ASH Hematology Review Series

Waldenstrom Macroglobulinemia
Rachid Baz, MD
Senior Member, Myeloma Section Head,
Department of Malignant Hematology
H. Lee Moffitt Cancer Center
Disclosures
• Member of Advisory Board: BMS, GSK, Pfizer, Oncopeptide, Shattuck Lab,
Karyopharm, Janssen, Sanofi, Takeda
• Member of Independent Response Assessment Committee: GSK
• Research Support: Janssen, Karyopharm, BMS, Sanofi
Outline
• Waldenstrom Macroglobulinemia
– Pathophysiology
– Differential diagnosis
– Clinical manifestation
– Management overview
• Amyloidosis
– Diagnosis and differential
– Pathophysiology
– Clinical manifestation
– Prognosis and overview on management
• POEMS
– What you need to know
 WM: Epidemiology
• Incidence about 1,500 new patients/ year in the US or Annual age adjusted incidence ≈ 3-
8/million-year1
• Incidence 0.92 /100,000 person years for men and 0.3/100,000 person years for women.
• Estimated prevalence 8,000 individuals in U.S (compare with ≈ 130,000 MM patients)
• More common among older white men1
• Familial predisposition with ≈ 20% of patients have a first degree relative with WM or a B cell
disorder2. Familial WM usually diagnosed at an earlier age and with greater BM involvement.
• Risk factors: IgM MGUS (Relative Risk=46)

1. Herrington LJ et al. Blood. 1993;82(10):3148-50

2. Treon, S et al Ann Oncol. 2006;3:488-494
WM Pathophysiology

• Cell of origin: B cell arrested after

somatic hypermutation in the
germinal center and before
differentiation to a plasma cell.
– IgH rearrangement not found
in WM
– Mutated Ig VH noted in WM
• Cytogenetics: 6q most frequently
reported. Significance unclear

Walsh S et al. Leuk Res. 2005;29:729-734

Kuppers R. Nature Reviews Immunology 2003;3:801-812
WM: Diagnosis

Abnormal lymphoplasmacytic aggregates in the bone

marrow and evidence of clonal B-cells and plasma cells

Immunophenotype: sIgM+, CD5 (+/-), CD10-, CD19+,

CD20+, CD22+, CD23-, CD138+

IgM Monoclonal protein of any concentration

“Molecular studies for MYD88 and CXCR4 mutations are

strongly encouraged”

“.. a diagnosis of LPL may be rendered in cases with

abnormal lymphoplasmacytic aggregates in the bone
marrow and evidence of clonal B-cells and plasma
cells, even when the aggregates represent <10% of
cellularity of the trephine biopsy.”

Dimopoulos M et al. J Clin Oncol. 2005;23(7):1564-77

Campo E. et al Blood 2022 June 2 Epub
MYD88 mutations
80-100% of patients with WM

10-80% of IgM MGUS, higher risk of

progression to WM

Can help distinguish WM from

common overlapping conditions (IgM
MM, MZL, CLL)

MYD88L265P pts are more likely to have

higher IgM than MYD88WT

MYD88L265P induces BTK in WM cells

Treon S et al N Engl J Med. 2012 Aug 30;367(9):826-33,

Treon et al N Engl J Med. 2015 Aug 6;373(6):584-6,
Jimenez et al Leukemia. 2013 Aug;27(8):1722-8,
Varettoni et al Blood. 2013 Mar 28;121(13):2522-8,
Varettoni et al. Blood. 2013 Sep 26;122(13):2284-5,
Poulain et al Blood. 2013 May 30;121(22):4504-11,
Xu et al Blood. 2013 Mar 14;121(11):2051-8
CXCR4 WHIM (Warts, Hypogammaglobulinemia,
Infection, and Myelokathexis)
30-40% of WM patients;
v. rare in other LPD
>30 Nonsense , Frameshift Mutations
High serum IgM levels / Hyperviscosity
Promote ibrutinib resistance through enhanced AKT/ERK signaling.

