title: Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016.
abstract: OBJECTIVE
  Waldenström macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, has witnessed several practice-altering advances in recent years. With availability of a wider array of therapies, the management strategies have become increasingly complex. Our multidisciplinary team appraised studies published or presented up to December 2015 to provide consensus recommendations for a risk-adapted approach to WM, using a grading system.
  
  
  METHODS
  Waldenström macroglobulinemia remains a rare, incurable cancer, with a heterogeneous disease course. The major classes of effective agents in WM include monoclonal antibodies, alkylating agents, purine analogs, proteasome inhibitors, immunomodulatory drugs, and mammalian target of rapamycin inhibitors. However, the highest-quality evidence from rigorously conducted randomized clinical trials remains scant.
  
  
  CONCLUSIONS
  Recognizing the paucity of data, we advocate participation in clinical trials, if available, at every stage of WM. Specific indications exist for initiation of therapy. Outside clinical trials, based on the synthesis of available evidence, we recommend bendamustine-rituximab as primary therapy for bulky disease, profound hematologic compromise, or constitutional symptoms attributable to WM. Dexamethasone-rituximab-cyclophosphamide is an alternative, particularly for nonbulky WM. Routine rituximab maintenance should be avoided. Plasma exchange should be promptly initiated before cytoreduction for hyperviscosity-related symptoms. Stem cell harvest for future use may be considered in first remission for patients 70 years or younger who are potential candidates for autologous stem cell transplantation. At relapse, retreatment with the original therapy is reasonable in patients with prior durable responses (time to next therapy ≥3 years) and good tolerability to previous regimen. Ibrutinib is efficacious in patients with relapsed or refractory disease harboring MYD88 L265P mutation. In the absence of neuropathy, a bortezomib-rituximab-based option is reasonable for relapsed or refractory disease. In select patients with chemosensitive disease, autologous stem cell transplantation should be considered at first or second relapse. Everolimus and purine analogs are suitable options for refractory or multiply relapsed WM. Our recommendations are periodically updated as new, clinically relevant information emerges.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Prashant
authors.initials: P
authors.lastname: Kapoor
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Asher
authors.initials: A
authors.lastname: Chanan-Khan
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kyle
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Shaji K
authors.initials: SK
authors.lastname: Kumar
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mikhael
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.affiliation: Division of Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michelle
authors.initials: M
authors.lastname: Mauermann
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Angela
authors.initials: A
authors.lastname: Dispenzieri
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Sikander
authors.initials: S
authors.lastname: Ailawadhi
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Martha Q
authors.initials: MQ
authors.lastname: Lacy
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Thompson
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Francis K
authors.initials: FK
authors.lastname: Buadi
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: David
authors.initials: D
authors.lastname: Dingli
authors.affiliation: Division of Hematopathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: William G
authors.initials: WG
authors.lastname: Morice
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Go
authors.affiliation: Division of Hematopathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Dragan
authors.initials: D
authors.lastname: Jevremovic
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Taimur
authors.initials: T
authors.lastname: Sher
authors.affiliation: Division of Hematopathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: King
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Esteban
authors.initials: E
authors.lastname: Braggio
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ann
authors.initials: A
authors.lastname: Novak
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Vivek
authors.initials: V
authors.lastname: Roy
authors.affiliation: Division of Laboratory Genetics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.affiliation: Division of Laboratory Genetics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Greipp
authors.affiliation: Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota.
authors.forename: Martha
authors.initials: M
authors.lastname: Grogan
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ivana N
authors.initials: IN
authors.lastname: Micallef
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Colgan
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.|Division of Nephrology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Nelson
authors.initials: N
authors.lastname: Leung
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Wilson I
authors.initials: WI
authors.lastname: Gonsalves
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: David J
authors.initials: DJ
authors.lastname: Inwards
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Suzanne R
authors.initials: SR
authors.lastname: Hayman
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Grzegorz S
authors.initials: GS
authors.lastname: Nowakowski
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Johnston
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Russell
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Zeldenrust
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Yi L
authors.initials: YL
authors.lastname: Hwa
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: John A
authors.initials: JA
authors.lastname: Lust
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Porrata
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: S Vincent
authors.initials: SV
authors.lastname: Rajkumar
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Morie A
authors.initials: MA
authors.lastname: Gertz
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Reeder
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage; D000069286:Bortezomib / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D000068338:Everolimus / Q000008:administration & dosage; D006801:Humans; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010880:Piperidines; D010951:Plasma Exchange; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D019233:Retreatment; D018570:Risk Assessment; D000069283:Rituximab / Q000008:administration & dosage; D008258:Waldenstrom Macroglobulinemia / Q000175:diagnosis* / Q000188:drug therapy*
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000069283:Rituximab; D000069286:Bortezomib; D003907:Dexamethasone; D003520:Cyclophosphamide; D000069461:Bendamustine Hydrochloride; D000068338:Everolimus; D000225:Adenine