Waldenström Macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by bone marrow infiltration with monoclonal immunoglobulin M-secreting lymphoplasmacytic cells 
. This disease usually has an indolent course, and its clinical presentation is heterogeneous, with signs and symptoms resulting from marrow or other tissue infiltration by clonal cells or from physicochemical or immunological properties of the monoclonal IgM 
As for other indolent lymphomas, treatment is indicated only in symptomatic patients, as guidelines recommend 
. Common indications to treat WM include significant anaemia, thrombocytopenia, lymphadenopathy and splenomegaly; neuropathy and renal dysfunction are less frequent manifestations requiring treatment. Although rarely, some patients may require a prompt therapeutic approach to avoid irreparable organ damage or fatal complications, such as in the case of hyperviscosity syndrome 
. Plasmapheresis is indicated in such cases to reduce IgM protein and consequently the risk of permanent organ impairment. However, the benefit of this procedure is time-limited, so systemic treatment should promptly follow 
Multiple therapy options are available for WM, including chemotherapy, monoclonal antibodies and proteasome inhibitors (PI). Latest insights on the disease pathophysiology have revealed that the neoplastic lymphoplasmacytic cells exhibit constitutive activation of the B-cell receptor signalling complex, of which Bruton tyrosine kinase (BTK) is a critical component 
. Considering its crucial role in WM pathogenesis, this kinase has appeared to be a potent therapeutic target and BTK inhibitors (BTKi) have emerged as another promising option within the therapeutic landscape of WM patients 
Given the rarity of the disease, most of the current regimens have been adopted from data derived from phase II studies; less often, data have emerged from prospective trials enrolling patients with several types of indolent B-cell lymphomas, including lymphoplasmacytic lymphomas, while randomized trials specifically addressed to WM are even rarer 
. Nevertheless, it is widely established that the selection of the optimal therapy is an individualized decision tailored by clinicians and patients together, taking into account several factors including characteristics of the patient (age, performance status, comorbidities, concomitant medications), disease (tumour burden, signs/symptoms requiring therapy), and treatment (rapidity in disease control, toxicity, management, costs) 
. For all these reasons, no standard first-line treatment has been univocally defined.
In the last decade, also patients’ genomic profiles have been demonstrated to play a significant role in providing insightful information for treatment selection. In particular, the somatic mutations in myeloid differentiation factor 88 (MYD88) and C-X-C chemokine receptor type 4 (CXCR4) have been extensively characterized 
mutation is present in more than 90% of WM patients and favours neoplastic cell survival and proliferation by persistently activating BCR signalling through BTK 
. A mutation in the CXCR4
gene can be identified in 30–40% of WM patients; this mutation is similar to the one observed in WHIM syndrome and leads to constitutive activation of the gene and its downstream signalling pathway. Two different types of CXCR4
mutations have been identified: nonsense and frameshift mutations 
Based on the presence or absence of these mutations, three specific genetic groups of patients may be identified in WM: MYD88L265P
(30–40%) and MYD88WT
. These subgroups characterize different clinical presentations and, most importantly, are predictive of treatment response and survival 
2. First Line Therapies
2.1. Cytotoxic Agents and AntiCD20 Monoclonal Antibodies
Before the introduction of rituximab-based combinations, single-agent chemotherapy and rituximab monotherapy were historically used. One of the largest prospective randomized trials compared chlorambucil with fludarabine, demonstrating better outcomes in terms of responses and progression-free survival (PFS), as well as overall survival (OS), in patients receiving the purine analogue 
. Furthermore, a significantly higher rate of secondary malignancies was observed in the chlorambucil arm (6-year cumulative incidence of 20.6% versus 3.7% in the fludarabine arm).
