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Purpose: The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström's macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE., Methods: Patients had confirmed symptomatic WM, either previously untreated or previously treated; patients with prior rituximab had at least a minor response to their last rituximab-based regimen. Patients were randomly assigned to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n = 75 per arm). The primary end point was progression-free survival (PFS). Secondary end points included response rate, time to next treatment, hemoglobin improvement, overall survival, and safety., Results: With a median follow-up of 50 (range, 0.5-63) months, median (95% CI) PFS was not reached (57.7 months to not evaluable) with ibrutinib-rituximab versus 20.3 months (13.0 to 27.6) with placebo-rituximab (hazard ratio, 0.250; P < .0001). PFS benefit was regardless of prior treatment status, MYD88 and CXCR4 mutation status, or key patient characteristics. Higher response rates (partial response or better) were observed with ibrutinib-rituximab (76% v 31% with placebo-rituximab; P < .0001) and were sustained over time. Median time to next treatment was not reached with ibrutinib-rituximab versus 18 months with placebo-rituximab. More patients receiving ibrutinib-rituximab versus placebo-rituximab had sustained hemoglobin improvement (77% v 43%; P < .0001). Median overall survival was not reached in either arm. Ibrutinib-rituximab maintained a manageable safety profile; the prevalence of grade ≥ 3 adverse events of clinical interest generally decreased over time., Conclusion: In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics., Competing Interests: Christian BuskeHonoraria: Roche/Genentech, Janssen, BeiGene, Novartis, Pfizer, Incyte, AbbVie, Gilead Sciences, Celltrion, MorphoSys, RegeneronConsulting or Advisory Role: Gilead Sciences, Janssen, Roche, Pfizer, BeiGene, Celltrion, AbbVie, Incyte, Regeneron, MorphoSys, NovartisSpeakers' Bureau: Roche, Janssen, BeiGene, Celltrion, AbbVie, Pfizer, Gilead SciencesResearch Funding: Roche/Genentech, Janssen, Celltrion, MSD, Pfizer, Amgen, Alessandra TedeschiConsulting or Advisory Role: Janssen, BeiGene, AstraZeneca, AbbVieSpeakers' Bureau: AbbVie, AstraZeneca, Janssen, BeiGene Judith TrotmanResearch Funding: BeiGene, Roche/Genentech, Pharmacyclics, Janssen-Cilag, Takeda, CelgeneTravel, Accommodations, Expenses: Roche/Genentech Ramón García-SanzHonoraria: Janssen, Takeda, Amgen, BeiGene, NovartisConsulting or Advisory Role: JanssenResearch Funding: Gilead Sciences, IncytePatents, Royalties, Other Intellectual Property: BIOMED-2 primersTravel, Accommodations, Expenses: Janssen, Takeda (I)Other Relationship: Spanish Society of Hematology (SEHH) David MacDonaldResearch Funding: Celgene, Servier Veronique LeblondHonoraria: AstraZeneca, Roche Pharma AG, BeiGene, Amgen, Janssen Oncology, AbbVie, MSD Oncology, LillyConsulting or Advisory Role: BeiGene, Janssen, AstraZeneca, Lilly, AbbVieSpeakers' Bureau: BeiGene, AstraZeneca, AbbVieTravel, Accommodations, Expenses: AbbVie Charles HerbauxHonoraria: Roche, Janssen-Cilag, AbbVieResearch Funding: TakedaTravel, Accommodations, Expenses: Janssen-Cilag, AbbVie, Roche Jeffrey V. MatousConsulting or Advisory Role: Pharmacyclics, BeiGene Constantine S. TamHonoraria: Janssen-Cilag, AbbVie, Novartis, BeiGene, PharmacyclicsConsulting or Advisory Role: Janssen, Loxo, Roche, AbbVieResearch Funding: Janssen-Cilag, AbbVie Leonard T. HeffnerSpeakers' Bureau: Kite, a Gilead companyResearch Funding: Pharmacyclics, Genentech, Kite, a Gilead Company, ADC Therapeutics, Astex Pharmaceuticals, Loxo, Cellectar Marzia VarettoniConsulting or Advisory Role: Janssen-Cilag, Roche, Janssen, AstraZenecaTravel, Accommodations, Expenses: Gilead Sciences, Janssen-Cilag, AbbVie, Janssen Lia PalombaStock and Other Ownership Interests: Seres Therapeutics (I)Honoraria: Flagship Biosciences (I), Evelo Therapeutics (I), Jazz Pharmaceuticals (I), Therakos (I), Amgen (I), Merck (I), Seres Therapeutics (I)Consulting or Advisory Role: Flagship Biosciences (I), Novartis (I), Evelo Therapeutics (I), Jazz Pharmaceuticals (I), Therakos (I), Amgen (I), Merck (I), Seres Therapeutics (I), Kite, a Gilead Company, BeiGeneResearch Funding: Seres Therapeutics (I)Patents, Royalties, Other Intellectual Property: Intellectual Property Rights (I), Juno Intellectual Property Rights Chaim ShustikExpert Testimony: Janssen Oncology Efstathios KastritisHonoraria: Amgen, Genesis Pharma, Janssen Oncology, Takeda, Prothena, PfizerConsulting or Advisory Role: Amgen, Janssen Oncology, Takeda, Genesis Pharma, Prothena, PfizerResearch Funding: Janssen Oncology, AmgenTravel, Accommodations, Expenses: Janssen Oncology, Genesis Pharma, Takeda, Pfizer Steven P. TreonConsulting or Advisory Role: Janssen, Pharmacyclics, BeiGene, X4 Pharmaceuticals, Bristol Myers SquibbResearch Funding: Pharmacyclics, Bristol Myers Squibb, X4 Pharmaceuticals, Lilly, BeiGene, AbbViePatents, Royalties, Other Intellectual Property: My institution holds patents related to the use of MYD88 and CXCR4 testing for which a predetermined financial distribution to the laboratory and individuals is provided. I have not received any income to this date related to these patents.Travel, Accommodations, Expenses: Janssen OncologyOther Relationship: Janssen, Pharmacyclics, BeiGene Jerry PingEmployment: AbbVieStock and Other Ownership Interests: AbbVieTravel, Accommodations, Expenses: AbbVie Bernhard HaunsEmployment: AbbVie/PharmacyclicsStock and Other Ownership Interests: AbbVieTravel, Accommodations, Expenses: AbbVie Israel Arango-HisijaraEmployment: Janssen Oncology, Abbvie/PharmacyclicsStock and Other Ownership Interests: Bristol Myers Squibb/Celgene, AbbvieHonoraria: Janssen Oncology, Abbvie/Pharmacyclics Meletios A. DimopoulosHonoraria: Amgen, Takeda, Janssen-Cilag, Bristol Myers Squibb, BeiGeneConsulting or Advisory Role: Amgen, Janssen-Cilag, Takeda, Bristol Myers Squibb, BeiGeneNo other potential conflicts of interest were reported.

