�Waldenstrom's Macroglobulinemia in 2025

Steven P. Treon MD, PhD, FRCP, FACP

Harvard Medical School

Bing Center for Waldenstrom’s Macroglobulinemia

Dana Farber Cancer Center, Boston MA

Manifestations of WM Disease

≤20% at diagnosis;

50-60% at relapse.

↓Hb>>> ↓PLT> ↓WBC

IgM related

Hyperviscosity Syndrome:

Epistaxis, Headaches

Impaired vision

>6,000 mg/dL or >4.0 CP

Treon S., Hematol Oncol. 2013; 31:76-80.

IgM Cold Agglutinemia (5%)

IgM Cryoglobulinemia (10%)

IgM Neuropathy (22%)

Light chain Amyloidosis (10-15%)

Hepcidin

↓Fe Anemia

Bone Marrow

Bing Neel

Syndrome

Primary Therapy of WM with Rituximab

Treon et al, Blood 2015 126:721-732; Rummel et al, Lancet Oncol 2016; 17:57-66.

WM–centric toxicities with commonly used therapies

Treon et al, Blood 2015 126:721-732; Treon et al, JCO 2020; 38:1198-1208.

MYD88 Directed Pro-survival Signaling in WM

Treon, et al. N Engl J Med. 2012;367(9):826-833.

Yang, et al. Blood. 2013;122(7):1222-1232.

Hodge, et al. Blood. 2014;123(7):1055-1058.

Yang, et al. Blood. 2016;127(25):3237-3252. 

Chen, et al. Blood. 2018;131(18):2047-2059. 

Liu, et al. Blood Adv. 2020;4(1):141-153.

Munshi, et al. Blood Cancer J. 2020;10:12.

Munshi, et al. Blood Adv. 2022.

MYD88 mutations occur in 95-97% WM Patients

BTK-Inhibitor Trials in WM

Median ORR: 93%; Major RR: 81%; >VGPR: 30%;

PFS 76% @ 4 yrs

• Hyperviscosity Syndrome
• Drug resistance

Bone Marrow Stroma

CXCR4 mutations are common in WM and impact disease presentation and treatment response.

WM Cell

CXCL12

Hunter et al, Blood 2013; Treon et al, Blood 2014; Roccarro et al, Blood 2014; Cao et al, Leukemia 2014.

• 30-40% of WM patients are CXCR4 mutated.
• >40 different CXCR4 mutations described, most common is S338X.

S338X

CXCR4

CXCR4 Impact on BTK-Inhibitor Outcomes in WM

Treon et al, J. Clin. Oncol. 2021;

​

​

Abs

CXCR4^Mut vs CXCR4^WT

Median Time to Major Response: (4.2 vs. 1.9 mos)

Median Major RR: 71% vs. 87%

Median >VGPR: 14% vs. 41%

PFS: 59% vs. 75% @4 years

Progression-Free Survival in Patients With CXCR4^MUT and Response Assessment by CXCR4 status

• In patients with CXCR4^MUT by NGS, zanubrutinib demonstrated deeper and faster responses, as well as favorable PFS, compared with ibrutinib

ASPEN – Long-term follow-up

Dimopoulos et al, IWWM-12, 2024

9

BeiGene Ltd. All rights reserved. Updated January 2024.

Adverse Events of Interest (Cohort 1)

ASPEN – Long-term follow-up

Bold text indicates rate of AEs with ≥10% (all grades) or ≥5% (grade ≥3) difference between arms.

Data cutoff: October 31, 2021.

*Descriptive purposes only, 1-sided P<0.025 in rate difference in all grades and/or grade ≥3. ^aAE categories (grouped terms) of preferred terms by Medical Dictionary for Regulatory Activities v24.0. ^bIncluding preferred terms of neutropenia, neutrophil count decreased, febrile neutropenia, and neutropenic sepsis.

AE=adverse event.

