Waldenström macroglobulinemia

Back to Top
Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!
Note: this page has regimens which are specific to Waldenström macroglobulinemia, including lymphoplasmacytic lymphoma (LPL). Please see the indolent lymphoma page for other regimens that have been tested in the broader population.
*We have moved How I Treat articles to a dedicated page.
Last updated on 2024-12-02:26 regimens on this page
30 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==EMN==
*2018: Gavriatopoulou et al. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias EuroPMC
==ESMO==
*2018: Kastritis et al. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2013: Buske et al. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
==IWWM==
*2020: Castillo et al. Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia EuroPMC
*2016: Leblond et al. Treatment recommendations from the Eighth International Workshop on Waldenström’s Macroglobulinemia EuroPMC
*2014: Dimopoulos et al. Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus EuroPMC
*2009: Dimopoulos et al. Update on treatment recommendations from the Fourth International Workshop on Waldenström's Macroglobulinemia EuroPMC
*2006: Treon et al. Update on treatment recommendations from the Third International Workshop on Waldenström's Macroglobulinemia EuroPMC
==mSMART==
*2017: Kapoor et al. Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016 EuroPMC
**2010: Ansell et al. Diagnosis and management of Waldenström macroglobulinemia: Mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines EuroPMC
==NCCN==
NCCN Guidelines - Waldenström's Macroglobulinemia / Lymphoplasmacytic Lymphoma
*2024: Kumar et al. Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology EuroPMC
*2012: Anderson et al. Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma, version 2.2013. EuroPMC
=First-line therapy, randomized data=
==Chlorambucil monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Leblond et al. 2012 (WM1)	2001-2009 	Phase 3 (E-switch-ic)	Fludarabine	Might have lower ORR (primary endpoint)ORR: 38.6% vs 47.8%Seems to have shorter OS (secondary endpoint)Median OS: 69.8 vs NYR mo(HR not reported, p=0.014)
====Eligibility criteria====
*At least 18 years old with previously untreated WM and an Eastern Cooperative Oncology Group (ECOG) performance status score less than or equal to 2
====Chemotherapy====
*Chlorambucil (Leukeran) by the following age-based criteria:
**75 years old or younger: 8 mg/m2 PO once per day on days 1 to 10
**Older than 75 years old: 6 mg/m2 PO once per day on days 1 to 10
====Supportive therapy====
*Recommended PCP prophylaxis with ONE of the following:
**Trimethoprim/Sulfamethoxazole (Bactrim SS) 1 tablet PO once per day
**Pentamidine (Nebupent) 300 mg inhaled once per month
28-day cycle for up to 12 cycles
===References===
# WM1: Leblond V, Johnson S, Chevret S, Copplestone A, Rule S, Tournilhac O, Seymour JF, Patmore RD, Wright D, Morel P, Dilhuydy MS, Willoughby S, Dartigeas C, Malphettes M, Royer B, Ewings M, Pratt G, Lejeune J, Nguyen-Khac F, Choquet S, Owen RG. Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated waldenstrom macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol. 2013 Jan 20;31(3):301-7. Epub 2012 Dec 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00566332; NCT00608374
==DRC==
DRC: Dexamethasone, Rituximab, Cyclophosphamide 
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Dimopoulos et al. 2007 (ECWM-1 phase 2)	2002-2006 	Phase 2 	 	
Awaiting publication (RAINBOWWM) 	2020-2029 	Phase 3 (C)	RI 	TBD if different co-primary endpoints of ORR6/PFS
Note: The body text of Dimopoulos et al 2007 said that the regimen is given for "six courses," whereas the abstract says that it is given for 6 months." To our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg IV once on day 1, given first
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO twice per day on days 1 to 5 (total dose per cycle: 1000 mg/m2) 
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1, given second
21-day cycle for 6 cycles
===References===
# ECWM-1 phase 2: Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Zervas K, Tsatalas C, Kokkinis G, Repoussis P, Symeonidis A, Delimpasi S, Katodritou E, Vervessou E, Michali E, Pouli A, Gika D, Vassou A, Terpos E, Anagnostopoulos N, Economopoulos T, Pangalis G. Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007 Aug 1;25(22):3344-9. Epub 2007 Jun 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01788020
## Update: Kastritis E, Gavriatopoulou M, Kyrtsonis MC, Roussou M, Hadjiharissi E, Symeonidis A, Repoussis P, Michalis E, Delimpasi S, Tsatalas K, Tsirigotis P, Vassou A, Vervessou E, Katodritou E, Gika D, Terpos E, Dimopoulos MA. Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenström macroglobulinemia: final analysis of a phase 2 study. Blood. 2015 Sep 10;126(11):1392-4. link to original article EuroPMC
#RAINBOWWM: NCT04061512
==DRC (SC rituximab)==
DRC: Dexamethasone, Rituximab, Cyclophosphamide 
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Buske et al. 2023 (ECWM-1)	Not reported 	Phase 3 (C)	B-DRC 	Did not meet primary endpoint of PFSPFS24: 72.8% vs 80.6%(HR not reported)