Low rates of overall response were reported with rituximab monotherapy (18–65%) translating into relatively short PFS, depending on different administration schedules 
. Importantly, it should be considered that the median time to response is long and, mostly when used in monotherapy, this agent can lead to a paradoxical rise in IgM, called “IgM flare”, with possible worsening of symptoms and complications secondary to hyperviscosity 
Compared to single agent-based treatment, regimens combining chemotherapy plus rituximab have resulted in superior response rates and sustained survival and thus have rapidly become leading players in the WM therapeutic scenario.
Purine nucleoside analogues-based regimens, including fludarabine-rituximab and fludarabine-cyclophosphamide-rituximab, showed to be highly effective in exerting prolonged PFS 
. Nevertheless, their administration in the frontline has actually declined due to a remarkable incidence of myelosuppression and immunosuppression with a high rate of infections; moreover, their use has been associated with an increased risk of secondary malignancies.
Since the publication of the study by Dimopoulos and colleagues in 2007, exploring the role of the combination of dexamethasone, rituximab and cyclophosphamide (DRC), this regimen has been widely adopted as one of the therapies of choice in treatment naïve (TN) patients, also due to its favourable toxicity profile in the elderly population 
DRC showed to be effective, leading to a high rate of overall response (83%) with 7% of complete remissions (CR) 
. Median PFS was reached at 35 months and, of note, the median time to the next treatment (TTNT) was more than 4 years (51 months) 
. The combination was well tolerated with the majority of patients (89%) completing the 6 planned cycles and with a rate of grade 3–4 infections of 12.5%. Long-term toxicity was also limited, and 10-years OS was not reached. However, it should be considered that this regimen does not allow rapid disease control as the median time to response is 4.1 months.
Bendamustine in combination with rituximab (BR) quickly emerged as an accepted standard frontline therapy after the publication of the StiL trial comparing BR versus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in patients with untreated indolent lymphomas, including 41 with lymphoplasmacytic lymphomas/WM 
. BR demonstrated to be superior to R-CHOP in terms of PFS (median PFS 69.5 months with BR versus 28.1 months with R-CHOP, p
= 0.0033). Although bendamustine was administered at the dosage of 90 mg/m2
on days 1–2, the regimen showed to be better tolerated compared to R-CHOP with a rate of all grade infections of 37% versus 50%. The efficacy of the BR regimen has been confirmed in other retrospective series. In the trial of the French Innovative Leukaemia Organization, it emerged that the reduction of bendamustine dosage or the number of cycles (44% of patients) did not influence the outcome in terms of PFS 
The impact of genotype on BR treatment in TN patients has been evaluated by Zanwar et al. 
. The very good partial response (VGPR) rates were comparable between patients with MYD88L265P
genotypes (41% and 50%, respectively, p
= 0.55), and the 4-year PFS was 71% for both groups. Differently, patients harbouring CXCR4
mutation showed a numerically lower rate of ≥VGPR (33% versus 57% for those with CXCR4WT
= 0.3) and a trend towards shorter PFS.
No prospective studies have directly compared BR with DRC; however, these two regimens were retrospectively analysed in a population of 160 patients (67 TN) treated at Mayo Clinic 
. In the TN setting, the overall response rate (ORR) was similar between the two regimes, but the median time to best response was shorter in the BR cohort (6.1 versus 11 months with DRC). Moreover, although not statistically significant, the 2-year PFS was superior in the BR group (88 versus 61% in the DRC arm, p
= 0.07), without an increase in toxicity. The MYD88
mutation status was available in only 48 patients of the entire cohort and did not result to have an impact on outcomes of both BR and DRC. CXCR4
mutations were not evaluated.
Despite some series reported positive outcomes for autologous stem cell transplant (ASCT) for WM in first-line setting 
, the lack of comparative trials made it difficult to provide strong evidence and high-quality recommendations on this topic. This became truer after the availability of BTKi.
Nevertheless, guidelines do not recommend frontline ASCT outside clinical trials, unless there are other indications such as amyloidosis or transformation to an aggressive lymphoma 
Considering the possibility of multiple relapses, the use of frontline stem cell toxic regimes in younger patients potentially candidates to salvage ASCT has been usually avoided 
2.2. Proteasome Inhibitor-Based Therapy
Combination strategies with bortezomib have shown significant activity in the treatment of WM.