Hunter ZR et al. Blood. 2014 Mar 13;123(11):1637-46

Treon S et al. Blood. 2014 May 1;123(18):2791-6
Cao Y et al Leukemia. 2015 Jan;29(1):169-76
Differential Diagnosis
• Presence of B cells with lymphoplasmacytic differentiation OR an IgM paraprotein are NOT diagnostic
of WM.
• IgM MGUS: IgM paraprotein with <10% bone marrow plasma cells and lacking lymphoplasmacytic B-
cell aggregates sufficient for a diagnosis of LPL, asymptomatic. 2 subtypes:
– Plasma cell type: Without a detectable B-cell component and with wild type MYD88, or t(11;14)… implied
progression to MM
– Not otherwise specified: MYD88 mutation and with detectable monoclonal B cells without abnormal
lymphoplasmacytic aggregates consistent with WM.
• SMZL: usually distinguished based on immunophenotype, some with IgM paraprotein
• IgM MM: based on clinical features, t(11;14)
• CLL: based on immunophenotype
• Primary cold agglutinin disease: lacks MYD88 mutation but with trisomies of 3,12, and 18 and
mutations in KMT2D and CARD11

Campo E. et al Blood 2022 June 2 Epub

Risk of progression from asymptomatic to
symptomatic WM
Risk factors: Risk groups mTTP
• Bone marrow infiltration ≥ 70% High 1.8y
• IgM levels ≥ 4500 mg/dL Intermediate 4.8 y
• B2m ≥ 4 mg/dL Low 9.3y
• Albumin ≤ 3.5 g/dL

MYD88 wt associated with higher risk

of progression (HR 2.7)

http://www.awmrisk.com/

Bustoros M, J Clin Oncol 2019; 37(16): 1403-11

 Symptomatic WM
A- Tumor Infiltration related Sx B- Monoclonal IgM related Sx
1- Circulating IgM

Cytopenia Hyperviscosity

Constitutional Sx Cryoglobulinemia

LAD Cold agglutinin

Organomegaly
2- Tissue IgM
Infiltration of virtually any Neuropathy (autoantibodies to
organ IgG, MAG positive)
Amyloidosis
IgM deposits causing renal
failure, macroglobulinemia cutis

Dimopoulos M et al Blood.1994;83:1452-9
Clinical Features & Presentation
Incidence, %

Lymphadenopathy and/or organomegaly 20-40

Bone marrow involvement 90
Hypercalcemia* 4
Lytic bone lesions* 2
Hyperviscosity 15
Cryoglobulinemia <20
Symptomatic cryoglobulinemia 2

Bing Neel Syndrome: CNS involvement

Schnitzler syndrome: associated urticaria
MAG Neuropathy: PN and commonly IgM paraprotein
Dimopoulos M et al Blood.1994;83:1452-9
WM IPSS
Risk factors:
– Age > 65 years
– Hgb < 11.5 g/dL
– Platelet count < 100 x109/L
– B2m > 3mg/L
– M protein >7g/dL
Distribution
Low Risk: 0-1 RF except age 27%
Intermediate Risk: 2 RF or age>65 38%
High Risk: > 2 RF 35%

Revised in 2010 with addition of LDH

Not validated in patients treated with BTK
Morel P et al. Blood 2009;113:4163-4170
Kastritis et al. Leuk Res 2010 Oct;34(10):1340-3
WM- Centric toxicity with commonly used therapies
Agent WM toxicity
Rituximab IgM Flare 50% -> hyperviscosity, worsening IgM related PN, cold agglutinin or
cryos.
Hypogammaglobulinemia -> infection
Intolerance
Fludarabine / Hypogammaglobulinemia -> infection
Cladribine Risk of MDS / AML
Transformation?
Bendamustine Myelosuppression
Risk of MDS/ AML
Bortezomib Neuropathy Gr 2+ in about 2/3 of patients
Discordant responses
Ibrutinib Atrial Fibrillation ,
Continuous therapy
Rituximab: Clinical Experience
• Time to response and IgM flare
– Seen in about ½ the patient and can persist for 4
month
– Associated with decreased response to therapy

Ghobrial I, et al Cancer. 2004;101(11):2593-8

Bortezomib Clinical Experience
• Rapid increase of serum IgM on cessation of therapy in 13 patients: in 3 patients this
subsequently decreased again without alternate therapy. etiology remains unclear. ER stress?

