri, A., Lacy, M.Q., Rajkumar, S.V., Geyer, S.M., Witzig, T.E., Fonseca, R., Lust,
J.A., Greipp, P.R., Kyle, R.A., Gertz, M.A., 2003. Poor tolerance to high doses of
thalidomide in patients with primary systemic amyloidosis. Amyloid Int. J. Exp.
Clin. Investig. 10, 257–261, http://dx.doi.org/10.3109/13506120309041743.
Dispenzieri, A., Gertz, M.A., Kyle, R.A., Lacy, M.Q., Burritt, M.F., Therneau, T.M.,
Greipp, P.R., Witzig, T.E., Lust, J.A., Rajkumar, S.V., Fonseca, R., Zeldenrust, S.R.,
McGregor, C.G.A., Jaffe, A.S., 2004. Serum cardiac troponins and N-terminal
pro-brain natriuretic peptide: a staging system for primary systemic
amyloidosis. J. Clin. Oncol. 22, 3751–3757, http://dx.doi.org/10.1200/JCO.2004.
03.029.
Dispenzieri, A., Lacy, M.Q., Zeldenrust, S.R., Hayman, S.R., Kumar, S.K., Geyer, S.M.,
Lust, J.A., Allred, J.B., Witzig, T.E., Rajkumar, S.V., Greipp, P.R., Russell, S.J., Kabat,
B., Gertz, M.A., 2007. The activity of lenalidomide with or without
dexamethasone in patients with primary systemic amyloidosis. Blood 109,
465–470, http://dx.doi.org/10.1182/blood-2006-07-032987.
Dispenzieri, A., Dingli, D., Kumar, S.K., Rajkumar, S.V., Lacy, M.Q., Hayman, S., Buadi,
F., Zeldenrust, S., Leung, N., Detweiler-Short, K., Lust, J.A., Russell, S.J., Kyle, R.A.,
Gertz, M.A., 2010. Discordance between serum cardiac biomarker and
immunoglobulin-free light-chain response in patients with immunoglobulin
light-chain amyloidosis treated with immune modulatory drugs. Am. J.
Hematol. 85, 757–759, http://dx.doi.org/10.1002/ajh.21822.
Dispenzieri, A., Buadi, F., Laumann, K., LaPlant, B., Hayman, S.R., Kumar, S.K., Dingli,
D., Zeldenrust, S.R., Mikhael, J.R., Hall, R., Rajkumar, S.V., Reeder, C., Fonseca, R.,
Bergsagel, P.L., Stewart, A.K., Roy, V., Witzig, T.E., Lust, J.A., Russell, S.J., Gertz,
M.A., Lacy, M.Q., 2012. Activity of pomalidomide in patients with
immunoglobulin light-chain amyloidosis. Blood 119, 5397–5404, http://dx.doi.
org/10.1182/blood-2012-02-413161.
Dispenzieri, A., Seenithamby, K., Lacy, M.Q., Kumar, S.K., Buadi, F.K., Hayman, S.R.,
Dingli, D., Litzow, M.R., Gastineau, D.A., Inwards, D.J., Micallef, I.N., Ansell, S.M.,
Johnston, P.B., Porrata, L.F., Patnaik, M.M., Hogan, W.J., Gertz, M.A.A., 2013.
Patients with immunoglobulin light chain amyloidosis undergoing autologous
stem cell transplantation have superior outcomes compared with patients with
multiple myeloma: a retrospective review from a tertiary referral center. Bone
Marrow Transplant 48, 1302–1307, http://dx.doi.org/10.1038/bmt.2013.53.
Dispenzieri, A., 2014. Still no certainty about the role of upfront bortezomib among
patients with AL amyloidosis. Leukemia 28, 2273–2275, http://dx.doi.org/10.
1038/leu.2014.271.
Dispenzieri, A., Buadi, F., Laumann, K., LaPlant, B., Hayman, S.R., Kumar, S.K., Dingli,
D., Zeldenrust, S.R., Mikhael, J.R., Rajkumar, S.V., Reeder, C., Fonseca, R.,
Bergsagel, P.L., Stewart, A.K., Roy, V., Lust, J.A., Russell, S.J., Gertz, M.A., Lacy,
M.Q., 2014. Long-term results of pomalidomide and dexamethasone for
patients with relapsed or refractory AL amyloidosis. Presented at the XIVth
International Symposium on Amyloidosis, Indianapolis.