Several trials have addressed the role of bortezomib plus rituximab with or without dexamethasone. The combinations allowed for achieving a high rate of responses (85–96%) with a very short time to median response (1.4 months–3.7 months) 
. Progression-free survival showed to be longer in the study of Treon et al., in which four cycles of induction were followed by four cycles of maintenance (median 66 months) compared to the only five courses considered in the European study (median 43 months). Peripheral neuropathy resulted a common AE, leading to a high rate of therapy discontinuation (60%) when the PI was administered twice weekly. Importantly, a significant reduction in neurological toxicity was obtained with a weekly administration of bortezomib. Concern remains about whether dexamethasone should be added to the combination, considering that the indirect comparison showed similar outcomes with or without the use of this agent.
The question of whether bortezomib-based regimens may be superior to the most common used CIT regimens was explored in three comparative trials of previously untreated patients.
BR, DRC and BDR were retrospectively compared by Abeykoon et al. in 220 cases 
. BR resulted superior to both DRC and BDR in terms of ORR (98% versus 78% versus 84%; respectively, p
= 0.003), MRR (95% versus 53% versus 68%, respectively, p
< 0.0001) and median time to best response (4.5 months versus 5.9 months versus 6.7 months, respectively, p
= 0.005). Treatment with BR was also associated with a better PFS (median 5.2 years vs. 4.3 years with DRC and 1.8 years with BDR; p
= 0.0003), even though OS was similar across the three groups.
Differently, no differences in terms of response rates were observed by Castillo et al. when the three regimens were retrospectively compared 
; however, a trend towards a better PFS was recorded in BR-treated patients with again no differences in terms of OS.
The addition of bortezomib to DRC (B-DRC) did not translate into a PFS advantage compared to DRC in the Multicenter European Phase II randomized trial 
. Importantly, the study confirmed that genotype did not influence outcomes in both treatment arms. Despite a higher occurrence of peripheral neuropathy in patients receiving B-DRC, rates of grade ≥ 3 AEs were comparable.
Second-generation neuropathy-sparing PI carfilzomib, administered in association with rituximab and dexamethasone for six induction plus six maintenance cycles, allowed to achieve a good quality of responses independent of MYD88
mutational status 
. Median PFS was achieved at 46 months. Importantly, only one grade 2 peripheral neuropathy (3.2%) occurred, with no grade 3–4 events.
Limited and not univocal evidence has addressed the role of maintenance with rituximab in WM. In the previously mentioned retrospective study by Castillo and colleagues, patients receiving prolonged rituximab administration as maintenance achieved higher ORR (97% versus 68%), longer median PFS (6.8 years versus 2.8 years) and better 10-year OS rate (84% versus 66%) compared to those discontinuing treatment after the induction phase 
. In the MAINTAIN trial patients received induction therapy with BR and were then randomised to observation or rituximab every 2 months for 2 years 
. The study confirmed the high efficacy of induction therapy with BR and did not demonstrate an advantage of rituximab maintenance in terms of OS or PFS. Moreover, both studies highlighted the higher rate of infections in the cohort receiving the antiCD20 monoclonal antibody with prolonged schedule.
