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Treatment Advances in Waldenstrom Macroglobulinemia

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Treatment Advances in Waldenstrom
Macroglobulinemia
Morie Gertz, MD, MACP
Professor of Medicine
Chair of General Internal ...

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Disclosures
Morie Gertz, MD, MACP
Advisory board or panel: AbbVie, Pharmacyclics, Proclara
Grants or research support: Aln...

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Learning Objectives
Discuss predictive and prognostic markers that can individualize treatment
selection for patients with...

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Treatment Advances in Waldenstrom Macroglobulinemia

  1. 1. Treatment Advances in Waldenstrom Macroglobulinemia Morie Gertz, MD, MACP Professor of Medicine Chair of General Internal Medicine Mayo Clinic
  2. 2. Disclosures Morie Gertz, MD, MACP Advisory board or panel: AbbVie, Pharmacyclics, Proclara Grants or research support: Alnylam, Amgen, Annexon, Apellis, Celgene, Ionis/Akcea, Janssen, Prothena, Spectrum Other financial or material support: DAVA Oncology, Johnson & Johnson, Teva i3 Health has mitigated all relevant financial relationships
  3. 3. Learning Objectives Discuss predictive and prognostic markers that can individualize treatment selection for patients with Waldenstrom macroglobulinemia Assess emerging efficacy and safety data on novel therapeutic strategies for Waldenstrom macroglobulinemia Evaluate strategies to optimize the safety and tolerability of novel therapies for Waldenstrom macroglobulinemia
  4. 4. A IgG IgA IgM k l Attributes of WM at Diagnosis WM = Waldenstrom macroglobulinemia; Ig =immunoglobulin. Image adapted from Vijay & Gertz, 2007.
  5. 5. Macroglobulinemia Definitions Sx = symptoms; MGUS = monoclonal gammopathy of undetermined significance. Gertz, 2019. Monoclonal serum IgM Marrow infiltration Sx due to IgM protein Sx due to mass WM symptomatic + + + + WM + + - - IgM-related disorder + - + - MGUS + - - -
  6. 6. MYD88 in Lymphoma LPD = lymphoproliferative disorder; GC = germinal center subgroup; B-CLL = B-cell chronic lymphocytic leukemia. Jiménez et al, 2013. Relative Frequency of MYD88L265P Mutation Among Different B-Cell LPDs
  7. 7. MYD88 in Smoldering WM CI = confidence interval. Abeykoon, Paludo et al, 2018. MYD88 Mutation Status Does Not Impact Rate of Progression to Symptomatic WM MYD88L265P cohort MYD88WT cohort Median time to progression to active disease 2.8 years (95% CI: 2.2-3.8) 1.9 years (95% CI: 0.7-3.1) P=0.21
  8. 8. Relevance of CXCR4 Cao et al, 2015; Treon et al, 2021. CXCR4S338X associated with clinical resistance to ibrutinib (found in 30%) Varying levels of resistance to other WM-relevant therapeutics, including bendamustine, fludarabine, bortezomib, and idelalisib Mavorixafor in vitro blocks CXCR4 signaling and can restore sensitivity 9 patients with MYD88 and CXCR4 mutations received mavorixafor and ibrutinib Minor response or better was seen in all and may represent a future option in CXCR4-mutated WM
  9. 9. How Does MYD88 Impact Outcomes in WM? WT = wild type; TTNT = time to next treatment; BTK = Bruton tyrosine kinase; OS = overall survival. Abeykoon, Paludo et al, 2018. 174 MYD88m, 17 smoldering; 45 MYD88WT, 1 smoldering The number of patients treated with ibrutinib was very small MYD88L265P mutation status does not impact OS, disease severity, or TTNT Patients with MYD88WT genotype appear to have similar outcomes and largely overlapping clinical features in comparison to MYD88L265P A higher frequency of transformation to high‐grade lymphoma or the development of therapy‐related myelodysplastic syndrome in the MYD88WT cohort MYD88 gene is a predictor for response in patients with WM that are treated with a BTK inhibitor–based regimen; it does not appear to be a disease‐defining feature in WM