• Discordant BM and paraprotein response were noted in 3/10 patients

• PN risk & discontinuation

Treon S et al. Clin Cancer Res; 2007.13(11):3320-5

Ibrutinib
N (%)
MYD88MUT MYD88MUT MYD88WT P value
VGPR 10 (16%)
CXCR4WT CXCR4WHIM CXCR4WT
PR 36 (57%)
MR 11 (17%) N 36 21 5
ORR 100% 85.7% 60% <0.01
ORR: 91%,
Major RR (PR and better) 73% Major 91.7% 61.9% 0% <0.01
Median time to MR and better: 4 weeks Response
Median time to PR and better: 8 weeks

Treon S et al N Engl J Med. 2015; 372(15): 1430

Treon S et al. 2015 N Engl J Med Aug 6;373(6):584-6
Ibrutinib: Side effects

Treon S et al N Engl J Med. 2015; 372(15): 1430

iNNOVATE (PCYC-1127) Study Design
Arm A
Key eligibility criteria 1:1 Randomization ibrutinib-RTX
•Confirmed WM* (N≈150) Oral ibrutinib 420 mg once daily until PD
•Measurable disease Stratification RTX 375 mg/m2 IV on
(serum IgM >0.5 g/dL) •IPSSWM (low vs day 1 of weeks 1–4 and 17–20
•RTX sensitive intermediate vs high)
– Not refractory to last •Number of prior regimens
prior (0 vs 1–2 vs ≥3) Arm B
RTX-based therapy •ECOG status (0–1 vs 2) placebo-RTX
– Had not received RTX 3 matching placebo capsules until PD
<12 months before RTX 375 mg/m2 IV on
first study dose day 1 of weeks 1–4 and 17–20

• Primary Endpoint: PFS by IRC

• Secondary Endpoints: Response rate, TTnT, sustained hematologic
improvement, PROs, OS, safety
*Treatment-naïve patients were allowed to enroll following a protocol amendment (Nov 2015); therefore, their
enrollment started later than relapsed patients.

Dimopoulos M, et al. N Engl J Med. 2018 Jun 21;378(25):2399-2410

Higher Response Rates* Were Observed With Ibrutinib-
RTX
ORR 100%
100 ORR 92% ORR 94% CR VGPR PR MR
3
90 6 19
ORR 81%
80
23 Major

Best Response (%)

72% 28
70
Major 27
60 73% ORR 55%
Major ORR 52%
ORR 47% 78% 54 Major
50 1 ORR 46% 4
64% Major
47 4 6 22
40 22%
Major 44
Major 36
30 32% Major
27 23 29%
44 48%
20
33
27
10 20 18
15 16 17
0 4
Ibrutinib- Placebo- Ibrutinib- Placebo- Ibrutinib- Placebo- Ibrutinib- Placebo-
RTX RTX RTX RTX RTX RTX RTX RTX
Overall MYD88L265P/CXCR4WT MYD88L265P/CXCR4WHIM MYD88WT/CXCR4WT

▪ Proportion of patients with genetic subtype†, ibrutinib-RTX vs

placebo-RTX:
– MYD88L265P/CXCR4WT: 46% vs 52%
– MYD88L265P/CXCR4WHIM: 38% vs 34%
– MYD88WT/CXCR4WT: 16% vs 13%

*Following modified 6th IWWM Response Criteria (NCCN 2014); required two consecutive assessments.
†Proportion of patients calculated after excluding patients for whom data were missing or unknown (ibrutinib-RTX: n = 6; placebo-

RTX: n = 8).

Dimopoulos M, et al. N Engl J Med. 2018 Jun 21;378(25):2399-2410

Safety Profile of Ibrutinib-RTX Was Similar to the
Known Profiles of Each Agent
Ibrutinib-RTX (n = 75) Placebo-RTX (n = 75)
Any Grade Grade ≥3 Any Grade Grade ≥3
AEs*, n (%) 75 (100) 45 (60) 75 (100) 46 (61)
Infusion-related reactions 32 (43) 1 (1) 44 (59) 12 (16)
Diarrhea 21 (28) 0 11 (15) 1 (1)
Anemia 14 (19) 8 (11) 22 (29) 13 (17)
Hypertension 14 (19) 10 (13) 4 (5) 3 (4)
Asthenia 12 (16) 0 19 (25) 2 (3)
Atrial fibrillation 11 (15) 9 (12) 2 (3) 1 (1)
Fatigue 10 (13) 2 (3) 20 (27) 1 (1)
IgM flare 6 (8) 0 35 (47) 2 (3)
▪ Ibrutinib-RTX: 55% of atrial fibrillation occurred in patients ≥75 years of age
▪ CHF 3% in Ibrutinib-RTX arm, 0% in RTX alone
▪ Major hemorrhage: 4% in each arm
– Anticoagulant/antiplatelet medication use
– Ibrutinib-RTX: 43%
– Placebo-RTX: 36%

