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WALDENSTRÖM'S MACROGLOBULINEMIA AND AMYLOIDOSIS

Morie Gertz, MD, MACP

Consultant Hematology

Mayo Clinic

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Nothing to disclose

REFERENCES TO OFF-LABEL USAGE(S) �OF PHARMACEUTICALS OR INSTRUMENTS

Bendamustine AL & WM
Bortezomib AL & WM

DISCLOSURE OF RELEVANT FINANCIAL RELATIONSHIP(S) WITH INELIGIBLE COMPANIES

All relevant financial relationships have been mitigated.

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MONOCLONAL GAMMOPATHIES�MAYO CLINIC: ROCHESTER, MN • JANUARY 1, 1960, TO DECEMBER 31, 2023

MGUS^†�58% (30,969)

Multiple myeloma*�18% (9,696)

AL amyloidosis�10% (5,093)

Lymphoproliferative^††�3% (1,496)

SMM 4% (2,068)

Solitary or extramedullary�2% (953)

Macro**�3% (1,523)

Other�2% (1,048)

n=53,246

^†Includes LC MGUS (n=1659)

* Excludes Poems (n=323)

^††Excludes Schnitzler (n=33)

** Includes SWM (n=234)

10:2:1

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78F RICHMOND KY

Ak found April 2021
Hb 16.8; M spike 13; IgA 1960; k/l 45.7/13.2 3.46 ratio
Reassured MGUS
Seen WFMC May 10, 2022
ROS: Weight loss 68 to 48 kg; numb feet; multiple syncopal episodes and diarrhea BP 94/64

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NEUROLOGY REFERRAL

71 yo M progressive sensory motor PN
Neurologist finds 1.1 g/dL Gl
Diagnosis MGUS-Neuropathy (CIDP like)
Plasma Exchange - IvIg tried over 8 months
Given azathioprine & prednisone
Progress and referred
Sural n biopsy + amyloid
Clues association of autonomic neuropathy; CTS; PAIN

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CONSIDER AL IN THE FOLLOWING

Non-diabetic nephrotic syndrome-check for light chains
Non-ischemic cardiomyopathy HFpEF with an echocardiogram showing “LVH”-check for light chains
Hepatomegaly or alkaline phosphatase elevation without imaging abnormality-check for light chains
Peripheral neuropathy with MGUS or CIDP with autonomic features
Atypical SMM/MGUS monoclonal light chains urine and modest marrow plasmacytosis
At 20 years 4% of MGUS will develop AL

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AMYLOID TYPING

Consider localized amyloid and non-AL amyloidosis
Verify that the amyloidosis is light chain with your pathologist

3-5% of elderly patients with localized, familial, and secondary amyloidosis will have an incidental unrelated MGUS
20% of ATTR wt have MGUS

Classic sites for localized amyloidosis are bladder, gastric ulcer, colon polyp larynx and skin

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66-YEAR-OLD MALE, DYSPNEA ON EXERTION X 1 YR

Previously healthy, no HTN
Bilateral carpal tunnel – 10 yrs ago
Echo – amyloid, EF 40%
Referred by cardiology
15 lb diuresis – much improved
Normal serum FLC/ratio, no urine or serum monoclonal protein
Negative fat aspirate

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Slide courtesy of the author.

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VENETOCLAX FOR RELAPSED REFRACTORY AL AMYLOIDOSIS�

43 RR AL patients; median lines of therapy 3
72% with t(11;14)

Redrawn from Premkumar et al, Blood Cancer Journal, 2021

Hematologic response rate

A�Best response in all evaluable

patients (n=38)

CR

VGPR

PR

SD/NR

Progression

B�Best response in non-t(11/14)

patients (n=10)

C�Best response in evaluable

t(11/14) patients (n=27)

78%�VGPR/CR

30%�VGPR/CR

63%�VGPR/CR

34%

29%

5%

26%

5%

20%

10%

40%

20%

41%

37%

4%

19%

A All evaluable patients; B Response in non-t(11;14) patients, C Response in (t11;14) patients

PFS

Time (months)

Survival probability

P=0.00073

HR t(11;14) positive vs negative = 0.14, (0.04, 0.53)

No. at risk

T(11/14) negative 11 7 3 3 0 0 0

T(11;14) positive 30 23 15 10 8 4 0

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ANDROMEDA STUDY DESIGN

Kastritis E, et al. Oral Presentation, ASCO 2021

Andromeda is a randomized, open-label, active-controlled, phase 3 study of D-VCd vs VCd alone in patients with newly diagnosed AL amyloidosis