  10. 10. LPL = lymphoplasmacytic. Abeykoon, Paludo et al, 2018. MYD88 Mutation Status Does Not Impact Overall Survival in WM Median OS MYD88L265P cohort MYD88WT cohort P value Active disease 10.2 years 13.9 years 0.86 ≥10% LPL cells in marrow at time of MYD88 mutation analysis 10.2 years 13.9 years 0.98 Median OS of patients with known MYD88 status was 10.7 years versus 11.8 years in patients in whom mutation status was unknown (P=0.75)
  11. 11. Abeykoon, Paludo et al, 2018. MYD88 Mutation Status Does Not Impact Time to Second Treatment MYD88L265P cohort MYD88WT cohort TTNT from frontline treatment 2.9 years (95% CI: 2.4-4.7) 3.1 years (95% CI: 0.6-4.5) P=0.48
  12. 12. BR = bendamustine hydrochloride/rituximab; DRC = dexamethasone/rituximab/cyclophosphamide; PFS = progression-free survival. Paludo, Abeykoon, Shreders et al, 2018. In contrast to ibrutinib, the MYD88 mutation status does not appear to impact the activity of BR or DRC A trend towards superior PFS was seen with the use of BR, without associated increased toxicity MYD88 Mutation Status and Chemotherapy Treatment of WM
  13. 13. MYD88 and Transformation Risk Of 1,147 patients with WM, 50 patients (4.3%) transformed to a high-grade lymphoma, with a median time to transformation of 4.5 years from dx of WM Transformation risk was higher in patients with MYD88WT status (odds ratio 6.1) MYD88WT status alone was an independent predictor of transformation MYD88WT status was independently associated with shorter time to transformation and a 5-year transformation rate of 16% for MYD88WT versus 2.8% for MYD88L265P-mutated patients (HR 7.9) dx = diagnosis; HR = hazard ratio. Zanwar et al, 2020.
  14. 14. Impact of MYD88L265P on Histological Transformation of WM MDS = myelodysplastic syndromes; t-MDS = therapy-related MDS; AML = acute myeloid leukemia. Paludo, Abeykoon, Shreder et al, 2018. Therapy-related MDS or transformation to high-grade lymphoma occurred in 5 (8%) patients at a median of 30 months (range 17-59) after BR and 5 (5%) patients at a median of 7 months (range 5-12) after DRC (P=0.5) Of the patients who developed t-MDS or transformed to high-grade lymphoma, 4 patients in the BR group and 5 in the DRC group also received alkylating agents and/or nucleoside analogs No patients with t-MDS progressed to AML
  15. 15. We Should Know When To Hold It! Hb ≤10g/dL (WM-related) PLT ≤100,000/µL on basis of WM Symptomatic hyperviscosity Moderate-severe peripheral neuropathy Symptomatic cryoglobulinemia or cold agglutinemia, AL amyloidosis, or symptomatic autoimmune- related events attributable to WM Consensus Panel Recommendations for Initiation of Therapy in WM Clinical pearls: There are specific indications for initiation of therapy When in doubt, observe and monitor the patient closely IgM size does not matter in an asymptomatic patient, and high IgM level alone does not justify starting therapy IPSSWM staging is relevant only in patients with active WM Hb = hemoglobin; PLT = platelet; AL = amyloid light chain; IPSSWM = International Prognostic Scoring System for Waldenstrom Macroglobulinemia. Abeykoon, Zanwar et al, 2018; Kyle et al, 2003.