Note: To our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO twice per day on days 1 to 5 (total dose per cycle: 1000 mg/m2) 
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once on day 1
*Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
**Cycles 2 to 6: 1400 SC once on day 1
28-day cycle for 6 cycles
===References===
#ECWM-1: Buske C, Dimopoulos MA, Grunenberg A, Kastritis E, Tomowiak C, Mahé B, Troussard X, Hajek R, Viardot A, Tournilhac O, Aurran T, Lepretre S, Zerazhi H, Hivert B, Leblond V, de Guibert S, Brandefors L, Garcia-Sanz R, Gomes da Silva M, Kimby E, Schmelzle B, Kaszynski D, Dreyhaupt J, Muche R, Morel P. Bortezomib-Dexamethasone, Rituximab, and Cyclophosphamide as First-Line Treatment for Waldenström's Macroglobulinemia: A Prospectively Randomized Trial of the European Consortium for Waldenström's Macroglobulinemia. J Clin Oncol. 2023 May 10;41(14):2607-2616. Epub 2023 Feb 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01788020
==Fludarabine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Leblond et al. 2012 (WM1)	2001-2009 	Phase 3 (E-switch-ic)	Chlorambucil	Might have higher ORR (primary endpoint)ORR: 47.8% vs 38.6%Seems to have longer OS (secondary endpoint)Median OS: NYR vs 69.8 mo(HR not reported, p=0.014)
====Eligibility criteria====
*At least 18 years old with previously untreated WM and an Eastern Cooperative Oncology Group (ECOG) performance status score less than or equal to 2
====Chemotherapy====
*Fludarabine (Fludara) by the following age-based criteria:
**75 years old or younger: 40 mg/m2 PO once per day on days 1 to 5
**Older than 75 years old: 30 mg/m2 PO once per day on days 1 to 5
====Supportive therapy====
*Recommended PCP prophylaxis with ONE of the following:
**Trimethoprim/Sulfamethoxazole (Bactrim SS) 1 tablet PO once per day 
**Pentamidine (Nebupent) 300 mg inhaled once per month
*Varicella zoster (shingles) prophylaxis with ONE of the following:
**Valacyclovir (Valtrex) 500 mg PO once per day 
**Acyclovir (Zovirax) 200 to 400 mg PO twice per day 
28-day cycle for up to 6 cycles
===References===
# WM1: Leblond V, Johnson S, Chevret S, Copplestone A, Rule S, Tournilhac O, Seymour JF, Patmore RD, Wright D, Morel P, Dilhuydy MS, Willoughby S, Dartigeas C, Malphettes M, Royer B, Ewings M, Pratt G, Lejeune J, Nguyen-Khac F, Choquet S, Owen RG. Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated waldenstrom macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol. 2013 Jan 20;31(3):301-7. Epub 2012 Dec 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00566332; NCT00608374
==Ibrutinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Treon et al. 2018 (DFCI 15-359)	2016 	Phase 2 	 	
Tam et al. 2020 (ASPEN) 	2017-01 to 2018-07 	Phase 3 (C)	Zanubrutinib 	Seems to have lower composite CR/VGPR rate1
Awaiting publication (CZAR-1) 	2021-2028 	Phase 3 (C)	Carfilzomib & Ibrutinib	TBD if different composite primary endpoint of CR/VGPR rate
1Reported efficacy is based on the 2022 abstract update.
====Biomarker eligibility criteria====
*ASPEN: MYD88 p.L265P
====Targeted therapy====
*Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
28-day cycles
===References===
# DFCI 15-359: Treon SP, Gustine J, Meid K, Yang G, Xu L, Liu X, Demos M, Kofides A, Tsakmaklis N, Chen JG, Munshi M, Chan G, Dubeau T, Raje N, Yee A, O'Donnell E, Hunter ZR, Castillo JJ. Ibrutinib monotherapy in symptomatic, treatment-naïve patients with Waldenström macroglobulinemia. J Clin Oncol. 2018 Sep 20;36(27):2755-2761. Epub 2018 Jul 25. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02604511
#ASPEN: Tam CS, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Sanz RG, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous JV, Motta M, Siddiqi T, Tani M, Trneny M, Minnema MC, Buske C, Leblond V, Trotman J, Chan WY, Schneider J, Ro S, Cohen A, Huang J, Dimopoulos M. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020 Oct 29;136(18):2038-2050. Epub 2020 Jul 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03053440
##Update: Dimopoulos MA, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Garcia-Sanz R, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous J, Motta M, Siddiqi T, Tani M, Trněný M, Minnema MC, Buske C, Leblond V, Treon SP, Trotman J, Chan WY, Schneider J, Allewelt H, Patel S, Cohen A, Tam CS. Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study. J Clin Oncol. 2023 Nov 20;41(33):5099-5106. Epub 2023 Jul 21. link to original article link to PMC article EuroPMC
##HRQoL analysis: Tedeschi A, Tam CS, Owen RG, Buske C, Leblond V, Dimopoulos M, Garcia-Sanz R, Castillo JJ, Trotman J, Treon SP, Yang K, Tang B, Allewelt H, Patel S, Chan WY, Cohen A, Chen S, Barnes G. Health-related quality of life in patients with Waldenström macroglobulinemia: results from the ASPEN trial. Future Oncol. 2024;20(25):1789-1798. Epub 2024 Jul 29. link to original article link to PMC article EuroPMC
#CZAR-1: NCT04263480
==Ibrutinib & Rituximab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016 	Phase 3 (E-RT-esc)	Rituximab 	Longer PFS1 (primary endpoint)Median PFS: NYR vs 20.3 mo(HR 0.25, 95% CI 0.15-0.42)
1Reported efficacy is based on the 2021 update.