Dimopoulos MA et al. JCO 2023 DOI: 10.1200/JCO.22.02830

Dimopoulos et al, IWWM-12, 2024

10

BeiGene Ltd. All rights reserved. Updated January 2024.

Mason et al. Br J Haematol. 2016

11

BeiGene Ltd. All rights reserved. Updated January 2024.

Do we give BTK-inhibitors or chemo-immunotherapy to treatment-naïve patients?

Comparative Efficacy of Bendamustine-Rituximab and Ibrutinib

in Treatment-Naïve WM (International Retrospective Study)

IPSS: International Prognostic Scoring System; VGPR: very good partial response; MR: minor response; NR: no response

Abeykoon et al, IWWM-12, 2024

©2025 Mayo Foundation for Medical Education and Research | WF1323006-13

Benda-R vs. Ibrutinib: Time-to-event analyses

TTNT: time-to-next therapy; VGPR: very good partial response; PFS: progression-free survival; OS: overall survival; NR; not reached

p=0.27

p=0.92

Progression Free Survival

Overall Survival

Abeykoon et al, IWWM-12, 2024

©2025 Mayo Foundation for Medical Education and Research | WF1323006-14

���BENDAMUSTINE AND RITUXIMAB (BR) IN WALDENSTROM MACROGLOBULINEMIA (WM): LONG-TERM RESULTS �A STUDY ON BEHALF OF THE FRENCH INNOVATIVE LEUKEMIA ORGANIZATION (FILO)�

Eveillard JR, Chaoui D, Cavalieri D, Dartigeas C, Willems L, Le Calloch R, Roos-Weil D, Merabet F, Roussel X, Bareau B, Tricot S, Dupuis J, Poulain S, Laribi K, Leblond V

Leblond et al, IWWM-12, 2024

��LATE-ONSET TOXICITIES ��

_

• Second malignancies: 12 patients
• 9 solid tumors ( 2 pancreas , 2 gastric, 1 colic,

1 oesophagus 1 lung, 1 skin, 1 breast)

• 3 myelodysplastic syndromes with 2 AML

• Long–lasting cytopenia occurred in 35 patients ( 51%)

Cumulative incidence of second malignancies of 17.66% [7.99-27.64] at 66 months.  

Leblond et al, IWWM-12, 2024

N=69

How do we manage covalent BTK-inhibitor resistant disease?

• The median follow-up was 22 months (IQR, 19.3–26.7)
• The PFS rate at 18 months was 61.4% (95%CI, 49.1-71.6)

Progression-Free Survival

Palomba et al, IWWM-12, 2024

Non-Covalent BTK-I Pirtobrutinib in Relapsed/Refractory WM Patients

Castillo et al, JCO 2021

ORR 84%; Major RR 81%

Median PFS: 30 mos.

Not impacted by CXCR4 mutation status.

Grade >3 neutropenia: 45%

Venetoclax for Previously Treated WM

PFS for All Pts

PFS by CXCR4 Mut Status

Dose escalation to 800 mg/day, 2 years treatment

What does the near future hold for WM therapy?

A Multi-Center, Open-Label, Single-Arm Phase II Trial of Bendamustine, Rituximab and the Next Generation BTK Inhibitor Acalabrutinib in Treatment Naïve WM - BRAWM

N=63

Berenstein et al, IWWM-12, 2024

Clinical Responses for Bendamustine, Rituximab and Acalabrutinib

for Treatment Naïve WM �

p=0.23

p=0.05

p=0.43

MRR=

100%

Screening

Informed Consent and Registration

Cycle 1

Pirtobrutinib 100 mg PO BID

​

Cycle 2

Pirtobrutinib 100 mg PO BID

Venetoclax weekly ramp up

100-200-400 mg PO QD

​

Cycle 3-24

Pirtobrutinib 100 mg PO BID

Venetoclax 400 mg PO QD

Progressive Disease or Unacceptable Toxicity

Stable Disease or Response

Stop therapy

Continue therapy until completion

www.clinicaltrials.gov:

NCT05734495

Follow-up

Dose reductions are allowed for toxicity

Phase II study of Pirtobrutinib plus Venetoclax in previously treated WM

• The median follow-up was 6 months (95% CI, 3-12)
• The PFS rate at 6 months 84% (95% CI 49-96%)

Progression-Free Survival

Castillo et al, IWWM-12, 2024

Pirtobrutinib and Venetoclax in Relapsed/Refractory WM Patients

Major RR by CXCR4 WT vs. Mut: 90% vs. 83%

Major RR by prior BTK-I Exp vs. Non-Exp: 86% vs. 89%

N=16

MRR=87%

BGB-16673: A Chimeric Degradation Activating Compound (CDAC)

• BTK inhibitors are effective in WM but are associated with toxicities and/or resistance development^1,2
• BGB-16673 is a bivalent CNS-penetrating small molecule that induces BTK degradation by binding specifically to BTK and the E3 ligase³ 
• In preclinical models, BGB-16673 degraded both wild-type and mutant BTK resistant to cBTK (C481S, C481F, C481Y, L528W, T474I) and ncBTK inhibitors (V416L, M437R, T474I, L528W), leading to tumor suppression^3,4
• BGB-16673 led to substantial reductions in BTK protein levels in peripheral blood and tumor tissue⁵
• Here, updated safety and efficacy results are presented in patients with R/R WM in phase 1 of CaDAnCe-101

cBTK, covalent BTK; CNS, central nervous system; ncBTK, noncovalent BTK; ub, ubiquitin.

1. Castillo JJ, et al. Lancet Haematol. 2020;7(11):e827-e837; 2. Ntanasis-Stathopoulos I, et al. Ther Adv Hematol. 2021;12:2040620721989586; �3. Feng X, et al. EHA 2023. Abstract P1239; 4. Wang H, et al. EHA 2023. Abstract P1219; 5. Seymour JF, et al. ASH 2023. Abstract 4401.

Overall Responses for BGB-16673 in R/R WM

• Responses were observed at the lowest dose (100 mg; 7/9) and in patients with prior cBTK inhibitor (22/27) or ncBTK inhibitor (4/4)

^a Efficacy-evaluable population. ^b Includes best overall response of MR or better. ^c Includes best overall response of PR or VGPR. ^d Includes best overall response of SD or better. ^�e In patients with a best overall response better than SD.

cBTK, covalent BTK; DCR, disease control rate; MR, minor response; ncBTK, noncovalent BTK; VGPR, very good partial response.

Seymour et al, IWWM-12, 2024

BGB-16673 Responses Occurred Regardless of Specific Mutations �(Response vs Baseline Mutation Heatmap)

cBTKi, covalent BTK inhibitor; MR, minor response; ncBTKi, noncovalent BTK inhibitor; NE, not evaluable; VGPR, very good partial response; WT, wild type.

Baseline mutation status

Responses

Prior BTKi

BTK mutation

Phase 1 Study of the Novel BCL2 Inhibitor Sonrotoclax �(BGB-11417) in R/R WM

17

5

17

20

11

17

38

21

50

38

60

47

13

20

11

0

20

40

60

80

100

80 mg

(n=6)

160 mg

(n=8)^c

320 mg

(n=5)

All patients

(N=19)

VGPR

PR

MR

SD

PD

ORR^a,b

67%

ORR^a,b

88%

ORR^a,b

80%

ORR^a,b

79%

Patients, %

Study follow-up^d,

median (range), �months

23.4

(7.6-27.1)

4.1

(2.7-8.5)

13.1

(2.1-20.0)

12.3

(0.2-27.1)

Time since first dose, months

Prior

BTKi

Garcia-Sanz et al, IWWM-12, 2024

13^th International Workshop on

Waldenstrom’s Macroglobulinemia

October 13-17, 2026

Palm Springs, California

http://waldenstromsworkshop.org