  16. 16. IPSSWM: International Prognosis Scoring System for WM Age>65 Hemoglobin ≤11.5 g/dL Platelet count ≤100,000/µl B2 microglobulin >3 mg/L Monoclonal IgM concentration >7 g/dL Morel et al, 2009. Factors Associated With Risk Categories for Prognosis Risk category Factors Median survival (months) Low 0 or 1 142.5 Intermediate 2 or age >65 98.6 High >2 43.5
  17. 17. How Common Is Hyperviscosity? When Is Therapy Required? Abeykoon, Zanwar et al, 2018. Patients with IgM levels >6,000 mg/dL who are otherwise asymptomatic can be safely observed Serum viscosity can vary widely among patients with similar IgM levels Serum viscosity, not serum IgM level at the time of diagnosis of WM, appears to be an independent predictor of the time to development of subsequent symptomatic hyperviscosity Survival outcome of patients with WM appears to be unaffected by the development of symptomatic hyperviscosity
  18. 18. Predictors of Symptomatic Hyperviscosity in WM NR = not reached; RR = risk ratio. Abeykoon, Zanwar et al, 2018. Median time to development of active disease in a cohort of patients with smoldering WM with serum IgM >6,000 mg/dL at diagnosis: 6.9 years (95% CI: 1.7-NR) Risk of developing symptomatic hyperviscosity in patients with serum viscosity >1.8 cp: RR 5.5 (95% CI: 1.8-19.9) (P=0.001) Symptomatic hyperviscosity At any point WM disease At WM diagnosis Not at WM diagnosis Without symptomatic at any point during WM disease course Median OS 11.5 years (95% CI: 9.6-14.3) 12.3 years (95% CI: 9.6-NR) 10.5 years (95% CI: 9.1-13.2) 11.6 years (95% CI: 10.7-12.5) P=0.63 P=0.35 P=0.15 -
  19. 19. WM and the Kidney Kidney involvement is seen in 5% of WM patients Most commonly related to amyloidosis (33%), followed by cryoglobulinemia (28%) Patients present with protein in the urine, high blood pressure, and fluid retention Vos et al, 2016; Higgins et al, 2018. When Renal Dysfunction Warrants Treatment
  20. 20. Death Due to WM Versus Other Causes of Death Dalal et al, 2020.
  21. 21. Rituximab Flare Ghobrial et al, 2004. Initial Upsurge in IgM Levels After Rituximab Treatment in Patients With WM
  22. 22. Bendamustine/Rituximab Becomes SOC for First-Line Treatment R-CHOP = rituximab/cyclophosphamide/doxorubicin/vincristine sulfate/prednisone; R = rituximab. Rummel et al, 2013; Gertz, 2018. 41 patients with WM (22 received bendamustine/rituximab, and 19 received R-CHOP) In both groups, the response rate was 95% The median PFS for R-CHOP was 36 months versus not reached with bendamustine/R (P0.0001) At analysis, there were 4 relapses (18%) in the bendamustine/R group and 11 relapses (58%) in the R-CHOP group
  23. 23. MRR ORR Clinical pearl: do not mistake “IgM flare” and “IgM rebound” for progression How Do We Assess Response to Treatment in WM? PD = progressive disease; BM = bone marrow; CR = complete response; IWWM = International Workshop on Waldenström's Macroglobulinemia; MR = minor response; PR = partial response; SD = stable disease; VGPR = very good partial response; MRR = major response rate; ORR = overall response rate. Owen et al, 2013; Kimby et al, 2006.
  24. 24. Response Depth Does Not Predict Overall Survival in WM TNT = time to next treatment. Guidez et al, 2018. 119 consecutive patients analyzed; 72 deaths Median age 70; Hb 9.4 g/dL Both PFS and TNT predicted OS but not response depth including minor response Cox Model for Survival After First Treatment Initiation Event of interest HR HR (95% CI) P Onset of first progression 2.94 (1.22-7.81) 0.02 Onset of second 2.56 (1.38-4.89) 0.006
  25. 25. How Long Responses Last Until New Therapy Is Required Adapted from Willian G. Wienda, MD; Paludo, Abeykoon, Ansell et al, 2018.