====Targeted therapy====
*Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
*Rituximab (Rituxan) as follows:
**Cycles 1 & 5: 375 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles
===References===
# iNNOVATE: Dimopoulos MA, Tedeschi A, Trotman J, García-Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C, Tam C, Orsucci L, Palomba ML, Matous JV, Shustik C, Kastritis E, Treon SP, Li J, Salman Z, Graef T, Buske C; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Phase 3 trial of ibrutinib plus rituximab in Waldenström's macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. Epub 2018 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02165397
##Update: Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. J Clin Oncol. 2022 Jan 1;40(1):52-62. Epub 2021 Oct 4. link to original article link to PMC article EuroPMC
==Rituximab monotherapy==
===Regimen variant #1, single course (4 doses)===
Study 	Dates of enrollment 	Evidence
Gertz et al. 2004 (ECOG E3A98)	2000-04-06 to 2002-01-25	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
7-day cycle for 4 cycles
===Regimen variant #2, "extended" course (8 doses)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Dimopoulos et al. 2002 	1999-2001 	Phase 2 	 	
Dimopoulos et al. 2002a 	1999-2002 	Phase 2, fewer than 20 pts in subgroup	 	
Treon et al. 2005 	Not reported 	Phase 2, fewer than 20 pts in subgroup	 	
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016 	Phase 3 (C) 	Ibrutinib & Rituximab	Shorter PFS1 (primary endpoint)Median PFS: 20.3 vs NYR mo(HR 4.00, 95% CI 2.38-6.67)
Note: In Treon et al. 2005, the second course began at the equivalent of cycle 4.
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycle 5: 375 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycle for 5 cycles
===References===
# Dimopoulos MA, Zervas C, Zomas A, Kiamouris C, Viniou NA, Grigoraki V, Karkantaris C, Mitsouli C, Gika D, Christakis J, Anagnostopoulos N. Treatment of Waldenström's macroglobulinemia with rituximab. J Clin Oncol. 2002 May 1;20(9):2327-33. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Dimopoulos MA, Zervas C, Zomas A, Hamilos G, Gika D, Efstathiou E, Panayiotidis P, Vervessou E, Anagnostopoulos N, Christakis J. Extended rituximab therapy for previously untreated patients with Waldenström's macroglobulinemia. Clin Lymphoma. 2002 Dec;3(3):163-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# ECOG E3A98: Gertz MA, Rue M, Blood E, Kaminer LS, Vesole DH, Greipp PR. Multicenter phase 2 trial of rituximab for Waldenström macroglobulinemia (WM): an Eastern Cooperative Oncology Group Study (E3A98). Leuk Lymphoma. 2004 Oct;45(10):2047-55. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Treon SP, Emmanouilides C, Kimby E, Kelliher A, Preffer F, Branagan AR, Anderson KC, Frankel SR; Waldenström's Macroglobulinemia Clinical Trials Group. Extended rituximab therapy in Waldenström's macroglobulinemia. Ann Oncol. 2005 Jan;16(1):132-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# iNNOVATE: Dimopoulos MA, Tedeschi A, Trotman J, García-Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C, Tam C, Orsucci L, Palomba ML, Matous JV, Shustik C, Kastritis E, Treon SP, Li J, Salman Z, Graef T, Buske C; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Phase 3 trial of ibrutinib plus rituximab in Waldenström's macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. Epub 2018 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02165397
##Update: Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. J Clin Oncol. 2022 Jan 1;40(1):52-62. Epub 2021 Oct 4. link to original article link to PMC article EuroPMC
==Zanubrutinib monotherapy==
===Regimen variant #1===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Tam et al. 2020 (ASPEN)	2017-01 to 2018-07 	Phase 3 (E-RT-switch-ic)	Ibrutinib 	Seems to have higher composite CR/VGPR rate1 (primary endpoint)CR/VGPR rate: 36% vs 22%
1Reported efficacy is based on the 2022 abstract update.
====Biomarker eligibility criteria====
*ASPEN: MYD88 p.L265P
====Targeted therapy====
*Zanubrutinib (Brukinsa) 160 mg PO twice per day on days 1 to 28
28-day cycles
===Regimen variant #2===
FDA-recommended dose
Note: this is not the dosing schedule that was used in the ASPEN study.