Dredge, K., Marriott, J.B., Macdonald, C.D., Man, H.-W., Chen, R., Muller, G.W.,
Stirling, D., Dalgleish, A.G., 2002. Novel thalidomide analogues display
anti-angiogenic activity independently of immunomodulatory effects. Br. J.
Cancer 87, 1166–1172, http://dx.doi.org/10.1038/sj.bjc.6600607.
Dredge, K., Horsfall, R., Robinson, S.P., Zhang, L.-H., Lu, L., Tang, Y., Shirley, M.A.,
Muller, G., Schafer, P., Stirling, D., Dalgleish, A.G., Bartlett, J.B., 2005. Orally
administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits
endothelial cell migration and Akt phosphorylation in vitro. Microvasc. Res. 69,
56–63, http://dx.doi.org/10.1016/j.mvr.2005.01.002.
Gatt, M.E., Palladini, G., 2013. Light chain amyloidosis 2012: a new era. Br. J.
Haematol. 160, 582–598, http://dx.doi.org/10.1111/bjh.12191.
Geitz, H., Handt, S., Zwingenberger, K., 1996. Thalidomide selectively modulates
the density of cell surface molecules involved in the adhesion cascade.
Immunopharmacology 31, 213–221.
Gertz, M.A., Lacy, M.Q., Dispenzieri, A., Ansell, S.M., Elliott, M.A., Gastineau, D.A.,
Inwards, D.J., Micallef, I.N.M., Porrata, L.F., Tefferi, A., Litzow, M.R., 2004.
Risk-adjusted manipulation of melphalan dose before stem cell transplantation
in patients with amyloidosis is associated with a lower response rate. Bone
Marrow Transplant 34, 1025–1031, http://dx.doi.org/10.1038/sj.bmt.1704691.
Gertz, M.A., Comenzo, R., Falk, R.H., Fermand, J.P., Hazenberg, B.P., Hawkins, P.N.,
Merlini, G., Moreau, P., Ronco, P., Sanchorawala, V., Sezer, O., Solomon, A.,
Grateau, G., 2005. Definition of organ involvement and treatment response in
immunoglobulin light chain amyloidosis (AL): a consensus opinion from the
10th International Symposium on Amyloid and Amyloidosis, Tours, France,
18–22 April 2004. Am. J. Hematol. 79, 319–328, http://dx.doi.org/10.1002/ajh.
20381.
 T. Jelinek et al. / Critical Reviews in Oncology/Hematology 99 (2016) 249–260
Gibbs, S.D.J., De Cruz, M., Sattianayagam, P.T., Lachmann, H.J., Gillmore, J.D.,
Hawkins, P.N., Wechalekar, A.D., (2009). Transient Post Chemotherapy Rise in
NT Pro-BNP in AL Amyloidosis: Implications for Organ Response Assessment.
[WWW Document]. BLOOD. URL http://discovery.ucl.ac.uk/93113/ (accessed
8.20.14).
Gillmore, J.D., Lane, T., Rannigan, L., Foard, D., Gibbs, S.D.J., Pinney, J.H., Venner, C.P.,
Banypersad, S., Lachmann, H.J., Wechalekar, A.D., Hawkins, P.N., 2012.
ALchemy—a large prospective real world study of chemotherapy in AL
amyloidosis Julian D Gillmore, Thirusha Lane, Lisa Rannigan, Darren Foard,
Simon DJ Gibbs, Jennifer H Pinney, Christopher P Venner, Sanjay Banypersad,
Helen J Lachmann, Ashutosh D Wechalekar Philip N Hawkins. Presented at the
XIIIth International Symposium on Amyloidosis.
Girnius, S., Seldin, D.C., Meier-Ewert, H.K., Sloan, J.M., Quillen, K., Ruberg, F.L., Berk,
J.L., Doros, G., Sanchorawala, V., 2014. Safety and efficacy of high-dose
melphalan and auto-SCT in patients with AL amyloidosis and cardiac
involvement. Bone Marrow Transplant 49, 434–439, http://dx.doi.org/10.1038/
bmt.2013.192.