  26. 26. Clinically Relevant End Points Based on Treatment Regimen aAll bold P values are <0.005, ie, they are statistically significant. R-benda = rituximab/bendamustine; BDR = bortezomib/dexamethasone/rituximab. Abeykoon et al, 2021. Parameters R-benda DRC BDR P valuea Overall response rate 98% 78% 84% 0.003 MRR 96% 53% 68% <0.001 Event-free survival, range, years (95% CI) NR (4.4-NR) 4.3 (2.4-5.8) 1.6 (0.6-5.6) <0.001 PFS, years (95% CI) 5.2 (4.5-NR) 4.3 (3.0-5.9) 1.8 (0.8-6.8) 0.001 TTNT, years (95% CI) NR (4.5-NR) 4.4 (3.0-5.9) 2.6 (0.9-6.9) 0.001 Time to best response, range, months (95% CI) 4.5 (3.8-5.1) 5.9 (4.8-7.6) 6.7 (5.1-9.0) 0.005 Duration of response, range, years (95% CI) NR (4.5-NR) 3.9 (1.8-6.3) 3.6 (1.0-NR) 0.001 4-year overall survival 90% 87% 87% 0.8
  27. 27. Frontline Treatment: R-Benda Versus DRC or BDR EFS = event-free survival. Abeykoon et al, 2021. ORR, MRR, TTNT, and EFS with frontline R-benda are superior in comparison with frontline DRC or BDR in patients with WM OS was similar for the patients in the 3 groups MYD88L265P mutation did not affect outcomes with any of the 3 regimens Toxicity profile across the 3 groups was comparable barring higher neuropathy, which led to premature treatment discontinuation in 15% of patients receiving BDR
  28. 28. Rituximab Maintenance in Macroglobulinemia NS = not significant. Rummel et al, 2019. Median progression-free survival for patients treated with R-benda: 78 months 218 randomized to R for 2 years versus observation Estimated 5-year survival: 78% 1 AML; 1 MDS (0.7%) PFS: 101 versus 83 months (P=0.32); OS (P=NS)
  29. 29. Proteasome Inhibitor–Based Primary Therapy BCR = bortezomib/cyclophosphamide/rituximab; CaRD = carfilzomib/rituximab/dexamethasone; FCR = fludarabine/cyclophosphamide/rituximab; IDR = ixazomib/dexamethasone/rituximab. Kapoor, 2017. Number of patients Regimen ORR (%) ≥PR/CR (%) TTNT PFS (months) OS (months) 26 Bortezomib/ rituximab 89% 66%/4% NR NR 96% at 1 year 23 BDR (WMCTG) 96% 91%/17% - 57% at 5 95% at 5 59 BDR (EMN) 85% 68%/3% 73 43 66% at 7 42 BCR 98% 79%/2% - - - 17 FCR (R2W) 82% 77%/0% - - - 31 CaRD 87% 67%/3% - NR - 26 IDR 88% 50%/0% - - -
  30. 30. Slide courtesy of the American Association for Cancer Research, 2018. Castillo, Meid et al, 2018. First-Line Therapy: Ixazomib/Dexamethasone/Rituximab
  31. 31. Weekly Ofatumumab Weekly 16 doses (90% prior R) 22/37 (59%) ≥PR 2/22 IgM flare Median PFS: 536 days Furman et al, 2017. Non-Chemotherapeutic Option for WM
  32. 32. Non–BTK Inhibitor–Based Primary Therapy for WM Gertz et al, 2004; Treon et al, 2005; Dimopoulos et al, 2002; Dimopoulos et al, 2007; Kastritis et al, 2015; Rummel et al, 2013; Rummel et al, 2019; Dimopoulos et al, 2013; Gavriatopoulou et al, 2017, Kapoor, 2017. Regimen ORR MRR PFS (months) OS Rituximab x4-8 52%-66% 35%-48% 16-18 NR DRC (dex/rituximab/cyclophosphamide) 83% 74% 35 64% at 8 years Rituximab/bendamustine 91%-93% 90% 65-70 78% at 5 years BDR (bortezomib/rituximab/dex) 85% 68% 43 66% at 7 years
  33. 33. How About Ibrutinib? Median 2 prior treatments Intended therapy consisted of 420 mg of oral ibrutinib daily for 2 years Median time to response of 4 weeks; median IgM 3,610- 1,340; Hb 10.5-12.6 g/dL Diarrhea, bleeding, atrial fibrillation (10.7%) Treon et al, 2013; Gustine et al, 2016. BTK Inhibitor Therapy Efficacy Response rate: 61.9% (95% CI: 48.8-73.9) PR: 50.8% VGPR: 11.1% Median duration of response: not reached 2.8+-18.8+ months)
