34 Waldenström's Macroglobulinemia (WM) Clinical Trials Recruiting Now (July 2026): BTK Inhibitors, Non-Covalent BTKi, BTK Degraders, Venetoclax, Bispecifics & CAR-T

Last updated: July 6, 2026

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Current Clinical Trial Landscape

About Waldenstrom's macroglobulinemia (WM):

WM is a rare B-cell lymphoma characterized by IgM-producing lymphoplasmacytic cells in the bone marrow. Most patients have MYD88 L265P mutation (~95%). Treatment is typically deferred until symptomatic.

Active research areas in 2026:

Covalent BTK inhibitors (zanubrutinib, ibrutinib, acalabrutinib) — the WM backbone
Non-covalent / reversible BTK inhibitors (pirtobrutinib, nemtabrutinib) — for BTK-inhibitor resistance
BTK degraders (BGB-16673, NX-5948, NX-2127) — the next resistance frontier
BCL2 inhibitors (venetoclax + rituximab)
Bispecific antibodies (epcoritamab) & CD19/CD22 CAR-T for heavily-pretreated disease

Standard of care: Watch & wait until symptomatic. First-line: BTK inhibitors (zanubrutinib, ibrutinib) or rituximab-based regimens (BR, R-CHOP). BTK inhibitors preferred for MYD88-mutated patients.

The Biomarkers That Drive WM Treatment: MYD88 & CXCR4

Two mutations shape treatment decisions in Waldenström's macroglobulinemia and determine which trials fit a given patient:

MYD88 L265P — present in roughly 90–95% of WM. It constitutively activates the BTK / NF-κB signaling pathway, which is exactly why BTK inhibitors are so effective in WM. MYD88-mutated patients respond well to BTK inhibitors; the roughly 5–10% who are MYD88 wild-type respond less well and are an area of active trial development.
CXCR4 mutations — present in roughly 30–40% of WM (WHIM-like frameshift/nonsense mutations). CXCR4-mutated disease is associated with higher IgM, greater risk of hyperviscosity, and slower or shallower responses to BTK inhibitors. Several trials stratify by, or specifically address, CXCR4 status.

Knowing your MYD88 and CXCR4 status — and your prior BTK-inhibitor history — is the single most useful thing for matching to the right WM trial. ClinTrialFinder's wizard asks for these.

Recruiting Trials by Drug Class

Curated corpus-verified subset of recruiting / not-yet-recruiting interventional WM trials as of July 2026, grouped by mechanism. The WM landscape is dominated by BTK-pathway therapies and, increasingly, the drugs that work after BTK-inhibitor resistance.

Covalent BTK Inhibitors — the WM Backbone (first-line & beyond)

Zanubrutinib, ibrutinib, and acalabrutinib — most effective in MYD88-mutated disease. The front-line question is chemo-free BTKi combinations vs. bendamustine-rituximab (BR) chemoimmunotherapy.

NCT04061512 - Rituximab + ibrutinib (RI) vs dexamethasone + rituximab + cyclophosphamide (DRC), first-line WM (Phase 2/3) — head-to-head of chemo-free BTKi combination vs chemoimmunotherapy.
NCT05914662 - Zanubrutinib + BR in newly-diagnosed symptomatic WM (Phase 2).
NCT06561347 - Zanubrutinib + bendamustine + rituximab in previously-untreated WM (Phase 2).
NCT04883437 - Acalabrutinib + obinutuzumab in previously-untreated WM (Phase 2).
NCT07169565 - Ibrutinib followed by time-limited BR (Phase 1, fixed-duration strategy).
NCT07169331 - Zanubrutinib in Chinese patients with WM (Phase 4).
NCT01804686 - Ibrutinib (PCI-32765) long-term extension (Phase 3).

Non-Covalent (Reversible) BTK Inhibitors — for BTK-Inhibitor Resistance

Pirtobrutinib, nemtabrutinib, and rocbrutinib bind BTK reversibly, retaining activity when covalent BTKi resistance (e.g. BTK C481 mutations) develops — a major unmet need in relapsed WM.