Hegenbart, U., Iacobelli, S., Hoek, J., Rovira, M., Imhoff, G., van Bandini, G.,
Mellqvist, U.-H., Leblond, V., Carlson, K., Zver, S., Blaise, D., Alessandrino, E.P.,
Garderet, L., Kröger, N., 2013. Center experience and calendar year of
transplantation strongly influence short term survival after autologous
peripheral blood transplantation in 1315 patients with light chain
amyloidosis: an EBMT analysis. Blood 122, 417–417.
Hideshima, T., Chauhan, D., Shima, Y., Raje, N., Davies, F.E., Tai, Y.T., Treon, S.P., Lin,
B., Schlossman, R.L., Richardson, P., Muller, G., Stirling, D.I., Anderson, K.C.,
2000. Thalidomide and its analogs overcome drug resistance of human
multiple myeloma cells to conventional therapy. Blood 96, 2943–2950.
Hinson, R.M., Williams, J.A., Shacter, E., 1996. Elevated interleukin 6 is induced by
prostaglandin E2 in a murine model of inflammation: possible role of
cyclooxygenase-2. Proc. Natl. Acad. Sci. U. S. A. 93, 4885–4890.
Iyer, C.G., Languillon, J., Ramanujam, K., Tarabini-Castellani, G., De las Aguas, J.T.,
Bechelli, L.M., Uemura, K., Martinez Dominguez, V., Sundaresan, T., 1971. WHO
co-ordinated short-term double-blind trial with thalidomide in the treatment
of acute lepra reactions in male lepromatous patients. Bull. World Health
Organ 45, 719–732.
Jaccard, A., Moreau, P., Leblond, V., Leleu, X., Benboubker, L., Hermine, O., Recher,
C., Asli, B., Lioure, B., Royer, B., Jardin, F., Bridoux, F., Grosbois, B., Jaubert, J.,
Piette, J.-C., Ronco, P., Quet, F., Cogne, M., Fermand, J.-P., 2007. Myélome
autogreffe (MAG) and intergroupe francophone du myélome (IFM) intergroup,
2007. High-dose melphalan versus melphalan plus dexamethasone for AL
amyloidosis. N. Engl. J. Med., http://dx.doi.org/10.1056/NEJMoa070484.
Jones, N.F., Hilton, P.J., Tighe, J.R., Hobbs, J.R., 1972. Treatment of primary renal
amyloidosis with melphalan. Lancet 2, 616–619.
Kastritis, E., Anagnostopoulos, A., Roussou, M., Toumanidis, S., Pamboukas, C.,
Migkou, M., Tassidou, A., Xilouri, I., Delibasi, S., Psimenou, E., Mellou, S., Terpos,
E., Nanas, J., Dimopoulos, M.A., 2007. Treatment of light chain (AL) amyloidosis
with the combination of bortezomib and dexamethasone. Haematologica 92,
1351–1358, http://dx.doi.org/10.3324/haematol.11325.
Kastritis, E., Terpos, E., Roussou, M., Gavriatopoulou, M., Pamboukas, C., Boletis, I.,
Marinaki, S., Apostolou, T., Nikitas, N., Gkortzolidis, G., Michalis, E., Delimpasi,
S., Dimopoulos, M.A., 2012. A phase 1/2 study of lenalidomide with low-dose
oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis.
Blood 119, 5384–5390, http://dx.doi.org/10.1182/blood-2011-12-396903.
Kotla, V., Goel, S., Nischal, S., Heuck, C., Vivek, K., Das, B., Verma, A., 2009.
Mechanism of action of lenalidomide in hematological malignancies. J.
Hematol. Oncol. 2, 36, http://dx.doi.org/10.1186/1756-8722-2-36.
Krönke, J., Udeshi, N.D., Narla, A., Grauman, P., Hurst, S.N., McConkey, M., Svinkina,
T., Heckl, D., Comer, E., Li, X., Ciarlo, C., Hartman, E., Munshi, N., Schenone, M.,
Schreiber, S.L., Carr, S.A., Ebert, B.L., 2014. Lenalidomide causes selective
degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343,
301–305, http://dx.doi.org/10.1126/science.1244851.
