In this issue of Blood, Gavriatopoulou and colleagues report the mature results of the European Myeloma Network (EMN)–conducted phase 2 trial evaluating the activity of bortezomib, dexamethasone, and rituximab (BDR) in treatment-naïve patients with Waldenström macroglobulinemia (WM).1  An array of combination regimens has been studied in WM, and the ever-growing list of bidders contributes to the conundrum of choosing an appropriate regimen.2 

The EMN investigators attempted to minimize the neurotoxicity of BDR and the consequent attrition rate by transitioning beyond the first cycle, from a biweekly (1.3 mg/m2) to a unique weekly (1.6 mg/m2) schedule of IV bortezomib for 4 weeks followed by a week off per cycle, for an additional 4 cycles.1  Rituximab, an anti-CD20 monoclonal antibody, with a single-agent activity of 25% to 40%, and a backbone of several combination regimens in WM, and dexamethasone were restricted to cycles 2 and 5. Importantly, the responses were durable (median duration of response, 65 months), and the median progression-free survival (PFS) and time-to-next therapy (TTNT) were 43 months and 73 months, respectively, after a follow-up of at least 6 years.1 

In parallel, during those 6 years, the field witnessed unprecedented advances, with the inflection points being the discoveries of somatic MYD88L265P and CXCR4 WHIM mutations in patients with WM, as well as the subsequent approval of Bruton tyrosine kinase inhibitor, ibrutinib, for the treatment of WM.2,3 

Analysis of mature data pertaining to indolent malignancies is arduous, but unfailingly rewarding. The EMN study brings to the fore 6 important aspects regarding the initial management of WM, an immunoglobulin M–associated lymphoma that afflicts 1500 to 2000 new patients in the United States each year.2 

First, the quest for the most suitable agent to target the proteasome in WM cells continues as researchers explore the activity of the next-generation proteasome inhibitors (PIs) (carfilzomib, oprozomib, and ixazomib) and continue to optimize the delivery of bortezomib to mitigate treatment-emergent peripheral neuropathy (PN). The WMCTG 05-180 study was the first prospective trial to evaluate BDR in previously untreated patients.4  Treatment consisted of a 4-cycle induction phase, with IV bortezomib and dexamethasone (days 1, 4, 8, and 11), and rituximab on day 11 as part of a 3-week cycle, followed by a 4-cycle BDR maintenance phase every 12 weeks. Biweekly administration of bortezomib led to an impressive overall response rate (ORR), but the patients with WM were exquisitely predisposed to PI-associated neurotoxicity; 30% developed grade 3 PN, with an alarmingly high proportion (60%) discontinuing therapy prematurely.4  However, a modified bortezomib schedule in the EMN study, without a maintenance phase, could improve the tolerability of this regimen (grade 3 PN, 7%) without substantially compromising its efficacy.1  That the high ORR of a bortezomib-based regimen is preserved with a subcutaneous, and less neurotoxic, route of administration, was attested to by the recently reported findings of the R2W study (see table), showing 0% grade 3 or greater PN.5  The rapidity of response and the lack of stem cell toxicity, without emergence of myelodysplastic syndrome, affirm the extra perks of bortezomib-based frontline regimens.

Table:

Commonly used primary combination regimens in Waldenström macroglobulinemia

Number of patientsRegimenORR (%)≥PR/CR (%)TTNT (mo)*PFS (mo)*OS (mo)*
Proteasome inhibitor–based 
 26 Bortezomib-rituximab 89 66/4 NR NR 96% at 1 y 
 23 BDR (WMCTG) 96 91/17 — 57% at 5y Median NR, 95% at 5 y 
 59 BDR (EMN) 85 68/3 73 43 66% at 7 y 
 42 BCR vs 98 79/2 — — — 
 17 FCR (R2W) 82 77/0 — — — 
 31† CaRD 87 67/3  NR — 
 26 IDR 88 50/0 — — — 
Non–proteasome inhibitor–based  
 169 Chlorambucil vs — 36  27 70 
 170 fludarabine (WM1) 46 38 NR 
 72 DRC 83 74/7 51  Median 95, 64% at 8 y 
 22 Bendamustine-rituximab vs 95 –/– — 70 — 
 19 R-CHOP (STiL) 95 28 
 29 Cladribine-rituximab 90 –/25 — — — 
 43 FCR 79 74/12 — NR 69 
Number of patientsRegimenORR (%)≥PR/CR (%)TTNT (mo)*PFS (mo)*OS (mo)*
Proteasome inhibitor–based 
 26 Bortezomib-rituximab 89 66/4 NR NR 96% at 1 y 
 23 BDR (WMCTG) 96 91/17 — 57% at 5y Median NR, 95% at 5 y 
 59 BDR (EMN) 85 68/3 73 43 66% at 7 y 
 42 BCR vs 98 79/2 — — — 
 17 FCR (R2W) 82 77/0 — — — 
 31† CaRD 87 67/3  NR — 
 26 IDR 88 50/0 — — — 
Non–proteasome inhibitor–based  
 169 Chlorambucil vs — 36  27 70 
 170 fludarabine (WM1) 46 38 NR 
 72 DRC 83 74/7 51  Median 95, 64% at 8 y 
 22 Bendamustine-rituximab vs 95 –/– — 70 — 
 19 R-CHOP (STiL) 95 28 
 29 Cladribine-rituximab 90 –/25 — — — 
 43 FCR 79 74/12 — NR 69 