  34. 34. Ibrutinib for Newly Diagnosed WM Treon et al, 2017. 30 newly diagnosed patients who received ibrutinib The major response rate was 80%, with no difference between patients with wild-type or mutated CXCR4
  35. 35. Practical Considerations for Ibrutinib CYP3A = cytochrome P450 3A; NSAIDs = nonsteroidal anti-inflammatories; EMA = European Medicines Agency. Gustine et al, 2018; Fuerst, 2017. Check MYD88 mutation status prior to initiating ibrutinib monotherapy Recommend pharmacy consult prior to initiation due to CYP3A-interacting meds Bleeding risk: 3% major Avoid in combination with warfarin if possible Instruct not to take with NSAIDs, fish oil, Seville oranges, grapefruit, and starfruit Need to stop 3 days prior to minor surgery and 7 days prior to major surgery 10% risk of atrial fibrillation 20% risk of hypertension Approved as primary therapy in WM by the FDA, Health Canada, and the EMA Should not be stopped unless toxicity or progression is suspected Increases in IgM and reductions in Hb can occur if ibrutinib is held (not to be regarded as treatment failure) Its optimal use continues to be a subject of investigation
  36. 36. Dimopoulos et al, 2018. Best Response Rates and a Comparison of IgM Levels. Ibrutinib/Rituximab Response Rates
  37. 37. Ibrutinib Is Effective for Bing-Neel Syndrome Multiple case reports of significant benefit using ibrutinib for central nervous system macroglobulinemia Ibrutinib is able to cross the blood-brain barrier In 28 patients with Bing-Neel syndrome symptoms, 5 patients (18%) had resolution, 19 (68%) had improvement, and 4 (14%) had no changes Castillo et al, 2019.
  38. 38. Monitoring and Managing Adverse Events Monitor IgM to detect IgM flare in Cycles 1 and 2 EKG monitoring for atrial fibrillation Track for onset of peripheral neuropathy CBC monitoring for myelosuppression requiring dose modification Inquire about rash, swelling, joint pain, bleeding, pneumonia EKG = electrocardiogram; CBC = complete blood count. Paydas, 2019; Gustine et al, 2018. Strategies for Novel Therapies for WM
  39. 39. ACE-WM-001: Acalabrutinib Phase 2 Trial Second-generation BTK inhibitor TNWM n=14; RRWM n=92 Dose: 100 mg PO BID ORR 93% for both populations MRR 79% in TN and 78% in RRWM VGPR 0% in TN and 9% in RRWM 2-yr PFS 90% in TN and 82% in RRWM 2-yr OS 92% in TN and 89% in RRWM AEs: headache (39%), diarrhea (33%), contusion 29%, dizziness 25%, fatigue 23%, nausea 23%, URTI 22%, constipation 22%, arthralgia 20% TNWM = treatment-naive WM; RRWM = relapsed/refractory WM; PO = orally; BID = twice daily; TN = treatment naive; AE = adverse event; URTI = upper respiratory tract infection. Owen et al, 2020. Acalabrutinib Is Active as Single-Agent Therapy
  40. 40. ACE-WM-001: Acalabrutinib Phase 2 Trial (cont.) 14 newly diagnosed; 92 R/R disease; median 2 prior therapies; median 6.1 years following diagnosis; median time from last therapy 16 months NDWM RR 93%; RRWM RR 93% Grade ≥3 neutropenia 16%; grade ≥3 pneumonia 7% Grade ≥3 bleeding 3% Grade ≥3 AF 1% Adverse events leading to discontinuation of therapy 7% 100 mg BID R/R = relapsed/refractory; NDWM = newly diagnosed WM; AF = atrial fibrillation. Owen et al, 2020. Acalabrutinib Has a Manageable Safety Profile
  41. 41. ACE-WM-001: Acalabrutinib (cont.) Owen et al, 2020. Response in Newly Diagnosed and Relapsed/Refractory WM Response duration PFS OS
  42. 42. ASPEN: Ibrutinib vs Zanubrutinib aDefined as any grade ≥3 hemorrhage or any-grade central nervous system hemorrhage. bIncluding PT terms of neutropenia, neutrophil count decreased, febrile neutropenia, agranulocytosis, neutropenic infection, and neutropenic sepsis. PT = pooled terms. Tam et al, 2020; Tam et al, unpublished data, 2021. Phase 3 Trial AE Categories of Interest (BTKi Class AEs) With Additional 5 Months of Follow-Up