Dimopoulos M, et al. N Engl J Med. 2018 Jun 21;378(25):2399-2410

Ibrutinib Rituximab or Ibrutinib: The CLL Experience

Woyach JA et al. N Engl J Med 2018 Dec 27;379(26):2517-2528

Ibrutinib Resistance
• 51 patient cohort with acquired ibrutinib resistance
• Median time from initiation to discontinuation of ibrutinib : 2 years
• Rapid increase in IgM following discontinuation of Ibrutinib in 60%, some with
symptomatic hyperviscosity
• BTK mutation testing in 21 patients: 7 with BTK C481S. No difference in time to
discontinuation among BTK C481S or BTK wt or in other baseline MYD88 or CXCR4
status
• 5 years OS was 44%.
• TP53 mutations (in 15%) associated with worse survival but BTK C481S mutations
didn’t impact survival

Gustine J, et al Hematologica 2021 June 24

ASPEN: Zanubrutinib versus Ibrutinib in MYD88 L265P
WM

FDA APPROVED
8-31-3021

Tam CS et al. Blood. 2020 Oct 29;136(18):2038-2050

Other Agents and Therapies on the Horizon
• Carfilzomib / Ixazomib
• Everolimus
• Acalabrutinib
• Zanubrutinib
• Obinutuzumab and Idelalisib
• Venetoclax
• Ulocuplumab (CXCR4 antagonist)
My Approach to Treatment Off Trial
Clinical Setting Therapy
1st line: Low IgM, mild symptoms, Rituximab
1st line: Mod / high IgM or significant Chemo-immunotherapy: Bendamustine
symptoms Rituximab or Cyclophosphamide
Dexamethasone and Rituximab (Rituximab
added cycle 2-3 to prevent flare)
MAG neuropathy Ibrutinib
Bing Neel Syndrome Ibrutinib
2nd line especially if short disease free interval Ibrutinib or Zanubrutinib (if at risk of CV
toxicity with ibrutinib)
Ibrutinib intolerant Zanubrutinib
Ibrutinib refractory Venetoclax or proteasome inhibitor, or
Idelalisib + Obinutuzmab
AMYLOIDOSIS & POEMS
Case 1
JM is a 73 yo man who presented with nephrotic range proteinuria, submandibular
swelling. Tongue biopsy consistent with amyloid AL kappa. Presumed renal, cardiac
IVSd 1.58 cm, liver involvement. BMBx 20% PC with t(11;14).
Rx: 5 cycles of bortezomib dexametasone completed in 2/2012. retreatment in 1/2018
with ixazomib
Case 2
LS 61 yo man presented with spontaneous splenic rupture while at work. Emergency
ex lap, spleen and liver with amyloid. BMBx with 8% plasma cells, kappa restricted.
Also with nephrotic syndrome but no cardiac involvement
Bort Dex, Added cytoxan, with a partial response
HD MEL , SCT in 8/2013 with heme CR, also achieved organ CR in kidney and liver
Amyloidoses
• Extracellular tissue deposition of fibrils of a variety of proteins.
• 25 different proteins currently identified
• Etiology: hereditary, neoplastic, inflammatory or unknown.
• Characterized by the type of protein deposited, pattern of deposition
(systemic or localized), and site of depositions.

Benson MD et al. Amyloid. 2018 Dec;25(4):215–9

Amyloidoses

Picken MM Acta Haematol 2020;143:322–334

Key to diagnosis : Index of Suspicion
• Nephrotic-range proteinuria with or without renal insufficiency
(nondiabetic)
• Infiltrative cardiomyopathy with restrictive hemodynamics and no
ischemic HD
• Hepatomegaly with no filling defects visible by imaging
• Nondiabetic peripheral neuropathy
• Fatigue, weight loss, dyspnea, edema, or paresthesias
• Macroglossia
• Classic amyloid purpura
• Atypical myeloma
Diagnostic Criteria: AL
• Presence of an amyloid-related systemic syndrome (eg, renal, liver, heart,
gastrointestinal tract or peripheral nerve involvement).
• Positive amyloid staining by Congo red in any tissue (eg, fat aspirate, bone
marrow or organ biopsy) or the presence of amyloid fibrils on electron
microscopy
• Evidence that the amyloid is light chain-related established by direct
examination of the amyloid
• Evidence of a monoclonal plasma cell proliferative disorder (eg, presence
of a serum or urine M protein, abnormal serum free light chain ratio, or
clonal plasma cells in the bone marrow).
Differential Diagnosis: Localized Amyloidosis
• Local amyloid deposits in tissues (often tracheobronchial tree, urinary tract,
or skin).
• These deposits are derived from monoclonal light chains, but are not due to
an underlying systemic clonal plasma cell disorder
• An underlying plasma cell disorder is not usually found
• Management is with local therapy and local recurrence not uncommon after
resection
Differential Diagnosis: Secondary Amyloid (AA)