DARA SC 1800 mg QW

Cycles 1-2 Q2W Cycles

3-6 VCd QW x 6 cycles

n=195

DARA SC 1800 mg Q4W

until major organ deterioration–PFS or maximum of 24 total cycles

Observation until major organ deterioration–PFS (if DARA SC discontinued prior to major organ deterioration–PFS)

VCd

QW x 6 cycles

n=193

Observation until major organ deterioration–PFS

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HEMATOLOGIC CR: PRIMARY ENDPOINT

Kastritis E., et al. Oral Presentation, ASCO 2021.

N Engl J Med. 2021 Jul 1;385(1):46-58

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CARDIAC RESPONSE RATE AT 6 AND 12 MONTHS

N Engl J Med. 2021 Jul 1;385(1):46-58

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RENAL RESPONSE RATE AT 6 AND 12 MONTHS

N Engl J Med. 2021 Jul 1;385(1):46-58

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ASCT FOR AL VERSUS MM�SURVIVAL* BASED ON DEPTH OF RESPONSE AND DIAGNOSIS

Redrawn from Dispenzieri et al, Bone Marrow Transplant. 2013;48(10):1302-7

*Only patients receiving ASCT within 12 months of diagnosis and surviving 3 months post ASCT included.

Months post-ASCT

Proportion surviving

AL amyloidosis, n=164

Myeloma, n=255

P<0.001

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POMALIDOMIDE IN AL AMYLOIDOSIS

¹Dispenzieri A et al, Blood. 2012;119(23):5397-404

²Sanchorawala V et al, Blood. 2016;128(8):1059-62

³Palladini G et al, Blood. 2017;129(15):2120-2123

Ref	Prior lines	N	Dosing	Median time to response	ORR/ ≥ VGPR	PFS	FU
1	2 (1-8)	33	2 mg daily Dex 40 mg/W	1.9 months	48%/18%	14 months	28 months
2	2 (1-6)	27	2/3 mg/d (n=15) 4 mg/d for 21 days (n=12) Dex 20 mg/W	3 months	50%/37.5%	18 months	17 months
3	2 (1-7)	28	2 mg/d (n=3) 4 mg/d daily (n=25) Dex 20/40 mg/W	1 month	68%/29%	16 months	44 months

Dose reduction: 48%¹, NR^2,32%³
Grade 3/4 toxicities:

Myelosuppression 26%-45%
Fatigue 18%
Pneumonia 11%-21%
Renal failure 3%-7.5%
Arrhythmias 0-21%

Rise in NT-proBNP was frequently seen, in most cases w/o clinical CHF

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OTHER TREATMENT OPTIONS FOR RELAPSED AL AMYLOIDOSIS�BENDAMUSTINE

¹Milani P et al, Blood 2018; ²Lentzsch et al, JCO 2020; 3Manwani R et al, Blood 2017

Ref	N	Prior lines	Dosing	Median time to response	ORR	≥ VGPR	PFS	FU, median
1	122	2 (0-3) 12 pts ND	IV Benda 60-100 mg/m², days 1,2 Prednisone 100 mg, days 1-4 Repeated 28 days Rituximab 375 mg/m² for IgM AL	3 months	35% 58% in IgM AL	10% 21% in IgM AL	9 months	31mo for living pts
2	31	2 (1-6)	IV Benda 100 mg/m², days 1,2 Dex 20-40 mg/W Repeated 28 days	2.8 months (1.8 PR 4.7 CR)	57%	29%	9.4 months	15 months
3	27, all LPL	22 ND, 5 RR	IV Benda 90 mg/m², days 1,2 Rituximab 375 mg/m² day 1 Repeated 28 days	1 month	59%	48%	34 months	18 months

Side effects: GI symptoms, fatigue, cytopenias, neutropenic fever 7%³

Dose reduction: Bendamustine 29%²Dexamethasone 48%

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CAR-T TRIALS AL

Study of NXC-201 CAR-T in Patients With Light Chain (AL) Amyloidosis (NEXICART-2) NCT06097832
FKC288 for Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis NCT05978661

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TECLISTAMAB IN RELAPSED OR REFRACTORY AL AMYLOIDOSIS�A MULTINATIONAL RETROSPECTIVE CASE SERIES