Kumar, S., Dispenzieri, A., Lacy, M.Q., Hayman, S.R., Buadi, F.K., Colby, C., Laumann,
K., Zeldenrust, S.R., Leung, N., Dingli, D., Greipp, P.R., Lust, J.A., Russell, S.J., Kyle,
R.A., Rajkumar, S.V., Gertz, M.A., 2012a. Revised prognostic staging system for
light chain amyloidosis incorporating cardiac biomarkers and serum free light
chain measurements. J. Clin. Oncol. 30, 989–995, http://dx.doi.org/10.1200/
JCO.2011.38.5724.
Kumar, S.K., Hayman, S.R., Buadi, F.K., Roy, V., Lacy, M.Q., Gertz, M.A., Allred, J.,
Laumann, K.M., Bergsagel, L.P., Dingli, D., Mikhael, J.R., Reeder, C.B., Stewart,
A.K., Zeldenrust, S.R., Greipp, P.R., Lust, J.A., Fonseca, R., Russell, S.J., Rajkumar,
S.V., Dispenzieri, A., 2012b. Lenalidomide, cyclophosphamide, and
dexamethasone (CRd) for light-chain amyloidosis: long-term results from a
phase 2 trial. Blood 119, 4860–4867, http://dx.doi.org/10.1182/blood-2012-
01-407791.
Kyle, R.A., Gertz, M.A., Greipp, P.R., Witzig, T.E., Lust, J.A., Lacy, M.Q., Therneau, T.M.,
1997. A trial of three regimens for primary amyloidosis: colchicine alone,
melphalan and prednisone, and melphalan, prednisone, and colchicine. N. Engl.
J. Med. 336, 1202–1207, http://dx.doi.org/10.1056/NEJM199704243361702.
Landau, H., Smith, M., Chou, J., Comenzo, R.L., Sean, M.D., Hassoun, H., Bello, C.,
Giralt, S., 2014. Event-free and overall survival following risk-adapted
melphalan stem cell transplant and consolidation for systemic light chain
amyloidosis. Presented at the XIVth International Symposium on Amyloidosis,
Indianapolis.
Licht, J.D., Shortt, J., Johnstone, R., 2014. From anecdote to targeted therapy: the
curious case of thalidomide in multiple myeloma. Cancer Cell 25, 9–11, http://
dx.doi.org/10.1016/j.ccr.2013.12.019.
259
Lu, G., Middleton, R.E., Sun, H., Naniong, M., Ott, C.J., Mitsiades, C.S., Wong, K.-K.,
Bradner, J.E., Kaelin, W.G., 2014. The myeloma drug lenalidomide promotes the
cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309,
http://dx.doi.org/10.1126/science.1244917.
Mahmood, S., Palladini, G., Sanchorawala, V., Wechalekar, A., 2014a. Update on
treatment of light chain amyloidosis. Haematologica 99, 209–221, http://dx.
doi.org/10.3324/haematol.2013.087619.
Mahmood, S., Venner, C.P., Sachchithanantham, S., Lane, T., Rannigan, L., Foard, D.,
Pinney, J.H., Gibbs, S.D.J., Whelan, C.J., Lachmann, H.J., Gillmore, J.D., Hawkins,
P.N., Wechalekar, A.D., 2014b. Lenalidomide and dexamethasone for systemic
AL amyloidosis following prior treatment with thalidomide or bortezomib
regimens. Br. J. Haematol. 166, 842–848, http://dx.doi.org/10.1111/bjh.12973.
Masferrer, J.L., Leahy, K.M., Koki, A.T., Zweifel, B.S., Settle, S.L., Woerner, B.M.,
Edwards, D.A., Flickinger, A.G., Moore, R.J., Seibert, K., 2000. Antiangiogenic and
antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 60,
1306–1311.
Merlini, G., Palladini, G., 2008. Amyloidosis: is a cure possible? Ann. Oncol. Off. J.
Eur. Soc. Med. Oncol. ESMO 19 (Suppl. (4)), 63–66, http://dx.doi.org/10.1093/
annonc/mdn200.
Merlini, G., Palladini, G., 2013. Light chain amyloidosis: the heart of the problem.
Haematologica 98, 1492–1495, http://dx.doi.org/10.3324/haematol.2013.
094482.