====Targeted therapy====
*Zanubrutinib (Brukinsa) 320 mg PO once per day on days 1 to 28
28-day cycles
===References===
#ASPEN: Tam CS, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Sanz RG, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous JV, Motta M, Siddiqi T, Tani M, Trneny M, Minnema MC, Buske C, Leblond V, Trotman J, Chan WY, Schneider J, Ro S, Cohen A, Huang J, Dimopoulos M. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020 Oct 29;136(18):2038-2050. Epub 2020 Jul 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03053440
##Update: Dimopoulos MA, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Garcia-Sanz R, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous J, Motta M, Siddiqi T, Tani M, Trněný M, Minnema MC, Buske C, Leblond V, Treon SP, Trotman J, Chan WY, Schneider J, Allewelt H, Patel S, Cohen A, Tam CS. Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study. J Clin Oncol. 2023 Nov 20;41(33):5099-5106. Epub 2023 Jul 21. link to original article link to PMC article EuroPMC
##HRQoL analysis: Tedeschi A, Tam CS, Owen RG, Buske C, Leblond V, Dimopoulos M, Garcia-Sanz R, Castillo JJ, Trotman J, Treon SP, Yang K, Tang B, Allewelt H, Patel S, Chan WY, Cohen A, Chen S, Barnes G. Health-related quality of life in patients with Waldenström macroglobulinemia: results from the ASPEN trial. Future Oncol. 2024;20(25):1789-1798. Epub 2024 Jul 29. link to original article link to PMC article EuroPMC
=First-line therapy, non-randomized or retrospective data=
==BDR==
BDR: Bortezomib, Dexamethasone, Rituximab
===Regimen variant #1===
Study 	Dates of enrollment 	Evidence
Treon et al. 2009 (WMCTG 05-180)	2005 to not reported	Phase 2
Note: some details are missing in Treon et al. 2009; the updated abstract provides these additional details. As shown here, there is no treatment in "cycle 5", which is an intentional 12-week pause.
====Targeted therapy====
*Bortezomib (Velcade) as follows:
**Cycles 1 to 4: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
**Cycles 6 to 9: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
*Rituximab (Rituxan) as follows:
**Cycles 1 to 4: 375 mg/m2 IV once on day 11
**Cycles 6 to 9: 375 mg/m2 IV once on day 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 4: 40 mg IV once per day on days 1, 4, 8, 11
**Cycles 6 to 9: 40 mg IV once per day on days 1, 4, 8, 11
====Supportive therapy====
*Varicella zoster (shingles) prophylaxis with ONE of the following recommended:
**Valacyclovir (Valtrex) 1000 mg PO once per day
**Acyclovir (Zovirax) 400 mg PO twice per day
*"The use of diphenhydramine, acetaminophen and, at the treating physician's discretion, corticosteroids and/or ranitidine or cimetidine was permitted for rituximab infusion prophylaxis. Granulocyte colony-stimulating factor, erythropoietin, and transfusions of packed RBCs or platelets were permitted to support patient's counts during therapy."
*"The prophylactic use of plasmapheresis was recommended for patients demonstrating an IgM level of greater than or equal to 5000 mg/dL before the administration of rituximab, given the potential for rituximab-mediated IgM flare and aggravation of hyperviscosity."
21-day cycle for 4 cycles, then 12-week cycle for 5 cycles
===Regimen variant #2=== 
Study 	Dates of enrollment	Evidence
Dimopoulos et al. 2013 (BDR-WM)	2007-03 to 2010-06 	Phase 2
Note: The schedule for this regimen can be confusing, in particular the first cycle is 21 days and the remaining cycles are 35 days.
====Targeted therapy====
*Bortezomib (Velcade) as follows:
**Cycle 1: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
**Cycles 2 to 5: 1.6 mg/m2 IV once per day on days 1, 8, 15, 22
*Rituximab (Rituxan) as follows:
**Cycles 2 and 5: 375 mg/m2 IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 2 and 5: 40 mg IV once per day on days 1, 8, 15, 22
====Supportive therapy====
*Acetaminophen (Tylenol) 1000 mg PO once per day on days 1, 8, 15, 22, prior to rituximab
*Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22, prior to rituximab
*Varicella zoster (shingles) prophylaxis with ONE of the following:
**Valacyclovir (Valtrex) (dose not specified)
**Acyclovir (Zovirax) (dose not specified)
21-day course, then 35-day cycle for 4 cycles
===References===