Blood Volume 143, Issue 8, 22 February 2024, Pages 734-737

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NEWLY DIAGNOSED AL AMYLOIDOSIS – TRANSPLANT ELIGIBLE

http://msmart.org. V10 April 2023

¹If daratumumab is not accessible, CyBorD is an acceptable alternative regimen (weekly bortezomib only)

²For CrCl <30, use Mel 140 mg/m2

³Decision to change therapy if in VGPR but < CR is based on a number clinical factors. Re-refer to amyloid center of excellence

⁴For patients with overt multiple, BMPCs ≥20%, and high-risk FISH (del 17p, t(4;14), t(14;16) and t(14;20)), use myeloma-type maintenance; refer to myeloma mSMART guidelines for choice of maintenance

Mel200 ASCT²

≥ Hematologic VGPR?³

Observation⁴

Yes

No

Option to continue with transplant-ineligible algorithm; for overt myeloma, HR FISH or high baseline BMPCs, transplant consolidation may be preferred

CR

At least hematological PR by 2 months & ≥ Hematologic VGPR by 4 months^2,3

Induction with 2-4 cycles of daratumumab-CyBorD¹

No

Stem cell collection

Relapsed/refractory algorithm

Yes

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NEWLY DIAGNOSED AL AMYLOIDOSIS – TRANSPLANT INELIGIBLE#

http://msmart.org. V10 April 2023

^#For IgM AL amyloidosis consider referral to amyloidosis center due to a more challenging management

¹If daratumumab-CyBorD, 6 cycles followed by daratumumab monotherapy, completing up to 24 cycles. If daratumumab is not accessible, CyBorD or BMDex for 6-12 cycles are acceptable alternative regimens (weekly bortezomib)

²If young, consider stem cell collection for eventual ASCT if eligibility for transplant is foreseeable

³Decision to change therapy if in VGPR but < CR is based on a number clinical factors. Re-refer to amyloid center of excellence

⁴Only for patients withovert multiple myeloma, BMPCs ≥20% or high-risk FISH consider extended duration daratumumab maintenance or other forms of maintenance used in myeloma. Lenalidomide should not be used in patients with advanced heart or autonomic nerve involvement

At least hematological PR by 2 months & ≥ Hematologic VGPR by 4 months^2,3

Complete 6 cycles of induction followed by daratumumab maintenance up to 18 cycles⁴

Relapsed/refractory algorithm

Yes

No

Daratumumab-CyBorD¹

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TREATMENT OF RELAPSED/REFRACTORY AL AMYLOIDOSIS – I

http://msmart.org. V10 April 2023

¹Induction should be considered in high-burden disease; For CrCl <30, use Mel 140 mg/m2

²Can be used with dexamethasone or as a single agent; No need for dose ramp up; dose can be capped at 400 mg/d

³infectious disease prophylaxis is recommended

Yes

No

Mel200 ASCT¹

ASCT-eligible?

Daratumumab-based therapy

No

Daratumumab naïve?

Yes

No

Daratumumab-based therapy

Daratumumab refractory

Positive

Negative

Venetoclax^2,3

t(11;14) status

ASCT, autologous stem cell transplant

Algorithm II

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TREATMENT OF RELAPSED/REFRACTORY AL AMYLOIDOSIS – II

http://msmart.org. V10 April 2023

¹Starting dose of lenalidomide should be no higher than 15 mg/d

²Melphalan-dexamethasone, bortezomib-melphalan-dexamethasone or Ixazomib-dexamethasone are appropriate if the patient has significant neuropathy

³Not recommended in patients with cardiac involvement

ASCT, autologous stem cell transplant

Paucity of data, but second ASCT, carfilzomib³, bendamustine can be considered

Pom-Dex or Len¹-Dex

CyBorD²

No

Yes

Dara-refractory, non-t(11;14)

Bortezomib refractory?