Merlini, G., Leleu, X., Arnulf, B., Zamagi, E., Mollee, P., Cibeira, T.M., Schönland, S.O.,
Moreau, P., Hajek, R., Jaccard, A., Nicolas-Virelizier, E., Filshie, R., Augustson, B.,
Mateos, M.-V., Milani, P., Dimopoulos, M.A., Hachula, E., Fermand, J.-P., Foli, A.,
Palumbo, A., Sonneveld, P., Johnsen, H.E., Kastritis, E., Palladini, G., 2014. A
randomized phase III trial of melphalan and dexamethasone (MDex) versus
bortezomib, melphalan and dexamethasone (BMDex) for untreated patients
with al amyloidosis, in: 56th ash annual meeting and exposition. Presented at
the 56th ASH Annual Meeting and Exposition, San Francisco.
Mikhael, J.R., Schuster, S.R., Jimenez-Zepeda, V.H., Bello, N., Spong, J., Reeder, C.B.,
Stewart, A.K., Bergsagel, P.L., Fonseca, R., 2012.
Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and
complete hematologic response in patients with AL amyloidosis. Blood 119,
4391–4394, http://dx.doi.org/10.1182/blood-2011-11-390930.
Milani, P., Rosin, M.V., Foli, A., Merlini, G., 2013. High-dose pomalidomide and
dexamethasone induce rapid responses in patients with AL amyloidosis
exposed to alkylators, immune modulatory drugs, and proteasome inhibitors.
Blood 122, 288–288.
Moreau, P., Jaccard, A., Benboubker, L., Royer, B., Leleu, X., Bridoux, F., Salles, G.,
Leblond, V., Roussel, M., Alakl, M., Hermine, O., Planche, L., Harousseau, J.-L.,
Fermand, J.-P., 2010. Lenalidomide in combination with melphalan and
dexamethasone in patients with newly diagnosed AL amyloidosis: a
multicenter phase 1/2 dose-escalation study. Blood 116, 4777–4782, http://dx.
doi.org/10.1182/blood-2010-07-294405.
Muller, G.W., Chen, R., Huang, S.Y., Corral, L.G., Wong, L.M., Patterson, R.T., Chen, Y.,
Kaplan, G., Stirling, D.I., 1999. Amino-substituted thalidomide analogs: potent
inhibitors of TNF-alpha production. Bioorg. Med. Chem. Lett. 9, 1625–1630.
Muthu Raja, K.R., Kovárová, L., Stossová, J., Hájek, R., 2011. Flow cytometric
phenotyping and analysis of T regulatory cells in multiple myeloma patients.
Klin. Onkol. Cas. Ceské Slov. Onkol. Spolecnosti 24 (Suppl), S30–33.
Palladini, G., Perfetti, V., Obici, L., Caccialanza, R., Semino, A., Adami, F., Cavallero,
G., Rustichelli, R., Virga, G., Merlini, G., 2004. Association of melphalan and
high-dose dexamethasone is effective and well tolerated in patients with AL
(primary) amyloidosis who are ineligible for stem cell transplantation. Blood
103, 2936–2938, http://dx.doi.org/10.1182/blood-2003-08-2788.
Palladini, G., Perfetti, V., Perlini, S., Obici, L., Lavatelli, F., Caccialanza, R., Invernizzi,
R., Comotti, B., Merlini, G., 2005. The combination of thalidomide and
intermediate-dose dexamethasone is an effective but toxic treatment for
patients with primary amyloidosis (AL). Blood 105, 2949–2951, http://dx.doi.
org/10.1182/blood-2004-08-3231.
Palladini, G., Russo, P., Nuvolone, M., Lavatelli, F., Perfetti, V., Obici, L., Merlini, G.,
2007. Treatment with oral melphalan plus dexamethasone produces
long-term remissions in AL amyloidosis. Blood 110, 787–788, http://dx.doi.
org/10.1182/blood-2007-02-076034.
Palladini, G., Russo, P., Lavatelli, F., Nuvolone, M., Albertini, R., Bosoni, T., Perfetti,
V., Obici, L., Perlini, S., Moratti, R., Merlini, G., 2009. Treatment of patients with
advanced cardiac AL amyloidosis with oral melphalan, dexamethasone, and
thalidomide. Ann. Hematol. 88, 347–350, http://dx.doi.org/10.1007/s00277-
008-0600-y.