# WMCTG 05-180: Treon SP, Ioakimidis L, Soumerai JD, Patterson CJ, Sheehy P, Nelson M, Willen M, Matous J, Mattern J 2nd, Diener JG, Keogh GP, Myers TJ, Boral A, Birner A, Esseltine DL, Ghobrial IM; WMCTG. Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol. 2009 Aug 10;27(23):3830-5. Epub 2009 Jun 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC content property of HemOnc.org NCT00250926
## Update: Abstract: Steven P Treon, Kirsten Meid, Joshua Gustine, Christopher J Patterson, Jeffrey V. Matous, Irene M. Ghobrial, Jorge J Castillo. Long-Term Outcome of a Prospective Study of Bortezomib, Dexamethasone and Rituximab (BDR) in Previously Untreated, Symptomatic Patients with Waldenstrom's Macroglobulinemia. Blood 2015 126:1833. link to abstract 
# BDR-WM: Dimopoulos MA, García-Sanz R, Gavriatopoulou M, Morel P, Kyrtsonis MC, Michalis E, Kartasis Z, Leleu X, Palladini G, Tedeschi A, Gika D, Merlini G, Kastritis E, Sonneveld P. Primary therapy of Waldenstrom's macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone and rituximab (BDR): long term results of a phase II study of the European Myeloma Network (EMN). Blood. 2013 Nov 7;122(19):3276-82. Epub 2013 Sep 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00832234
## Update: Gavriatopoulou M, García-Sanz R, Kastritis E, Morel P, Kyrtsonis MC, Michalis E, Kartasis Z, Leleu X, Palladini G, Tedeschi A, Gika D, Merlini G, Sonneveld P, Dimopoulos MA. BDR in newly diagnosed patients with WM: final analysis of a phase 2 study after a minimum follow-up of 6 years. Blood. 2017 Jan 26;129(4):456-459. Epub 2016 Nov 21. link to original article EuroPMC
==CaRD==
CaRD: Carfilzomib, Rituximab, Dexamethasone
===Regimen===
Study 	Dates of enrollment 	Evidence
Treon et al. 2014 (DFCI 11-279)	2011 to not reported	Phase 2
====Targeted therapy====
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV over 20 minutes once per day on days 1, 2, 8, 9 
**Cycles 2 to 6: 36 mg/m2 IV over 30 minutes once per day on days 1, 2, 8, 9
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 2 & 9, given third
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg IV once per day on days 1, 2, 8, 9
====Supportive therapy====
*Acyclovir (Zovirax) 400 mg PO twice per day for duration of therapy and continue for 6 months
*Famotidine (Pepcid) 20 mg PO twice per day during active therapy
*Dexamethasone (Decadron) 10 mg PO the night prior to rituximab was recommended
*Prophylactic plasmapheresis and hold on rituximab was recommended for patients demonstrating an IgM level of greater than or equal to 4000 mg/dL
21-day cycle for 6 cycles
====Subsequent treatment====
*DFCI 11-279, patients with SD or better: CaRD maintenance, beginning 8 weeks later
===References===
# DFCI 11-279: Treon SP, Tripsas CK, Meid K, Kanan S, Sheehy P, Chuma S, Xu L, Cao Y, Yang G, Liu X, Patterson CJ, Warren D, Hunter ZR, Turnbull B, Ghobrial IM, Castillo JJ. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia. Blood. 2014 Jul 24;124(4):503-10. Epub 2014 May 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01470196
==Everolimus monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Treon et al. 2016 (WMCTG 09-214)	2009-2011 	Phase 2
====Targeted therapy====
*Everolimus (Afinitor) 10 mg PO once per day on days 1 to 28
28-day cycles
===References===
# WMCTG 09-214: Treon SP, Meid K, Tripsas C, Heffner LT, Eradat H, Badros AZ, Xu L, Hunter ZR, Yang G, Patterson CJ, Gustine J, Castillo JJ, Matous J, Ghobrial IM. Prospective, multicenter clinical trial of everolimus as primary therapy in Waldenstrom macroglobulinemia (WMCTG 09-214). Clin Cancer Res. 2017 May 15;23(10):2400-2404. Epub 2016 Nov 11. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00976248
==Fludarabine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Dhodapkar et al. 2001 (SWOG S9003)	1992-1998 	Phase 2
====Chemotherapy====
*Fludarabine (Fludara) 30 mg/m2 PO once per day on days 1 to 5
28-day cycle for 4 to 8 cycles
===References===
# SWOG S9003: Dhodapkar MV, Jacobson JL, Gertz MA, Rivkin SE, Roodman GD, Tuscano JM, Shurafa M, Kyle RA, Crowley JJ, Barlogie B. Prognostic factors and response to fludarabine therapy in patients with Waldenström macroglobulinemia: results of United States intergroup trial (Southwest Oncology Group S9003). Blood. 2001 Jul 1;98(1):41-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Dhodapkar MV, Jacobson JL, Gertz MA, Crowley JJ, Barlogie B. Prognostic factors and response to fludarabine therapy in Waldenstrom's macroglobulinemia: an update of a US intergroup trial (SW0G S9003). Semin Oncol. 2003 Apr;30(2):220-5. link to original article EuroPMC 
## Update: Dhodapkar MV, Hoering A, Gertz MA, Rivkin S, Szymonifka J, Crowley J, Barlogie B. Long-term survival in Waldenstrom macroglobulinemia: 10-year follow-up of Southwest Oncology Group-directed intergroup trial S9003. Blood. 2009 Jan 22;113(4):793-6. Epub 2008 Oct 17. link to original article link to PMC article EuroPMC
==Fludarabine & Rituximab (FR)==
FR: Fludarabine & Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Treon et al. 2008 (UCLA-0101063)	2001-2003 	Phase 2