• Underlying chronic inflammatory conditions (RA, Crohn's, osteomyelitis,

FMF).
• Inflammation leads to increased hepatic production of the acute phase
reactant serum amyloid A, which is then degraded by macrophages into
amyloid A fragments that deposits
• Treat the underlying condition
Differential Diagnosis: Hereditary Amyloid
• Implicated “amyloidogenic proteins” transthyretin (TTR), the alpha chain
of fibrinogen A, apolipoprotein AI and AII, lysozyme, and gelsolin.
• ATTRv commonly underdiagnosed cause of CHF and PN.
• Over 120 TTR mutations noted
• Val122Ile noted in 3-4% of AA in the US and is predominantly cardiac

Jacobson DR et al. Amyloid. 2015;22(3):171–4.

Differential Diagnosis: Senile Amyloid
• Commonly deposits of wild type transthyretin into the organs of often
older adults
• Supportive therapy for CHF but transthyretin stabilizer recently approved
for ATTR Cardiomyopathy (Tafamidis)
• Concurrent MGUS in up to 40% of patients and possible diagnostic
implications
• Outcomes better than with AL amyloid involving the myocardium

Maurer MS et al. N Engl J Med. 2018, 13;379(11):1007-1016

Phull P et al. Amyloid. 2018 Mar;25(1):62–7.
Fat Pad Biopsy
Mayo ISA
Clinic
13%

10% Fat +/Marrow + Sensitivity 72% 82%

Fat +/Marrow -
55% Fat -/Marrow +
Fat -/Marrow -
22% Specificity 99% 99%

Nephr Dial Transplant 22:1608; 2007

Blood 79:1817, 1992
AL Amyloidosis Diagnostic Work-up

Gertz M. Am J Hematol 2020 Jul;95(7):848-86

Amyloid Typing by Mass Spectrometry

Sensitivity and
Specificity
100%

Validation set (41)

identified the correct
amyloid type in 98%
Recommended Staging
• Cardiac: ECG, ECHO, NT-proBNP, Troponin (T or I) , +/- MRI
• Renal: 24-hour urine protein, estimated GFR
• Gastrointestinal: EGD or colonoscopy and biopsy (if indicated)
• Liver: alkaline phosphatase >1.5 times ULN indicates involvement
• Peripheral and autonomic nervous system: orthostatic vital signs, EMG testing
• Skeletal survey or PET/CT or WB MRI if myeloma related organ damage is
suspected
Cardiac Involvement Predicts Outcome
Score Stage Median OS
(mo)
0 1 73
1 2 35
2 3 15
3 4 5
Risk Factors:
• hs-cTroponin T ≥ 40 pg/mL;
• N-terminal pro–BNP≥1800 pg/mL;
• Difference between serum free
light chain levels >180 mg/L.

Kumar S et al. J Clin Oncol 2019 Jan 10;37(2):171-173

 Understanding AL Amyloidosis and LCDD

LCDD

Amyloidosis

Current Treatment Paradigm:

Target the Plasma Cell Clone to
Reduce Light Chain Production
Hematologic Response and Outcomes
1.0

0.9
p=0.01
0.8

0.7 p<0.001
Proportion surviving

0.6
Survival

0.5
p<0.001
0.4

0.3
CR (97 patients, 3.6 deaths/100 py)
VGPR (233 patients, 9.6 deaths/100 py)
0.2
PR (140 patients, 23.7 deaths/100 py)
NR (179 patients, 47.2 deaths/100 py)
0.1

Pts at risk 649 422 251 138 57

0.0
0 12 24 36 48

Time (months)

Palladini G, et al. J Clin Oncol 2012, 30(36): 4541

Palladini G et al. Blood Cancer J 2021 Feb 16;11(2):34
Melphalan Prednisone for Amyloidosis

Kyle RA, et al. NEJM 1997 Apr 24;336(17):1202-7.