Palladini, G., Dispenzieri, A., Gertz, M.A., Kumar, S., Wechalekar, A., Hawkins, P.N.,
Schönland, S., Hegenbart, U., Comenzo, R., Kastritis, E., Dimopoulos, M.A.,
Jaccard, A., Klersy, C., Merlini, G., 2012a. New criteria for response to treatment
in immunoglobulin light chain amyloidosis based on free light chain
measurement and cardiac biomarkers: impact on survival outcomes. J. Clin.
Oncol. 30, 4541–4549, http://dx.doi.org/10.1200/JCO.2011.37.7614.
Palladini, G., Russo, P., Foli, A., Milani, P., Lavatelli, F., Obici, L., Nuvolone, M.,
Brugnatelli, S., Invernizzi, R., Merlini, G., 2012b. Salvage therapy with
lenalidomide and dexamethasone in patients with advanced AL amyloidosis
refractory to melphalan, bortezomib, and thalidomide. Ann. Hematol. 91,
89–92, http://dx.doi.org/10.1007/s00277-011-1244-x.
Palladini, G., Russo, P., Milani, P., Foli, A., Lavatelli, F., Nuvolone, M., Perlini, S.,
Merlini, G., 2013. A phase II trial of cyclophosphamide, lenalidomide and
dexamethasone in previously treated patients with AL amyloidosis.
Haematologica 98, 433–436, http://dx.doi.org/10.3324/haematol.2012.073593.
260 T. Jelinek et al. / Critical Reviews in Oncology/Hematology 99 (2016) 249–260
Palladini, G., Milani, P., Foli, A., Obici, L., Lavatelli, F., Nuvolone, M., Caccialanza, R.,
Perlini, S., Merlini, G., 2014a. Oral melphalan and dexamethasone grants
extended survival with minimal toxicity in AL amyloidosis: long-term results
of a risk-adapted approach. Haematologica 99, 743–750, http://dx.doi.org/10.
3324/haematol.2013.095463.
Palladini, G., Milani, P., Foli, A., Vidus Rosin, M., Basset, M., Lavatelli, F., Nuvolone,
M., Obici, L., Perlini, S., Merlini, G., 2014b. Melphalan and dexamethasone with
or without bortezomib in newly diagnosed AL amyloidosis: a matched
case-control study on 174 patients. Leukemia 28, 2311–2316, http://dx.doi.
org/10.1038/leu.2014.227.
Payvandi, F., Wu, L., Haley, M., Schafer, P.H., Zhang, L.-H., Chen, R.S., Muller, G.W.,
Stirling, D.I., 2004. Immunomodulatory drugs inhibit expression of
cyclooxygenase-2 from TNF-alpha IL-1beta, and LPS-stimulated human PBMC
in a partially IL-10-dependent manner. Cell. Immunol. 230, 81–88, http://dx.
doi.org/10.1016/j.cellimm.2004.09.003.
Quach, H., Ritchie, D., Stewart, A.K., Neeson, P., Harrison, S., Smyth, M.J., Prince,
H.M., 2010. Mechanism of action of immunomodulatory drugs (IMiDS) in
multiple myeloma. Leukemia 24, 22–32, http://dx.doi.org/10.1038/leu.2009.
236.
Rajkumar, S.V., 2004. Thalidomide: tragic past and promising future. Mayo Clin.
Proc. 79, 899–903, http://dx.doi.org/10.1016/S0025-6196(11) 62157-5.
Reece, D.E., Hegenbart, U., Sanchorawala, V., Merlini, G., Palladini, G., Bladé, J.,
Fermand, J.-P., Hassoun, H., Heffner, L., Vescio, R.A., Liu, K., Enny, C., Esseltine,
D.-L., Velde van de, H., Cakana, A., Comenzo, R.L., 2011. Efficacy and safety of
once-weekly and twice-weekly bortezomib in patients with relapsed systemic
AL amyloidosis: results of a phase 1/2 study. Blood 118, 865–873, http://dx.doi.
org/10.1182/blood-2011-02-334227.
Sampaio, E.P., Sarno, E.N., Galilly, R., Cohn, Z.A., Kaplan, G., 1991. Thalidomide
selectively inhibits tumor necrosis factor alpha production by stimulated
human monocytes. J. Exp. Med. 173, 699–703.