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25

IgG IgA IgM κ λ

A

C

B

D

Personal collection of Morie Gertz

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MACROGLOBULINEMIA�DEFINITIONS

MYD88 does not distinguish types

	Monoclonal Serum IgM	Marrow Infiltration	Sx. Due to IgM Protein	Sx Due to Tumor Mass
WM Symptomatic	+	+	+	+
WM Smoldering	+	+	–	–
IgM-related Disorder	+	–	+	–
MGUS	+	–	–	–

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B-R VS CHOP-R AS FIRST-LINE TREATMENT�(SUBANALYSIS OF THE STiL NHL1 STUDY IN WM PATIENTS)

Redrawn from Rummel et al. Lancet 2013

B-R CHOP-R

N=22 N=19

Months

Overall Survival

5 yrs 6 yrs

B-R 90.4% 90.4%

CHOP-R 58.3% 58.3%

Months

Hazard ratio, 0.33 (95% CI 0.11 – 0.64), p=0.0033

Progression-Free Survival

Median (months)

B-R 69.5

CHOP-R. 28.1

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RITUXIMAB MAINTENANCE IN MACROGLOBULINEMIA

Median progression-free survival for patients treated with R bendamustine 78 months
218 randomized to R for 2 years vs obs
5-year survival 78%
1 AML 1 MDS 0.7%
PFS 101 versus 83 months p= 0.32; OS P=ns

ASH abstract 343; 2019 MAINTAIN trial

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RITUXIMAB FLARE SOME REGIMENS DELAY R UNTIL CYCLE 2

Cancer. 2004 Dec 1;101(11):2593-8

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EFFICACY OF ZANUBRUTINIB VS IBRUTINIB

CR+VGPR rates were 36.3% with zanubrutinib vs 25.3% ibrutinib
Median time to CR+ VGPR was 6.7 months with zanubrutinib vs 16.6 months ibrutinib
Median PFS and OS were not reached

Patient (%)

44.4 months

Response in Patients with MYD88^MUT

MRR

81%

PD

SD

MR

PR

VGPR

MRR

80%

Progression-free

survival probability (%)

Progression-Free Survival in Cohort 1*

Months

	Zanubrutinib	Ibrutinib
Events, n (%)	20 (19.6)	30 (30.3)
HR (95% CI)	0.63 (0.36, 1.12)
+Censored

78.3%

69.7%

Zanubrutinib

Ibrutinib

*As the primary endpoint of the trial was not met, all subsequent analyses are exploratory and descriptive in nature.

J Clin Oncol. 2023 Nov 20;41(33):5099-5106.

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ASPEN: ZANUBRUTINIB VS IBRUTINIB �PHASE 3 TRIAL

	All Grades		Grade ≥3
AE Categories^a, n (%) (pooled terms)	Ibrutinib (n=98)	Zanubrutinib (n=101)	Ibrutinib (n=98)	Zanubrutinib (n=101)
Infection	78 (79.6)	80 (79.2)	27 (27.6)	22 (21.8)
Bleeding	61 (62.2)	56 (55.4)	10 (10.2)	9 (8.9)
Diarrhea	34 (34.7)	23 (22.8)	2 (2.0)	3 (3.0)
Hypertension*	25 (25,5)	15 (14.9)	20 (20.4)*	10 (9.9)
Atrial fibrillation/flutter*	23 (23.5)*	8 (7.9)	8 (8.2)*	2 (2.0)
Anemia	22 (22.4)	18 (17.8)	6 (6.1)	12 (11.9)
Neutropenia*^b	20 (20.4)	35 (34.7)*	10 (10.2)	24 (23.8)*
Thrombocytopenia	17 (17.3)	17 (16.8)	6 (6.1)	11 (10.9)
Second primary malignancy/ nonskin cancers	17 (17.3)/ 6 (6.1)	17 (16.8)/ 6 (5.9)	3 (3.1)/ 3 (3.1)	6 (5.9)/ 4 (4.0)

AE Categories of Interest (BTKi Class AEs) with 44 Months of Follow-Up

J Clin Oncol. 2023 Nov 20;41(33):5099-5106.

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BTK INHIBITOR–BASED PRIMARY THERAPY FOR WM

Study	N	ORR (%)	MRR (%)	VGPR (%)	PFS (%)
Phase 2: ibrutinib	30	100%	83%	20%	1.5-yr 92%
Phase 3 iNNOVATE:
ibrutinib/rituximab (IR) vs placebo/rituximab (R)	34/75 34/75	92% 44%	76% 31%	29% 4%	2-year 84%; 4.5-year 68% 2-year 59%; 4.5-year 25%
Acalabrutinib	14/106	93%	79%	7%	2-yr 90%
Tirabrutinib	18/27	94%	89%	17%	NR
Phase 1/2 BGB-3111 AU-003	24/77	100%	88%	33%	2-year 92%
Phase 3 (ASPEN):
zanubrutinib vs ibrutinib	19/102 18/99	95% 89%	74% 67%	26% 17%	1.5 years 78% 1.5 years 94%
ASPEN ARM C: zanubrutinib (MYD88^WT)	5	80%	40%	20%	1.5-year 60%
Pirtobrutinib (prior cBTKi)	55	64%	40%	24%	DOR 83%@6 mos

Leukemia. 2023 Jan;37(1):35-46.