  43. 43. ASPEN: Ibrutinib Versus Zanubrutinib * = Excluded 2 patients with VGPR by IRC: MR (EMD present) and PR (IgM assessment by local SPEP M-protein.) ☨ = Adjusted for stratification factors and age group. P value is for descriptive purpose only. EMD = extramedullary disease; IRC = independent review committee; SPEP = serum protein electrophoresis. Tam et al, 2020; Tam et al, unpublished data, 2021. Secondary Efficacy End Points Area under the curve (AUC) for IgM reduction over time was significantly greater for zanubrutinib versus ibrutinib (P=0.037)
  44. 44. 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% 87% 33% 2-year 81% Phase 3 (ASPEN): zanubrutinib vs ibrutinib 19/102 18/99 94% 89% 67% 73% 26% 17% 1-year 94% 1-year 78% ASPEN ARM C: zanubrutinib (MYD88WT) 5 80% 40% 20% 1.5-year 60% BTK Inhibitor–Based Primary Therapy for WM Treon et al, 2018; Dimopoulos et al, 2018; Buske et al, 2020; Owen et al, 2020; Sekiguchi et al, 2020; Trotman et al, 2020; Tam et al, 2020; Dimopoulos et al, 2020.
  45. 45. Efficacy and Safety of Orelabrutinib in RRWM TRAE = treatment-related AE; IQR = interquartile range. Zhou et al, 2021. Orelabrutinib is a novel, highly potent small-molecule inhibitor of BTK The proportion of patients with MYD88L265P CXCR4WT was 83% ORR was 87.2%; 97.9% patients achieved disease control Decline in the serum IgM levels from baseline was observed, with a median reduction by 79.0% (IQR: -89.4, -57.2) There was no reported grade ≥3 atrial fibrillation, atrial flutter, or diarrhea. Only 1 TRAE (2.1%) resulted in drug discontinuation
  46. 46. Bendamustine/Rituximab/Bortezomib for RRWM Second-line therapy Treatment plan provided: rituximab 375 mg/m2 intravenously on Day 1 followed by intravenous bendamustine 90 mg/m2 on Days 1 and 2 and subcutaneous bortezomib 1.3 mg/m2 on Days 1, 8, 15, and 22 (every 28 days for 6 months) ORR (CR+VGPR+PR) of 82% (95% CI: 66-92) PFS was 84% (95% CI: 68-92%) at 18 months, 81% (95% CI: 65-91) at 24 months, and 79% (95% CI: 62-89) at 30 months Benevolo et al, 2021. Novel Combination With Potential for Deep Antitumor Activity
  47. 47. Venetoclax in RRWM 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) BTKi = BTK inhibitor. Castillo, Gustine et al, 2018. Option for R/R Patients, Including Patients Treated With BTKi
  48. 48. • IgM MGUS (<10% lymphoplasmacytic infiltration) • Asymptomatic/smoldering WM • Hemoglobin ≥11 g/dL • Platelets ≥120x109/L • Bulky disease • Profound cytopenias - Hemoglobin ≤10 g/dL - Platelets <100x109/L • Constitutional symptoms • Hyperviscosity symptoms Single-agent rituximabb (1 cycle, no maintenance therapy) Observation Hyperviscosity symptoms Yes No Plasmapheresis Bendamustine/rituximab (BR)a x4-6 cycles No rituximab maintenance therapy Consensus for Newly Diagnosed WM aDexamethasone/rituximab/cyclophosphamide (DRC) x6 cycles is an alternative if the disease burden is low. bPlasmapheresis if hyperviscosity develops with treatment. Ansell et al, 2010. • IgM-related neuropathy • WM-associated hemolytic anemia • Symptomatic cryoglobulinemia
  49. 49. When To Treat Relapsed Disease Ghobrial et al, 2004; Paludo, Abeykoon, Ansell et al, 2018; Treon et al, 2015. Symptomatic disease or significant cytopenias Same indications as for initial therapy Notes Rituximab-induced IgM flare ≠ failure of prior treatment IgM response lag ≠ failure of prior treatment BM response lag (ibrutinib) ≠ failure of prior treatment