Purpose: Observation is the current standard of care for smoldering multiple myeloma. We hypothesized that early intervention with lenalidomide could delay progression to symptomatic multiple myeloma., Methods: We conducted a randomized trial that assessed the efficacy of single-agent lenalidomide compared with observation in patients with intermediate- or high-risk smoldering multiple myeloma. Lenalidomide was administered orally at a dose of 25 mg on days 1 to 21 of a 28-day cycle. The primary end point was progression-free survival, with disease progression requiring the development of end-organ damage attributable to multiple myeloma and biochemical progression., Results: One hundred eighty-two patients were randomly assigned-92 patients to the lenalidomide arm and 90 to the observation arm. Median follow-up is 35 months. Response to therapy was observed in 50% (95% CI, 39% to 61%) of patients in the lenalidomide arm, with no responses in the observation arm. Progression-free survival was significantly longer with lenalidomide compared with observation (hazard ratio, 0.28; 95% CI, 0.12 to 0.62; P = .002). One-, 2-, and 3-year progression-free survival was 98%, 93%, and 91% for the lenalidomide arm versus 89%, 76%, and 66% for the observation arm, respectively. Only six deaths have been reported, two in the lenalidomide arm versus four in the observation arm (hazard ratio for death, 0.46; 95% CI, 0.08 to 2.53). Grade 3 or 4 nonhematologic adverse events occurred in 25 patients (28%) on lenalidomide., Conclusion: Early intervention with lenalidomide in smoldering multiple myeloma significantly delays progression to symptomatic multiple myeloma and the development of end-organ damage.

Purpose: Idiotypes (Ids), the unique portions of tumor immunoglobulins, can serve as targets for passive and active immunotherapies for lymphoma. We performed a multicenter, randomized trial comparing a specific vaccine (MyVax), comprising Id chemically coupled to keyhole limpet hemocyanin (KLH) plus granulocyte macrophage colony-stimulating factor (GM-CSF) to a control immunotherapy with KLH plus GM-CSF., Patients and Methods: Patients with previously untreated advanced-stage follicular lymphoma (FL) received eight cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone. Those achieving sustained partial or complete remission (n=287 [44%]) were randomly assigned at a ratio of 2:1 to receive one injection per month for 7 months of MyVax or control immunotherapy. Anti-Id antibody responses (humoral immune responses [IRs]) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included IR and time to subsequent antilymphoma therapy., Results: At a median follow-up of 58 months, no significant difference was observed in either PFS or time to next therapy between the two arms. In the MyVax group (n=195), anti-Id IRs were observed in 41% of patients, with a median PFS of 40 months, significantly exceeding the median PFS observed in patients without such Id-induced IRs and in those receiving control immunotherapy., Conclusion: This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study., (© 2014 by American Society of Clinical Oncology.)

Purpose: The aims of this multicenter study were to evaluate the response rate, progression-free survival, and toxicity of the combination of bortezomib, bendamustine, and rituximab in patients with follicular lymphoma whose disease was relapsed or refractory to prior treatment., Patients and Methods: Patients received five 35-day cycles of bortezomib, bendamustine, and rituximab: bortezomib administered intravenously (IV) at a dose of 1.6 mg/m(2) on days 1, 8, 15, and 22, cycles one to five; bendamustine 50, 70, or 90 mg/m(2) IV over a 60-minute infusion on days 1 and 2, cycles one to five; and rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle one and day 1 of subsequent cycles. Patients were assessed using the International Workshop Response Criteria, with the primary end point of 60% complete response rate., Results: Seventy-three patients were enrolled. During the dose-escalation phase, the maximum-tolerated dose for bendamustine was not reached; the 90 mg/m(2) dose level was expanded for the efficacy assessment, and a total of 63 patients received bendamustine 90 mg/m(2). In these 63 patients, the overall response rate was 88% (including 53% complete response). Median duration of response was 11.7 months (95% CI, 9.2 to 13.3). Median progression-free survival was 14.9 months (95% CI, 11.1 to 23.7). Toxicities were manageable; myelosuppression was the main toxicity (25% and 14% of patients experienced grade 3 to 4 neutropenia and grade 3 to 4 thrombocytopenia, respectively). Transient grade 3 to 4 neuropathy occurred in 11% of patients., Conclusion: The combination of bortezomib, bendamustine, and rituximab is highly active in patients with follicular lymphoma who have received previous treatment.