Sanchorawala, V., Doros, G., Quillen, K., Sloan, J.M., Shelton, A.C., Brauneis, D., Finn,
K.T., Seldin, D.C., 2014a. Long-term outcome of patients with AL amyloidosis
treated with high-dose melphalan and stem cell transplantation: 19 year
experience at a single center. Biol. Blood Marrow Transpl. 20, S47–S48, http://
dx.doi.org/10.1016/j.bbmt.2013.12.045.
Sanchorawala, V., Patel, J.M., Sloan, J.M., Shelton, A.C., Zeldis, J.B., Seldin, D.C., 2013.
Melphalan, lenalidomide and dexamethasone for the treatment of
immunoglobulin light chain amyloidosis: results of a phase II trial.
Haematologica 98, 789–792, http://dx.doi.org/10.3324/haematol.2012.075192.
Sanchorawala, V., Shelton, A., Stephen, L., Sloan, J.M., Seldin, D.C., 2014b.
Pomalidomide and dexamethasone in patients with relapsed light-chain
amyloidosis (AL): results of a phase 1 study. Presented at the XIVth
International Symposium on Amyloidosis, Indianapolis.
Sanchorawala, V., Skinner, M., Quillen, K., Finn, K.T., Doros, G., Seldin, D.C., 2007a.
Long-term outcome of patients with AL amyloidosis treated with high-dose
melphalan and stem-cell transplantation. Blood 110, 3561–3563, http://dx.doi.
org/10.1182/blood-2007-07-099481.
Sanchorawala, V., Wright, D.G., Rosenzweig, M., Finn, K.T., Fennessey, S., Zeldis, J.B.,
Skinner, M., Seldin, D.C., 2007b. Lenalidomide and dexamethasone in the
treatment of AL amyloidosis: results of a phase 2 trial. Blood 109, 492–496,
http://dx.doi.org/10.1182/blood-2006-07-030544.
Sedlarikova, L., Kubiczkova, L., Sevcikova, S., Hajek, R., 2012. Mechanism of
immunomodulatory drugs in multiple myeloma. Leuk. Res. 36, 1218–1224,
http://dx.doi.org/10.1016/j.leukres.2012.05.010.
Seldin, D.C., Choufani, E.B., Dember, L.M., Wiesman, J.F., Berk, J.L., Falk, R.H., O’Hara,
C., Fennessey, S., Finn, K.T., Wright, D.G., Skinner, M., Sanchorawala, V., 2003.
Tolerability and efficacy of thalidomide for the treatment of patients with light
chain-associated (AL) amyloidosis. Clin. Lymphoma 3, 241–246.
Skinner, M., Anderson, J., Simms, R., Falk, R., Wang, M., Libbey, C., Jones, L.A., Cohen,
A.S., 1996. Treatment of 100 patients with primary amyloidosis: a randomized
trial of melphalan, prednisone, and colchicine versus colchicine only. Am. J.
Med. 100, 290–298.
Skinner, M., Sanchorawala, V., Seldin, D.C., Dember, L.M., Falk, R.H., Berk, J.L.,
Anderson, J.J., O’Hara, C., Finn, K.T., Libbey, C.A., Wiesman, J., Quillen, K., Swan,
N., Wright, D.G., 2004. High-dose melphalan and autologous stem-cell
transplantation in patients with AL amyloidosis: an 8-year study. Ann. Intern.
Med. 140, 85–93.
Tapan, U., Seldin, D.C., Finn, K.T., Fennessey, S., Shelton, A., Zeldis, J.B.,
Sanchorawala, V., 2010. Increases in B-type natriuretic peptide (BNP) during
treatment with lenalidomide in AL amyloidosis. Blood 116, 5071–5072, http://
dx.doi.org/10.1182/blood-2010-09-305136.
Venner, C.P., Lane, T., Foard, D., Rannigan, L., Gibbs, S.D.J., Pinney, J.H., Whelan, C.J.,
Lachmann, H.J., Gillmore, J.D., Hawkins, P.N., Wechalekar, A.D., 2012.
Cyclophosphamide, bortezomib, and dexamethasone therapy in AL
amyloidosis is associated with high clonal response rates and prolonged
progression-free survival. Blood 119, 4387–4390, http://dx.doi.org/10.1182/
blood-2011-10-388462.