The Role of Transplant
Center N Phase TRM,% HRR, HCR, Organ Median
% % RR,% OS (mo)

BU 277 II 13 79 40 44 57
Mayo 270 II 11 71 33 NR NR
CIBMTR 107 II 18 32 16 36 47
IFM 50 III 24 67 40 45 22
 The Role of Transplant
• ASCT candidates > Non-ASCT candidates Decreasing 100-day mortality over time

• ASCT candidates: ASCT > No ASCT

• ASCT candidates: Early ASCT > Late ASCT
Dispenzieri A., et al. J Clin Oncol. 2001;19:3350.
Dispenzieri A., et al. Blood. 2004;103:3960.
Sanchorawala V., et al. BMT. 2004;33:381.

• 65-75% response rate with 30% CR

– Similar to MD (worse in at least one
trial)
Gertz MA., et al. BMT. 2004;34:1025.
Jaccard, et al. NEJM. 2008

Hasib Sidiqi M et al J Clin Oncol 2018 May 1;36(13):1323-1329

Transplant Eligibility
• Age ≤ 70 years
• ECOG PS ≤2
• ≤2 major organs involved,
• Tn T < 0.06 ng/mL LESS THAN 20% OF
• Creatinine clearance > 30 ml/min AMYLOID PATIENTS

• Systolic BP > 90 mmHg

• NYHA functional class I or II
• NT-proBNP < 8500 ng/L *

Gertz M. Am J Hematol 2020 Jul;95(7):848-86

MD versus ASCT for AL amyloid
Arm HRR, HCR, PFS, OS, TRM,
% % month month %
MD 68 47 32.5 55.9 0
HDMel 67 40 32 22.2 24

Jaccard et al. NEJM, 357: 1083, 2007

Kharfan-Dabaja M et al. Biol Blood Marrow Transplant. 2009;15(8):893-902.
 ANDROMEDA: Study Design
Treatment Phase Post-treatment Phase
DARA SC 1,800
Key eligibility criteria: DARA SC 1,800 Observation until MOD-
mg QW Cycles 1-
mg Q4W until PFS
• AL amyloidosis with 1 organ 2, Q2W Cycles 3-6

Screening (Day

Randomisation
MOD-PFS or (if DARA SC
impacted + CyBorDa
maximum of discontinued prior to

(N = 388)
• No prior therapy for AL weekly × 6 cycles
24 total cycles MOD-PFS)

−28)
1:1
amyloidosis or MM n = 195

• Cardiac stage I-IIIA (Mayo 2004) CyBorDa

weekly × 6 cycles Observation until MOD-
• eGFR 20 mL/min PFS
n = 193

Stratification criteria: Primary endpoint: Overall hematologic CR rate

▪ Cardiac stage (I vs II vs IIIA)
▪ Transplant typically offered in local country (yes vs no) Secondary endpoints: MOD-PFS, organ response rate, time to
▪ Creatinine clearance (≥60 mL/min vs <60 mL/min) haematologic response, overall survival, safety

ANDROMEDA is a randomised, open-label, active-controlled, phase 3 study of

DARA SC plus CyBorD vs CyBorD alone in newly diagnosed AL amyloidosis
MM, multiple myeloma; eGFR, estimated glomerular filtration rate; QW, weekly; Q2W, every 2 weeks; Q4W, every 4 weeks; MOD-PFS, major organ deterioration progression-free survival; CR, complete response; IV,
intravenous; PO, oral.
aDexamethasone 40 mg IV or PO, followed by cyclophosphamide 300 mg/m 2 IV or PO, followed by bortezomib 1.3 mg/m2 SC on Days 1, 8, 15, and 22 in every 28-day cycle for a maximum of 6 cycles. Patients will receive

dexamethasone 20 mg on the day of DARA SC dosing and 20 mg on the day after DARA SC dosing.

Kastritis E et al. N Engl J Med 2021 Jul 1;385(1):46-5

 Demographics and Baseline Characteristics
Characteristic DARA-CyBorD (n = 195) CyBorD (n = 193) Characteristic DARA-CyBorD (n = 195) CyBorD (n = 193)
Age, years
Involved organs, %
Median (range) 62 (34-87) 64 (35-86)
Median (range) 2 (1-5) 2 (1-6)
≥65, % 45 50
≥2 organs 66 65
Male, % 55 61
Heart 72 71
Race, %
Kidney 59 59
White 77 74
Liver 8 8
Black/African American 3 4
Otherc 65 63
Unknown 4 3
ECOG performance status,a % Cardiac stage,d %
0 46 37 I 24 22
1 44 55 II 39 42
2 10 8 IIIA 36 33
AL isotype,b % IIIBe 1 3
Lambda 81 77
Kappa 19 23 Renal stage, %
Time from diagnosis, days N 193 193
Median (range) 48 (8-1,611) 43 (5-1,102) I 55 52
Baseline dFLC, mg/L II 35 38
Median (range) 200 (2-4,749) 186 (1-9,983) III 10 9

