MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.).

Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01614821.).

Key Points Highly recurring mutations are present in WM, including MYD88 L265P, warts, hypogammaglobulinemia, infection, and myelokathexis-syndrome–like mutations in CXCR4, and ARID1A. Small, previously undetected CNAs affecting B-cell regulatory genes are highly prevalent in WM.

Key Points• MYD88 L265P is expressed in WM and IgM MGUS patients using AS-PCR assays with potential use in diagnostic discrimination and response assessment.By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor kB activity and is present in >90% of Waldenström macroglobulinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin G MGUS (0/9) patients as well as healthy donors (0/40; P < 1.5 3 10 25 for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P DC T and BM disease involvement (r 5 0.89, P 5 .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early

Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. In this study, we designed a multi-kinase degrader by conjugating a highly promiscuous kinase inhibitor with a cereblon-binding ligand, and used quantitative proteomics to discover 28 kinases, including BTK, PTK2, PTK2B, FLT3, AURKA, AURKB, TEC, ULK1, ITK, and nine members of the CDK family, as degradable. This set of kinases is only a fraction of the intracellular targets bound by the degrader, demonstrating that successful degradation requires more than target engagement. The results guided us to develop selective degraders for FLT3 and BTK, with potentials to improve disease treatment. Together, this study demonstrates an efficient approach to triage a gene family of interest to identify readily degradable targets for further studies and pre-clinical developments.

• Activating MYD88 as well as nonsense and frameshift WHIM-like CXCR4 somatic mutations are common in WM.• CXCR4 NS mutations are present in aggressive cases including hyperviscosity syndrome, and MYD88 status is a determinant of survival.

140-HELD-420 denotes that this patient was on 140 mg/d of ibrutinib prior to hospitalization that was held upon admission; he experienced worsening hypoxia after ibrutinib was held and required mechanical ventilation, following which he was restarted on 420 mg/d of ibrutinib and showed rapid improvement in oxygenation.

Key Points• MYD88 L265P is a widely expressed somatic mutation in WM patients that supports NF-kB signaling through stimulation of BTK and IRAK 1/4. • Combined suppression of BTK and IRAK in MYD88 L265P expressing WM cells promotes synergistic inhibition of NF-kB signaling and WM cell killing.Myeloid differentiation factor 88 (MYD88) L265P somatic mutation is highly prevalent in Waldenström macroglobulinemia (WM) and supports malignant growth through nuclear factor kB (NF-kB