  50. 50. When To Repeat the Previous Treatment Gertz, 2021; Dimopoulos & Kastritis, 2019. Prolonged disease response (3-4 years) with prior fixed-duration therapy May consider repeating the same regimen Notes Consider previous toxicity/tolerability issues Consider new comorbidities since previous treatment
  51. 51. Treatment Options in RRWM FCR = fludarabine/cyclophosphamide/rituximab; FR = fludarabine/rituximab. Kapoor et al, 2017; Gertz, 2021; Dimopoulos & Kastritis, 2019. Same options available for initial therapy Preferred/commonly used: BR, DRC, BDR, BTKi Newer options/less commonly used: Ibrutinib/R, ixazomib/dex/R, venetoclax, everolimus/bortezomib/R, everolimus Least preferred/historical use: R-CHOP, FCR, FR, chlorambucil, fludarabine, cladribine
  52. 52. Treatment Options in RRWM (cont.) SQ = subcutaneous. Kapoor, 2017; Gertz, 2020; Dimopoulos & Kastritis, 2019. Notes BR 4-6 cycles, preferred option at Mayo Clinic DRC Lower disease burden, low toxicity BDR Caution if peripheral neuropathy present; SQ bortezomib preferred BTKi (ibrutinib, acalabrutinib, zanubrutinib) Comparable efficacy Zanubrutinib: ↓ AF, ↑ neutropenia Ibrutinib: Bing-Neel syndrome Ibrutinib/rituximab If considering ibrutinib in MYD88WT patients Venetoclax Relapse after BTKi
  53. 53. Efficacy of Vaccine BNT162b2 (Pfizer-BioNTech) in WM Each data point represents an individual’s anti-spike IgG response to BNT162b2, 21 days post–first dose, as measured by flow cytometry. (A) compares mean anti-spike IgG difference between the whole WM (n=34) and FL (n=34) cohorts and healthy volunteer controls (n=13). (B) compares mean anti-spike IgG difference between the difference treatment cohorts of WM and FL. Beaton et al, 2021.
  54. 54. Zanubrutinib, ibrutinib/rituximab, acalabrutinib, or ibrutinibcontinuously until progression/intolerable side effects Bendamustine/rituximab (BR) x4-6 cycles Dexamethasone/rituximab/cyclophosphamide (DRC) x6 cycles Repeat original therapy Bortezomib (weekly, SQ)/dexamethasone/rituximab (BDR) x5 cycles Autologous stem cell transplantation (ASCT) in select patients Carfilzomib Fludarabine Cladribine Everolimus Venetoclax Alemtuzumab Asymptomatic • Bulky disease • Profound cytopenias • Hemoglobin ≤10 g/dL • Platelets <100x109/L • Hyperviscosity symptoms • Constitutional symptoms RRWM Observe WM Salvage Therapy Gertz, 2021.
  55. 55. Key Takeaways There are specific indications for initiation of therapy When in doubt, observe and monitor the patient closely IgM size does not matter in an asymptomatic patient, and high IgM level alone does not justify starting therapy ISSWM staging is relevant only in patients with active WM
  56. 56. Case Study 1 nl = normal. 67-year-old man, past history not contributory Referred when on routine physical; total protein was 9.1 g/dL with SPE showing the following: M spike 2.2 g/dL Quantitative Ig: IgM 2,700; IgA 75; IgG 1,800 Complains of easy fatiguability Hb 15.2; WBC 4.4; platelets 265; metabolic panel normal Viscosity 2.2; marrow 30%; LPL MYD88–mutated; CXCR4WT No neuropathy, eye grounds nl
  57. 57. Case Study 1 (cont.) Which of the following do you recommend? A. Ibrutinib/R B. Zanubrutinib C. Bortezomib/R D. Bendamustine/R E. Repeat testing in 3 months
  58. 58. Case Study 1 (cont.) 6276274 IgM (mg/dL) Hemoglobin (g/dL) Time (years)
  59. 59. Case Study 1 (cont.) IgM (mg/dL) Time (years)
  60. 60. Case Study 1 (cont.) Hemoglobin (g/dL) Time (years)
  61. 61. gertm@mayo.edu @moriegertz
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