Demographics and baseline characteristics were well balanced between arms

ECOG, Eastern Cooperative Oncology Group; dFLC, difference between involved and uninvolved free light chain.
aECOG performance status is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability; bBased on immunofixation or light chain; cIncludes gastrointestinal tract, lung, nervous system,

and soft tissue; dBased on the European Modification of the Mayo staging system (Wechalekar AD, et al. Blood. 2013;121(17):3420-3427); cardiac stage was based on 2 biomarker risk factors: NT-ProBNP and high-sensitivity cardiac
troponin; ePatients in IIIB category should be excluded from participation per protocol. All were known IIIA at screening; however, some converted to IIIB at Cycle 1, Day 1 (results by central lab were only made available after Cycle 1, Day 1).

Kastritis E et al. N Engl J Med 2021 Jul 1;385(1):46-5

Hematologic CR: Primary Endpoint
Best Response of Haematologic CR
Odds ratio 5.1 • Assessed by blinded Independent Review Committee
(95% CI, 3.2-8.2); P <0.0001 • CR per Comenzo criteria1 with clarifications:
60 – Abnormal FLC ratio does not preclude CR2
53%
– CR requires confirmation

40 • The CR rate at 6 months was consistent with overall CR

rate
– 50% DARA-CyBorD vs 14% CyBorD
20 18% (odds ratio 6.1; P <0.0001)
‒ Median time to CRa:
0 – DARA-CyBorD: 60 days
DARA-CyBorD CyBorD – CyBorD: 85 days
n = 195 n = 193

Responses with DARA-CyBorD were deeper and achieved more rapidly

CI, confidence interval; FLC, free light chain.
aAmong CR responders (DARA-CyBorD, n = 104; CyBorD, n = 35).

1. Comenzo RL, et al. Leukemia. 2012;26(11):2317-2325. 2. Sidana S, et al. Leukemia. 2019;34(5):1472-1475.

Kastritis E et al. N Engl J Med 2021 Jul 1;385(1):46-5

 Hematologic Overall Response
100 Overall Response • The ≥VGPR rate (a secondary endpoint)
92%
was improved with DARA-CyBorD vs
77%
80 CyBorD
18
60 ≥VGPR:
53 – 79% DARA-CyBorD vs 49% CyBorD
ORR, %

≥VGPR
79% : (odds ratio 3.8; P <0.0001)
40 31
49%
25 CR • Median time to ≥VGPRa:
20 VGPR 28
13 PR – DARA-CyBorD: 17 days
0
DARA-CyBorD CyBorD – CyBorD: 25 days
n = 195 n = 193

Significantly higher rates of response were observed with DARA-CyBorD

ORR, overall response rate; VGPR, very good partial response; PR, partial response.
aAmong ≥VGPR responders (DARA-CyBorD, n = 153; CyBorD, n = 95).

Kastritis E et al. N Engl J Med 2021 Jul 1;385(1):46-5

 Major Organ Deterioration (MOD)-EFSa
100
‒ Median time to next treatment:
% surviving without progression

75
• DARA-CyBorD: not
DARA SC + CyBorD
reached
• CyBorD: 10.4 months
50
CyBorD DARA-CyBorD CyBorD
Events,b n (%) (n = 195) (n = 193)
DARA-CyBorD vs CyBorD
25
Hematologic
HR (95% CI) 0.40 (0.28-0.57) 7 (4) 22 (11)
progression
P value <0.0001
0
Major organ
1 (<1) 6 (3)
0 2 4 6 8 10 12 14 16 18 20 22 deterioration
Months
No. at risk Death 25 (13) 19 (10)
CyBorD 193 169 143 126 75 50 33 23 13 9 2 0
DARA SC + CyBorD 195 178 167 151 119 90 64 46 27 10 1 0 Subsequent therapyc 13 (7) 45 (23)

Treatment with DARA-CyBorD substantially improved event-free survival

MOD-EFS, major organ deterioration event-free survival.
aDefined as haematologic progression, end-stage cardiac or renal disease, initiation of subsequent non–cross-resistant anti–plasma cell therapy, or death, whichever comes first; bPatients may have had more than 1

event; for MOD-EFS, the earliest event date was used; cSubsequent treatment was adjudicated by the IRC.