2.4. BTK Inhibitors
Ibrutinib, at a dosage of 420 mg daily until disease progression or unacceptable toxicity, was the first drug that FDA and EMA specifically approved for the treatment of WM 
After the first report in the relapse/refractory (R/R) setting 
, ibrutinib was explored by Treon and colleagues in 30 untreated WM patients 
. Considering the poor outcome of MYD88WT
patients treated with ibrutinib, only MYD88MUT
patients were enrolled in this study. With the longer follow-up of 50.1 months, overall and major response rates were 100% and 87%, respectively; none of the patients achieved a CR 
. The median time for minor and major responses was 1 and 1.9 months, respectively. The median PFS was not reached and the 4-year PFS rate was 76%. No deaths were recorded during active ibrutinib treatment, for an OS rate of 100%. Most of the AEs were mild, while grade ≥ 2 atrial fibrillation occurred in 20% of patients. About 10% of patients had to reduce ibrutinib dosage or discontinue treatment, respectively, due to adverse events. Importantly, one ventricular fibrillation was reported. When patients were stratified according to CXCR4
mutational status, CXCR4MUT
patients (47% of the whole population) showed numerical lower, despite not significant, rate of VGPR, a significantly longer median time to major response and a sixfold increased risk of progression or death (HR 6.03; 95% CI: 0.7–51.6; p
In the phase III iNNOVATE trial, the addition of ibrutinib to rituximab resulted in higher ORR, MRR, and PFS compared to rituximab monotherapy even in the TN patients enrolled in the study 
. Of note, the addition of rituximab to ibrutinib was able to abrogate the negative impact of CXCR4
mutational status. Moreover, while response rates were slightly inferior in cases not harbouring the MYD88L265P
mutation, these minor differences did not affect the PFS benefit.
The second-generation BTKi acalabrutinib was developed to be more selective than ibrutinib. Only 14 TN patients received acalabrutinib in a phase II multicenter study 
. As with ibrutinib, the majority of patients achieved a response (93%) with no VGPR or CR. Estimated 66-months PFS and OS were 84% and 91%, respectively. In this study, patients were not stratified according to CXCR4
mutational status. Acalabrutinib was discontinued in 50% of patients, AEs being the main reason. Grade 1–2 atrial fibrillation and haemorrhage were reported in 7 and 71%, with no grade 3–4 events.
Zanubrutinib, a potent irreversible next-generation BTKi, was first evaluated in a phase I/II trials enrolling subjects with B-Cell lymphoid malignancies 
. In the cohort of 24 TN WM patients, overall and major response rates resulted in 100 and 87.5%, respectively. The median time to major response was 2.8 months, and the quality of response increased while on treatment. The 2-year estimated EFS was 91.5%. Among AEs of special interest, 62.3% of subjects experienced bleeding events, mostly of grade 1–2; atrial fibrillation was reported only in 5.2% of patients.
Based on these promising results, the phase III ASPEN trial was designed as a head-to-head comparison of zanubrutinib to ibrutinib 
. Of 201 patients enrolled, 37 were TN WM unsuitable for standard CIT. Considering the inferior activity of ibrutinib on MYD88WT
cases, only patients with MYD88
mutation were randomised, while in a second cohort MYD88WT
patients were directly assigned to zanubrutinib.
At the first follow-up of the study, categorical responses of TN patients were similar between the two BTKi. The follow up was too short to draw conclusions on survival outcomes. In the 43 months follow-up of the study, only aggregate results were considered, and outcomes were not categorised according to treatment status 
. Patients treated with zanubrutinib achieved deeper responses with a shorter time to reach VGPR (5.6 and 22.1 months, respectively, p
= 0.35). Progression-free survival and OS were still not reached. Importantly, longer follow-up highlighted the better efficacy of zanubrutinib toward CXCR4
mutated patients. The incidence of BTKi-related AEs was lower with zanubrutinib. Only neutropenia occurred more frequently in the next-generation BTKi arm, not leading to a higher incidence of grade 3–4 infections. Of note, patients receiving zanubrutinib showed an inferior rate of discontinuation and dose reductions.
In cohort 2, including 28 MYD88WT
patients (5 TN), treatment with zanubrutinib led to a remarkable 80% ORR, with 40% MRR and 20% of VGPR 
. After a median follow-up of 43 months, PFS and OS rates were 53.8% and 83.9%, respectively 
No prospective trials have directly compared BTKi versus CIT. Only a retrospective study on 246 MYD88MUT
patients, comparing BR and ibrutinib, at 4.2 years of follow-up showed similar PFS and OS rates, with deeper responses attained in the CIT cohort