NCT07231952 - Pirtobrutinib + venetoclax + rituximab in WM (Phase 2).
NCT07548450 - Mosunetuzumab + pirtobrutinib in relapsed/refractory WM (Phase 2).
NCT04728893 - Nemtabrutinib (MK-1026) in B-cell malignancies including WM (Phase 2).
NCT07464210 - Nemtabrutinib + bortezomib + rituximab for WM (Phase 2).
NCT07609862 - Rocbrutinib + lacutoclax (Phase 1/2).

BTK Degraders — the Next Resistance Frontier

Instead of blocking BTK, these agents tag the BTK protein for degradation — a distinct mechanism designed to overcome resistance to both covalent and non-covalent BTK inhibitors.

NCT05006716 - BGB-16673 (BTK degrader) in B-cell malignancies including WM (Phase 1/2).
NCT05131022 - NX-5948 (BTK degrader) in relapsed/refractory B-cell malignancies (Phase 1).
NCT04830137 - NX-2127 (BTK degrader) in relapsed/refractory B-cell malignancies (Phase 1).
NCT07249905 - MDX2003 in B-cell malignancies (Phase 1/2).

BCL2 Inhibitors (Venetoclax)

Venetoclax targets BCL2-mediated survival and has activity in WM, including after BTK-inhibitor exposure; usually combined with rituximab.

NCT05099471 - Venetoclax + rituximab in WM (Phase 2).
NCT04840602 - Venetoclax + rituximab comparison study (Phase 2).
NCT07387471 - Oral venetoclax in WM (Phase 2).

Bispecific Antibodies & CAR-T — for Heavily-Pretreated Disease

T-cell-engaging bispecifics (CD20×CD3, BCMA) and CAR-T cell therapies are entering WM for patients who have exhausted BTK-pathway and chemoimmunotherapy options.

NCT06510491 - Epcoritamab (CD20×CD3 bispecific) in previously-treated WM (Phase 2).
NCT07420959 - ABBV-383 (BCMA bispecific) in relapsed/refractory WM (Phase 1/2).
NCT05281809 - Local-manufacture CAR-T for B-cell malignancies (Phase 2).
NCT04545762 - Anti-CD19 CAR-T cells for relapsed/refractory disease (Phase 1).
NCT06340737 - Anti-CD22 CAR-T cells for recurrent/refractory disease (Phase 1).

Frequently Asked Questions

How do I find Waldenstrom's macroglobulinemia clinical trials?

Paste your medical summary into ClinTrialFinder to get AI-matched WM trials in minutes. The tool considers your MYD88 mutation status, CXCR4 status, and prior treatments including BTK inhibitor history.

What Waldenstrom's macroglobulinemia trials are currently recruiting?

There are 34 recruiting interventional trials for Waldenstrom's macroglobulinemia in July 2026 (plus about 12 not-yet-recruiting). Active drug classes: covalent BTK inhibitors (zanubrutinib, ibrutinib, acalabrutinib), non-covalent/reversible BTK inhibitors for BTK-inhibitor resistance (pirtobrutinib, nemtabrutinib, rocbrutinib), BTK degraders (BGB-16673, NX-5948, NX-2127), BCL2 inhibitors (venetoclax + rituximab), and T-cell-engaging therapies for heavily-pretreated disease (epcoritamab and other bispecifics, CD19/CD22 CAR-T).

How do MYD88 and CXCR4 mutations affect Waldenström's treatment and trial options?

MYD88 L265P (present in ~90–95% of WM) activates the BTK/NF-κB pathway and predicts strong response to BTK inhibitors — it's the reason BTK inhibitors are so central in WM. The ~5–10% who are MYD88 wild-type respond less well and are a focus of trial development. CXCR4 mutations (~30–40%) are associated with higher IgM, greater hyperviscosity risk, and slower or shallower BTK-inhibitor responses. Your MYD88 and CXCR4 status, plus your prior BTK-inhibitor history, are the most useful facts for matching to the right WM trial.

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