Venner, C.P., Gillmore, J.D., Sachchithanantham, S., Mahmood, S., Lane, T., Foard, D.,
Rannigan, L., Gibbs, S.D.J., Pinney, J.H., Whelan, C.J., Lachmann, H.J., Hawkins,
P.N., Wechalekar, A.D., 2014. A matched comparison of cyclophosphamide,
bortezomib and dexamethasone (CVD) versus risk-adapted
cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis.
Leukemia 28, 2304–2310, http://dx.doi.org/10.1038/leu.2014.218.
Wang, C.Y., Mayo, M.W., Korneluk, R.G., Goeddel, D.V., Baldwin, A.S., 1998.
NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and
c-IAP2 to suppress caspase-8 activation. Science 281, 1680–1683.
Wechalekar, A.D., Goodman, H.J.B., Lachmann, H.J., Offer, M., Hawkins, P.N.,
Gillmore, J.D., 2007. Safety and efficacy of risk-adapted cyclophosphamide,
thalidomide, and dexamethasone in systemic AL amyloidosis. Blood 109,
457–464, http://dx.doi.org/10.1182/blood-2006-07-035352.
Wechalekar, A.D., Schonland, S.O., Kastritis, E., Gillmore, J.D., Dimopoulos, M.A.,
Lane, T., Foli, A., Foard, D., Milani, P., Rannigan, L., Hegenbart, U., Hawkins, P.N.,
Merlini, G., Palladini, G., 2013. A European collaborative study of treatment
outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood 121,
3420–3427, http://dx.doi.org/10.1182/blood-2012-12-473066.
Wechalekar, A., Foard, D., Rannigan, L., Lane, T., Sachachtanatham, S., Mahmood, S.,
Sayed, R., Patel, K., Whelan, C., Lachmann, H., Hawkins, P., Gillmore, J., 2014.
Characteristics and outcomes of 714 patients with systemic AL
amyloidosis—analysis of a prospective study (ALChemy study). Presented at
the XIVth International Symposium on Amyloidosis, Indianapolis.
Zou, W., 2005. Immunosuppressive networks in the tumour environment and their
therapeutic relevance. Nat. Rev. Cancer 5, 263–274, http://dx.doi.org/10.1038/
nrc1586.
Biographies
Tomas Jelinek is a physician at the Department of Haematooncology at the
University Hospital Ostrava, Czech Republic. In 2011 he earned his degree at
Masaryk University in Brno, Czech Republic. During his studies at university he
conducted internships at Hospital Anna Costa, Santos, Brazil; Universidade de Coim-
bra, Portugal and Autonomous University of Zacatecas, Mexico. He started his
career at the Department of Internal Medicine—Hematology and Oncology, Uni-
versity Hospital Brno and since 2013 he has been working at the Intensive Care and
Transplant Unit at University Hospital Ostrava. Dr. Jelinek is a member of Czech Soci-
ety of Hematology and Czech Myeloma Group. He has several publications in the
field of hematological malignancies. His current research interest includes multiple
myeloma and other plasma cell disorders. He is also interested in modern diagnostic
methods, dominantly flow cytometry and its clinical and scientific application.
Roman Hajek is Professor of Oncology and Vice-rector at the Ostrava University
and Head of the Department of Haematooncology at the University Hospital Ostrava,
Czech Republic. After qualifying in medicine in 1988 from J.E. Purkyne (Masaryk)
University, Faculty of Medicine Brno, Dr. Hajek received a PhD in hematology in
1995 and completed degrees in Internal Medicine in 1996 and in Medical Oncology
in 1998. Dr. Hajek was a founder member of the Czech Myeloma Group. He is an
active chairman of the Czech Myeloma Group, main investigator of the randomized
clinical trials phase III of Czech Myeloma Group and phase I/II/III of other clinical
trials in MM including experimental immunotherapy and main investigator of more
than 30 national grants. He is a member of several scientific societies, including the
European Hematology Association and the Amercian Society of Hematology. He has
published over 300 scientific articles and book chapters and he is an Editor of the
European Journal of Hematology. His research interests include multiple myeloma,
bone marrow transplantation and amyloidosis.