Kastritis E et al. N Engl J Med 2021 Jul 1;385(1):46-5

Organ Response at 6 monthsa
70 DARA- CyBorD
CyBorD
P= 0.0029b P <0.0001b
60
54%
Response rate, %

50
42%
40
30 27%
22%
20
10
0
n = 118 n = 117 n = 113 n = 117
Cardiac response1 Renal response2

Cardiac and renal response rates were doubled with DARA-CyBorD vs CyBorD
aOrgan response evaluable set (patients with organ involvement); organ responses were assessed by blinded IRC; bNominal P value.
1. Palladini G, et al. J Clin Oncol. 2012;30(36):4541-4549. 2. Palladini G, et al. Blood. 2014;124(15):2325-2332.

Kastritis E et al. N Engl J Med 2021 Jul 1;385(1):46-5

My Approach to Treatment for AL Amyloid
Clinical Setting Therapy
1st line: not otherwise frail DaraCyBorD (dose reduce/omit bortezomib if PN
or hypotension)
Consider upfront transplant if eligible and no
significant heart involvement
1st line: Amyloid + MM DaraCyBorD -> HDT (if candidate) ->
maintenance
2nd line: no prior Dara, no recent PI Bortezomib Dara Dex / consider HDT if
candidate
3rd line, or dara /PI refractory Alkylating agent or IMID
Relapsed and refractory with t(11;14) Consider venetoclax

Hematologic CR is important. Evolving role for MRD monitoring

Role of maintenance is unclear. Responses are generally more durable than in MM
Case: POEMS
• 57 yo baseball coach presented with bilateral cramping pain in the calves and rapid weakness in
2012.
• Diagnosed with neuropathy and in the work up was found to have a sclerotic lesion in the right iliac
bone along with multiple lytic bone lesions in the pelvis and femurs
• CT guided biopsy of the lesion c/w plasmacytoma lambda restricted
• BMBx normocellular, no increase in plasma cells, no amyloid.
• Normal renal function, ca, and creatinine
• Small M spike IgA lambda 0.4g/dL , free lambda 75.8 mg/mL ; ratio 0.21 (0.26-1.62)
• VEGF level 500 pg/ml (up to 100 is normal)
• Free testosterone 25 pg/mL (low)
Case continued
• Received XRT to the dominant sclerotic lesion
• Lenalidomide dexamethasone with normalization of the VEGF level and
improved PS but the sFLC ratio remained elevated
• HD Mel in 9/2013 in continued CR
POEMS: Diagnosis
Mandatory
• Demyelinating polyneuropathy
• Monoclonal plasma cell disorder
Major
• Sclerotic bone lesions
• Elevated VEGF (Typically plasma levels >200 pg/mL)
• Castleman disease
Minor
• Extravascular volume overload (Peripheral edema, pleural effusions, and ascites)
• Organomegaly (Hepatosplenomegaly, lymphadenopathy)
• Endocrinopathy (Hypogonadism; adrenal, parathyroid, and pituitary dysfunction. Given the frequent occurrence of thyroid
dysfunction and diabetes mellitus, these conditions alone are not diagnostic of POEMS syndrome)
• Skin changes
• Papilledema
• Polycythemia and thrombocytosis

The diagnosis of POEMS syndrome is confirmed when both of the mandatory one major criterion
and one minor criterion are present

Khouri J et al. JAMA Oncol. 20201 jun 3

Frequency of Clinical Findings
• Polyneuropathy (chronic, progressive demyelinating, not autonomic, motor>sensory) – 100%
• Monoclonal plasma cell disorder (usually lambda) – 100 %
• Increased cerebrospinal fluid protein (>50 mg/dL) – 100 %
• Osteosclerotic bone lesions – 97 %
• Skin changes – 68 %
• Endocrinopathy – 67 %
• Organomegaly (hepatomegaly, splenomegaly, lymphadenopathy) – 50 %
• Weight loss (>10 pounds) – 37 %
• Fatigue – 31 %
• Papilledema – 29 %
• Edema, ascites, pleural effusion – 29 %
• Castleman's disease – 15 %
• Clubbing – 5 %

Dispenzieri A et al. Blood. 2003;101(7):2496

POEMS Treatment
• No randomized study
• Limited disease: 1-3 sclerotic lesions / no marrow involvement: XRT40-
50Gy
• Multiple sclerotic lesions / marrow involvement / progression despite XRT:
systemic therapy:
– Rd,
– HDT / ASCT if eligible
QUESTIONS?

Rachid.Baz@Moffitt.org