====Chemotherapy====
*Fludarabine (Fludara) as follows:
**Cycles 2 to 4: 25 mg/m2 (route not specified) once per day on days 1 to 5
**Cycles 5 to 7: 25 mg/m2 (route not specified) once per day on days 8 to 12
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycle 5: 375 mg/m2 IV once per day on days 1 & 8
**Cycle 8: 375 mg/m2 IV once per day on days 15 & 22
28-day cycle for 8 cycles
===References===
# UCLA-0101063: Treon SP, Branagan AR, Ioakimidis L, Soumerai JD, Patterson CJ, Turnbull B, Wasi P, Emmanouilides C, Frankel SR, Lister A, Morel P, Matous J, Gregory SA, Kimby E. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia. Blood. 2009 Apr 16;113(16):3673-8. Epub 2008 Nov 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00020800
==IDR==
IDR: Ixazomib, Dexamethasone, Rituximab
===Regimen=== 
Study 	Dates of enrollment	Evidence
Castillo et al. 2018 (DFCI 14-559)	2015-2016 	Phase 2
====Targeted therapy====
*Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
*Rituximab (Rituxan) as follows:
**Cycles 3 to 6: 375 mg/m2 IV once on day 1
**Cycles 7 to 12: 375 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15
28-day cycle for 6 cycles, then 56-day cycle for 6 cycles 
===References===
# DFCI 14-559: Castillo JJ, Meid K, Gustine JN, Dubeau T, Severns P, Hunter ZR, Yang G, Xu L, Treon SP. Prospective Clinical Trial of Ixazomib, Dexamethasone, and Rituximab as Primary Therapy in Waldenström Macroglobulinemia. Clin Cancer Res. 2018 Jul 15;24(14):3247-3252. Epub 2018 Apr 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02400437
##Update: Castillo JJ, Meid K, Flynn CA, Chen J, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Patterson CJ, Yang G, Hunter Z, Treon SP. Ixazomib, dexamethasone, and rituximab in treatment-naive patients with Waldenström macroglobulinemia: long-term follow-up. Blood Adv. 2020 Aug 25;4(16):3952-3959. link to original article link to PMC article EuroPMC
==PCR==
PCR: Pentostatin, Cyclophosphamide, Rituximab
PER: Pentostatin, Endoxan (Cyclophosphamide), Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Herth et al. 2014	2005-2010 	Phase 2
====Chemotherapy====
*Pentostatin (Nipent) 4 mg/m2 IV once on day 2
*Cyclophosphamide (Cytoxan) 600 mg/m2 (route not specified) on day 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1 (see dose and schedule modifications)
21-day cycle for 6 cycles
====Subsequent treatment====
*Herth et al. 2014, patients with PR/CR: Rituximab maintenance
====Dose and schedule modifications====
*Rituximab is only given in cycle 1 if WBC count is up to 50 x 109/L
===References===
# Herth I, Hensel M, Rieger M, Horstmann K, Hiddemann W, Dreyling M, Koniczek S, Witzens-Harig M, Ho AD. Pentostatin, cyclophosphamide and rituximab is a safe and effective treatment in patients with Waldenström's macroglobulinemia. Leuk Lymphoma. 2015 Jan;56(1):97-102. Epub 2014 Jun 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Maintenance after first-line therapy=
==CaRD==
CaRD: Carfilzomib, Rituximab, Dexamethasone
===Regimen===
Study 	Dates of enrollment 	Evidence
Treon et al. 2014 (DFCI 11-279)	2011 to not reported	Phase 2
====Preceding treatment====
*CaRD induction x 6 cycles
====Targeted therapy====
*Carfilzomib (Kyprolis) 36 mg/m2 IV once per day on days 1 & 2
*Rituximab (Rituxan) 375 mg/m2 IV once on day 2, given third
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg IV once per day on days 1 & 2
8-week cycle for 8 cycles
===References===
# DFCI 11-279: Treon SP, Tripsas CK, Meid K, Kanan S, Sheehy P, Chuma S, Xu L, Cao Y, Yang G, Liu X, Patterson CJ, Warren D, Hunter ZR, Turnbull B, Ghobrial IM, Castillo JJ. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia. Blood. 2014 Jul 24;124(4):503-10. Epub 2014 May 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01470196
==Rituximab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Herth et al. 2014	2005-2010 	Phase 2
====Preceding treatment====
*PER induction x 6
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
3-month cycle for 8 cycles (2 years)
===References===
# Herth I, Hensel M, Rieger M, Horstmann K, Hiddemann W, Dreyling M, Koniczek S, Witzens-Harig M, Ho AD. Pentostatin, cyclophosphamide and rituximab is a safe and effective treatment in patients with Waldenström's macroglobulinemia. Leuk Lymphoma. 2015 Jan;56(1):97-102. Epub 2014 Jun 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Relapsed or refractory, randomized data=
==Ibrutinib & Rituximab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016 	Phase 3 (E-RT-esc)	Rituximab 	Longer PFS1 (primary endpoint)Median PFS: NYR vs 20.3 mo(HR 0.25, 95% CI 0.15-0.42)
1Reported efficacy is based on the 2021 update.