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VENETOCLAX IN R/R WM�OPTION FOR R/R PATIENTS, INCLUDING PATIENTS TREATED WITH BTKI

Weekly ramp-up 200 mg → 400 mg → 800 mg per day
N=30 (15 patients BTKi-exposed)
ORR 87% (VGPR 17%; PR 63%; MR 7%)
VGPR 7% in BTKi-exposed versus 27% in those not exposed; lower in those with CXCR4 mutation (6% vs 29%)
Grade 3/4 AEs: neutropenia (n=7), anemia (n=2), back pain (n=1), constipation (n=1), diarrhea (n=1), headache (n=1), URTI (n=1)

. J Clin Oncol. 2022 Jan 1;40(1):63-71

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VENETOCLAX IN PREVIOUSLY TREATED WALDENSTRÖM MACROGLOBULINEMIA

Content of this presentation is the property of the author, licensed by ASCO. Permission required for reuse.

Castillo et al. J Clin Oncol 2022.

19

61

19

76

20

30

10

27

60

13

63

7

25

65

9

54

29

57

12

65

25

58

29

43

8

75

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Ibrutinib and Venetoclax as Primary Therapy in Symptomatic, Treatment-naïve Waldenström Macroglobulinemia

Jorge J. Castillo,Andrew R. Branagan,David Sermer,Catherine A. Flynn,Kirsten Meid,Megan Little,Katherine Stockman,Timothy White,Alexa Canning,Maria L. Guerrera,Amanda Kofides,Shirong Liu,Xia Liu,Kris Richardson,Nicholas Tsakmaklis,Christopher J. Patterson,Zachary R. Hunter,Steven P. Treon,Shayna Sarosiek, Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia, Blood, 2024,

Conclusion: Study therapy was stopped early because of a higher-than-expected rate of ventricular arrhythmia in 4 of the 45 participants (9%), including 2 deaths (NCT04273139).

50%

29%

59%

12%

42%

53%

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NEWLY DIAGNOSED WALDENSTRÖM MACROGLOBULINEMIA

Redrawn from Ansell S. et al. Mayo Clin Proc. 2010; 85(9):824-833.; Kapoor P et al. JAMA Oncol. 2017;3(9):1257-1265 mSMART v6 //last reviewed Feb 2023

¹Initiate plasmapheresis if symptomatic hyperviscosity develops in the setting of IgM flare. Avoid rituximab monotherapy if baseline IgM level

≥4000 mg/dL and consider preemptive plasmapheresis prior to initiating rituximab to avert IgM flare associated hyperviscosity symptoms.

²May use Bendamustine-rituximab (BR) X 4 cycles in young, fit patients with symptomatic cold agglutinin anemia. Sutimlimab may be used in patients with symptomatic cold agglutinin anemia, unresponsive to B cell directed therapies.

³Measure baseline serum viscosity and initiate plasmapheresis followed by cytoreductive therapy; alternatively, may directly proceed to cytoreductive therapy but omit rituximab for 1-2 cycles to avoid IgM flare induced worsening of symptoms.

⁴May consider auto SCT in select young patients in first remission if concurrent ALH amyloidosis with adequate cardiorenal function.

⁵Continuous zanubrutinib until progression or unacceptable toxicity is an alternative to BR for patients without concurrent AHL, irrespective of the MYD88 gene mutation status.