BCR, bortezomib-cyclophosphamide-rituximab; CaRD, carfilzomib-rituximab-dexamethasone; CR, complete response; FCR, fludarabine-cyclophosphamide-rituximab; IDR, ixazomib-dexamethasone-rituximab; NR, not reached; OS, overall survival; PR, partial response; R-CHOP, rituximab-doxorubicin-cyclophosphamide-vincristine-prednisone; WM1, Waldenström macroglobulinemia 1; WMCTG, Waldenström Macroglobulinemia Clinical Trials Group.

*

Median (in months), unless otherwise specified.

Heterogeneous cohort, including relapsed and/or refractory patients with WM.

Second, notwithstanding the inherent risks, comparisons across single-arm studies are unavoidable in WM owing to the absence of data from randomized studies.2  In this context, the efficacy and tolerability of bendamustine-rituximab has been particularly remarkable, making it an attractive and a widely used neuropathy-sparing alternative (see table).2,6 

Third, the role of maintenance therapy in WM remains unclear, with the current practice of fixed-duration induction being largely driven by the lack of prospective data supporting prolonged therapy.2  The WMCTG study drew attention to the unsuitability of BDR for maintenance. The ongoing Study group indolent Lymphomas (StiL) MAINTAIN study, which by design allows random assignment of rituximab-responsive patients to either 2 years of rituximab maintenance every 2 months, or observation after a maximum of 6 cycles of bendamustine-rituximab induction plus 2 cycles of rituximab, is expected to throw light on this strategy.

Fourth, the TTNT remains an extremely relevant end point in WM because patients typically do not require salvage therapy with a mere increase in the M-protein (ie, upon biochemical progression); therapy is deferred until the symptoms reemerge, or significant anemia or thrombocytopenia develops.2  In this context, the TTNT of the EMN study is particularly noteworthy, and substantially longer than that observed with the dexamethasone rituximab cyclophosphamide (DRC) regimen (see table).1,7 

Fifth, the preliminary data from a few small studies suggest that both PI and non-PI–based regimens are effective in WM, irrespective of the MYD88 mutation status5,8 ; in contrast, the activity of ibrutinib is primarily confined to the MYD88 mutant subpopulation. The EMN study did not delineate outcome on the basis of the patients’ MYD88 mutation status, nor could the patients be longitudinally evaluated for clonal evolution, a phenomenon that has recently been documented in WM with both PI-based and Bruton tyrosine kinase inhibitor–based therapies.9 

Finally, and most importantly, collaborative efforts remain indispensable in the face of sparse high-level evidence to inform hematologists of the optimal approach to managing WM, a rare and, to date, incurable malignancy. The WM1 study, a phase 3 international trial, demonstrated how consequential the choice of initial therapy can be, even for a typically indolent disorder such as WM; the use of frontline fludarabine favorably affected survival (see table) compared with chlorambucil.10  In addition, the study exemplified the feasibility of a coordinated effort to enhance patient accrual and underscored the obligation to conduct large comparative trials to effectively assist clinicians and patients alike in making unbiased decisions.

The EMN and other studies have firmly established the role of bortezomib, in partnership with rituximab, as a primary therapy of WM.1,4,5  We can now infer with certainty that bortezomib should not be administered more frequently than once per week, and that the optimal route of administration is subcutaneous. However, it remains to be determined how this combination can suitably be integrated with other existing therapies to enhance its activity, particularly for the high-risk WM (only 15% of the patients with IPSSWM 3 were alive and progression-free in the EMN study at 7 years), without adversely affecting its safety profile. The results of an ongoing phase 3 trial (NCT01788020) of DRC ± subcutaneous weekly bortezomib are bound to be instructive. Stay tuned!

Conflict-of-interest disclosure: Research support from Amgen, Takeda, and Celgene has been provided to P.K.'s institution for the conduct of clinical trials on which P.K. serves as a principal investigator.

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