====Targeted therapy====
*Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
*Rituximab (Rituxan) as follows:
**Cycles 1 & 5: 375 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles
===References===
# iNNOVATE: Dimopoulos MA, Tedeschi A, Trotman J, García-Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C, Tam C, Orsucci L, Palomba ML, Matous JV, Shustik C, Kastritis E, Treon SP, Li J, Salman Z, Graef T, Buske C; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Phase 3 trial of ibrutinib plus rituximab in Waldenström's macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. Epub 2018 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02165397
##Update: Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. J Clin Oncol. 2022 Jan 1;40(1):52-62. Epub 2021 Oct 4. link to original article link to PMC article EuroPMC
==Rituximab monotherapy==
===Regimen variant #1, single course (4 doses)===
Study 	Dates of enrollment 	Evidence
Gertz et al. 2004 (ECOG E3A98)	2000-04-06 to 2002-01-25	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
7-day cycle for 4 cycles
===Regimen variant #2, "extended" course (8 doses)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Dimopoulos et al. 2002 	1999-2001 	Phase 2 	 	
Treon et al. 2005 	Not reported 	Phase 2, fewer than 20 pts in subgroup	 	
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016 	Phase 3 (C) 	Ibrutinib & Rituximab	Shorter PFS1 (primary endpoint)Median PFS: 20.3 vs NYR mo(HR 4.00, 95% CI 2.38-6.67)
Note: In Treon et al. 2005, the second course began at the equivalent of cycle 4.
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycle 5: 375 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycle for 5 cycles
===References===
# Dimopoulos MA, Zervas C, Zomas A, Kiamouris C, Viniou NA, Grigoraki V, Karkantaris C, Mitsouli C, Gika D, Christakis J, Anagnostopoulos N. Treatment of Waldenström's macroglobulinemia with rituximab. J Clin Oncol. 2002 May 1;20(9):2327-33. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# ECOG E3A98: Gertz MA, Rue M, Blood E, Kaminer LS, Vesole DH, Greipp PR. Multicenter phase 2 trial of rituximab for Waldenström macroglobulinemia (WM): an Eastern Cooperative Oncology Group Study (E3A98). Leuk Lymphoma. 2004 Oct;45(10):2047-55. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Treon SP, Emmanouilides C, Kimby E, Kelliher A, Preffer F, Branagan AR, Anderson KC, Frankel SR; Waldenström's Macroglobulinemia Clinical Trials Group. Extended rituximab therapy in Waldenström's macroglobulinemia. Ann Oncol. 2005 Jan;16(1):132-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# iNNOVATE: Dimopoulos MA, Tedeschi A, Trotman J, García-Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C, Tam C, Orsucci L, Palomba ML, Matous JV, Shustik C, Kastritis E, Treon SP, Li J, Salman Z, Graef T, Buske C; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Phase 3 trial of ibrutinib plus rituximab in Waldenström's macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. Epub 2018 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02165397
##Update: Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. J Clin Oncol. 2022 Jan 1;40(1):52-62. Epub 2021 Oct 4. link to original article link to PMC article EuroPMC
=Relapsed or refractory, non-randomized or retrospective data=
==Bendamustine & Rituximab (BR)==
BR: Bendamustine, Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Treon et al. 2011	Not reported 	Retrospective
====Chemotherapy====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on either day 1 or 2
28-day cycles
===References===
# Retrospective: Treon SP, Hanzis C, Tripsas C, Ioakimidis L, Patterson CJ, Manning RJ, Sheehy P. Bendamustine therapy in patients with relapsed or refractory Waldenström's macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):133-5. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
==Everolimus monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Ghobrial et al. 2010 (MC048G)	2006-04 to 2008-08 	Phase 2
====Targeted therapy====
*Everolimus (Afinitor) 10 mg PO once per day on days 1 to 28, taken on an empty stomach
====Supportive therapy====
*WBC growth factors per physician discretion if neutropenia occurred, but it was not to be used prophylactically in order to maintain dosing.
*Erythropoietin for anemia allowed per physician discretion.
28-day cycles
===References===
# MC048G: Ghobrial IM, Gertz M, Laplant B, Camoriano J, Hayman S, Lacy M, Chuma S, Harris B, Leduc R, Rourke M, Ansell SM, Deangelo D, Dispenzieri A, Bergsagel L, Reeder C, Anderson KC, Richardson PG, Treon SP, Witzig TE. Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia. J Clin Oncol. 2010 Mar 10;28(8):1408-14. Epub 2010 Feb 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00436618
## Update: Ghobrial IM, Witzig TE, Gertz M, LaPlant B, Hayman S, Camoriano J, Lacy M, Bergsagel PL, Chuma S, DeAngelo D, Treon SP. Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom Macroglobulinemia. Am J Hematol. 2014 Mar;89(3):237-42. link to original article EuroPMC
==Fludarabine & Rituximab (FR)==
FR: Fludarabine & Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Treon et al. 2008 (UCLA-0101063)	2001-2003 	Phase 2, fewer than 20 pts in subgroup
====Chemotherapy====
*Fludarabine (Fludara) as follows:
**Cycles 2 to 4: 25 mg/m2 (route not specified) once per day on days 1 to 5
**Cycles 5 to 7: 25 mg/m2 (route not specified) once per day on days 8 to 12
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycle 5: 375 mg/m2 IV once per day on days 1 & 8
**Cycle 8: 375 mg/m2 IV once per day on days 15 & 22
28-day cycle for 8 cycles
===References===
# UCLA-0101063: Treon SP, Branagan AR, Ioakimidis L, Soumerai JD, Patterson CJ, Turnbull B, Wasi P, Emmanouilides C, Frankel SR, Lister A, Morel P, Matous J, Gregory SA, Kimby E. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia. Blood. 2009 Apr 16;113(16):3673-8. Epub 2008 Nov 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00020800
==Ibrutinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Treon et al. 2015 (DFCI 12-015) 	2012-2013 	Phase 2 (RT)
Dimopoulos et al. 2016 (iNNOVATE substudy)	2014-2015 	Non-randomized
====Targeted therapy====
*Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
28-day cycle for up to 26 cycles (2 years)
===References===
# DFCI 12-015: Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, Argyropoulos KV, Yang G, Cao Y, Xu L, Patterson CJ, Rodig S, Zehnder JL, Aster JC, Harris NL, Kanan S, Ghobrial I, Castillo JJ, Laubach JP, Hunter ZR, Salman Z, Li J, Cheng M, Clow F, Graef T, Palomba ML, Advani RH. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015 Apr 9;372(15):1430-40. link to original article EuroPMC NCT01614821
## Subgroup analysis: Treon SP, Xu L, Hunter Z. MYD88 mutations and response to ibrutinib in Waldenström's macroglobulinemia. N Engl J Med. 2015 Aug 6;373(6):584-6. link to original article EuroPMC
## Update: Treon SP, Meid K, Gustine J, Yang G, Xu L, Liu X, Patterson CJ, Hunter ZR, Branagan AR, Laubach JP, Ghobrial IM, Palomba ML, Advani R, Castillo JJ. Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia. J Clin Oncol. 2021 Feb 20;39(6):565-575. Epub 2020 Sep 15. link to original article link to PMC article EuroPMC
# iNNOVATE substudy: Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, Tournilhac O, Ma S, Oriol A, Heffner LT, Shustik C, García-Sanz R, Cornell RF, de Larrea CF, Castillo JJ, Granell M, Kyrtsonis MC, Leblond V, Symeonidis A, Kastritis E, Singh P, Li J, Graef T, Bilotti E, Treon S, Buske C; iNNOVATE Study Group and the European Consortium for Waldenström's Macroglobulinemia. Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017 Feb;18(2):241-250. Epub 2016 Dec 9. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02165397
==Lenalidomide monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Fouquet et al. 2015 (RV-WM-0426)	2009 to not reported	Phase 1/2, fewer than 20 pts
Note: This is the MTD determined in the phase 1 portion of the study.
====Targeted therapy====
*Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
28-day cycles
===References===
# RV-WM-0426: Fouquet G, Guidez S, Petillon MO, Louni C, Ohyba B, Dib M, Poulain S, Herbaux C, Martin A, Thielemans B, Brice P, Choquet S, Bakala J, Bories C, Demarquette H, Nudel M, Tournilhac O, Arnulf B, LeGouill S, Morel P, Banos A, Karlin L, Salles G, Leblond V, Leleu X. Lenalidomide is safe and active in Waldenström macroglobulinemia. Am J Hematol. 2015 Nov;90(11):1055-9. Epub 2015 Oct 6. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02302469
==RVR==
RVR: RAD-001 (Everolimus), Velcade (Bortezomib), Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Ghobrial et al. 2015 (DFCI 09-280)	2010-2013 	Phase 1/2
Note: These are the doses of the phase 2 portion of the study.
====Targeted therapy====
*Everolimus (Afinitor) 10 mg PO once per day on days 1 to 28
*Bortezomib (Velcade) as follows:
**Cycles 1 to 6: 1.6 mg/m2 IV once per day on days 1, 8, 15
*Rituximab (Rituxan) as follows:
**Cycles 1 & 4: 375 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles
===References===
# DFCI 09-280: Ghobrial IM, Redd R, Armand P, Banwait R, Boswell E, Chuma S, Huynh D, Sacco A, Roccaro AM, Perilla-Glen A, Noonan K, MacNabb M, Leblebjian H, Warren D, Henrick P, Castillo JJ, Richardson PG, Matous J, Weller E, Treon SP. Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia. Leukemia. 2015 Dec;29(12):2338-46. Epub 2015 Jul 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01125293
==Venetoclax monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Castillo et al. 2021 (DFCI 15-491)	2016-06 to 2018-02 	Phase 2
Note: this dosing is a mid-protocol modification.
====Targeted therapy====
*Venetoclax (Venclexta) as follows:
**Cycle 1: 400 mg PO once per day on days 1 to 7, then 800 mg PO once per day on days 8 to 28
**Cycles 2 to 26: 800 mg PO once per day on days 1 to 28
28-day cycle for up to 26 cycles (2 years)
===References===
#DFCI 15-491: Castillo JJ, Allan JN, Siddiqi T, Advani RH, Meid K, Leventoff C, White TP, Flynn CA, Sarosiek S, Branagan AR, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Xu L, Yang G, Patterson CJ, Hunter ZR, Davids MS, Furman RR, Treon SP. Venetoclax in Previously Treated Waldenström Macroglobulinemia. J Clin Oncol. 2022 Jan 1;40(1):63-71. Epub 2021 Nov 18. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02677324
=Response criteria=
==Current==
*2012: Response assessment in Waldenström macroglobulinaemia: Update from the VIth International Workshop
==Older==
*2003: Uniform response criteria in Waldenstrom's macroglobulinemia: Consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia
Category:Waldenström macroglobulinemia regimens
Category:Disease-specific pages
Category:Indolent lymphomas