IgM MGUS (<10% clonal infiltrate)
Smoldering (asymptomatic) WM

IgM-related neuropathy
WM-associated hemolytic anemia
Symptomatic cryoglobulinemia

Bulky (≥5 cm max. diameter) or symptomatic lymphadenopathy
Clinically significant cytopenias:

Hemoglobin ≤10g/dL
Platelet count <100 x10⁹/L

Hyperviscosity symptoms³
Constitutional symptoms
Concurrent ALH amyloidosis⁴

Observation

(irrespective of IgM level)

Rituximab x 1 cycle^1,2

( no maintenance therapy)

Bendamustine-Rituximab (BR) x 6 cycles⁴ (no rituximab maintenance) or
Zanubrutinib⁵

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WALDENSTRÖM MACROGLOBULINEMIA: FIRST RELAPSE�

Redrawn from Ansell S. et al. Mayo Clin Proc. 2010; 85(9):824-833.; Kapoor P et al. JAMA Oncol. 2017;3(9):1257-1265 mSMART v6 //last reviewed Feb 2023

¹Bulky (≥5 cm max. diameter) or symptomatic lymphadenopathy, clinically significant cytopenias (hemoglobin ≤10 g/dL; platelet count <100 x109/L), hyperviscosity-related symptoms or constitutional symptoms.

²If symptomatic hyperviscosity suspected, measure baseline serum viscosity, perform fundoscopic examination and initiate plasmapheresis followed by cytoreductive therapy; alternatively, may directly proceed to cytoreductive therapy, but omit rituximab for 1-2 cycles to avoid IgM flare induced worsening of symptoms

³If chemoimmunotherapy not used previously. In the frail patient population, DRC (Dexamethasone, Rituximab, Cyclophosphamide) regimen may be used as an alternative to BR.

⁴If a BTK inhibitor not used previously; ibrutinib alone (only if the patient has MYD88mut), ibrutinib-rituximab or acalabrutinib may be used if zanubrutinib unavailable.

⁵May consider repeating original fixed-duration chemoimmunotherapy if durable response obtained previously (time-to- previous therapy ≥4 years) and patient not a candidate for a BTK inhibitor.

Relapsed/Refractory WM

Relapse on a covalent BTK inhibitor- (ibrutinib, zanubrutinib, acalabrutinib, orelabrutinib or tirabrutinib) based regimen

First Symptomatic Relapse¹

Asymptomatic

Observe

Relapse off therapy, relapse post BR/ other chemoimmunotherapy, or covalent BTK inhibitor-naïve

Bendamustine-Rituximab (BR) x 6 cycles^2,3

Zanubrutinib⁴
Repeat original fixed-duration therapy⁵

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WALDENSTRÖM MACROGLOBULINEMIA: SECOND OR LATER SYMPTOMATIC RELAPSE^1,2

Redrawn from Ansell S. et al. Mayo Clin Proc. 2010; 85(9):824-833.; Kapoor P et al. JAMA Oncol. 2017;3(9):1257-1265 mSMART v6 //last reviewed Feb 2023

¹Bulky (≥5 cm max. diameter) or symptomatic lymphadenopathy, clinically significant cytopenias (hemoglobin ≤10 g/dL; platelet count <100 x109/L), hyperviscosity-related symptoms or constitutional symptoms.

²If symptomatic hyperviscosity suspected, measure baseline serum viscosity, perform fundoscopic examination and initiate plasmapheresis followed by therapy; alternatively, may directly proceed to therapy, but omit rituximab for 1-2 cycles to avoid IgM flare induced worsening of symptoms.

³Until progression or unacceptable toxicity

⁴BDR consists of a single 21-day cycle of bortezomib alone (1.3 mg/m2 subcutaneously on days 1, 8, and 15), followed by weekly subcutaneous bortezomib (1.6 mg/m2 on days 1, 8, 15, and 22) for 4 additional 35-day cycles, with IV dexamethasone (40 mg) and IV rituximab (375 mg/m2) on cycles 2 and 5, for a total treatment duration of 23 weeks.). Use only in the absence of peripheral neuropathy or if preexisting peripheral neuropathy < Grade 2 .

⁵May consider autologous stem cell transplantation (ASCT) as an option if not exercised previously for a fit patient with chemosensitive disease or concurrent AHL amyloidosis.

⁶May consider repeating original fixed-duration chemoimmunotherapy if durable response obtained previously (time-to-previous therapy ≥4 years) and patient not a candidate for a BTK inhibitor. Purine analog-based regimens and everolimus are effective, but owing to their side effects, are best reserved for patients without alternatives.

Previously received both chemoimmunotherapy and covalent BTKi-based therapies

Venetoclax³
Pirtobrutinib³
BDR⁴
ASCT in select patients⁵
Repeat previously used fixed duration therapy⁶

Refer to the algorithm for first relapse

YES

NO