Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström’s Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study

[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.Supported by Pharmacyclics LLC, an AbbVie Company. Pharmacyclics LLC sponsored and designed the study.Peer reviewe

Outcome of Second Primary Malignancies Developing in Multiple Myeloma Patients

Background: There is an increased risk of second primary malignancies (SMPs) in patients with multiple myeloma (MM). This multinational 'real-world' retrospective study analyzed the characteristics and outcomes of MM patients that developed SPMs.Results: 165 patients were analyzed: 62.4% males; 8.5% with a prior cancer; 113 with solid SPMs, mainly =stage 2; and 52 with hematological SPM (hemato-SPM), mainly MDS/AML. Patients with hemato-SPM were younger (p = 0.05) and more frequently had a prior AutoHCT (p = 0.012). The time to SPM was shorter in the older (&gt;65 years) and more heavily pretreated patients. One hundred patients were actively treated at the time of SPM detection. Treatment was discontinued in 52, substituted with another anti-MM therapy in 15, and continued in 33 patients. Treatment discontinuation was predominant in the patients diagnosed with hemato-SPM (76%). The median OS following SPM detection was 8.5 months, and the main cause of death was SPM. A poor ECOG status predicted a shorter OS (PS 3 vs. 0, HR = 5.74, 2.32-14.21, p &lt; 0.001), whereas a normal hemoglobin level (HR = 0.43, 0.19-0.95, p = 0.037) predicted longer OS.Conclusions: With the continuing improvement in OS, a higher proportion of MM patients might develop SPM. The OS following SPM diagnosis is poor; hence, frequent surveillance and early detection are imperative to improve outcomes

Plain Language Summary of the iNNOVATE study: ibrutinib plus rituximab is well-tolerated and effective in people with Waldenström's macroglobulinemia

This article provides a short summary of 5-year results from the iNNOVATE trial. The original paper was published in the Journal of Clinical Oncology in October 2021. People with Waldenström's macroglobulinemia (WM) were randomly divided into two groups of 75 people each. One group received a combination treatment composed of two drugs, ibrutinib plus rituximab, and the other group took placebo (“sugar pill”) plus rituximab. Ibrutinib (also known by the brand name Imbruvica®) is a drug that reduces cancer cells' ability to multiply and survive. Ibrutinib is an FDA-approved drug for the treatment of WM. Rituximab is a drug that helps the immune system find and kill cancer cells. Participants in the trial were treated and their health monitored for up to 5 years (63 months).Editorial support for development of this summary was provided by Cindi A. Hoover, PhD, and was funded by Pharmacyclics LLC, an AbbVie Company.Peer reviewe

Phase III Study of PSC-833 (Valspodar) in Combination with Vincristine, Doxorubicin, and Dexamethasone (Valspodar/VAD) versus VAD Alone in Patients with Recurring or Refractory Multiple Myeloma (E1A95)

BACKGROUND. Preliminary studies have shown valspodar (PSC-833: Novartis Pharmaceuticals, East Hanover, NJ) to be a potent inhibitor of multidrug resistance (MDR), one cause of resistance to chemotherapy. An international randomized control study (Phase III) evaluated the use of vincristine, doxorubicin, and dexamethasone (VAD) with (n 46) and without (n 48) valspodar in the treatment of patients with recurring or refractory multiple myeloma. METHODS. Patients with documented recurrence or refractory myeloma were stratified based on prior treatment exposure and creatinine and randomized. Because of interaction of valspodar with vincristine and doxorubicin, the doses of these drugs were reduced compared with the VAD-alone arm, and the doxorubicin was further reduced in the last 15 patients when given with valspodar based on pharmacokinetic and toxicity studies. RESULTS. There were no complete or near-complete responses. There were 29% partial responses (PRs) in the VAD-alone arm and 44% with valspodar (P 0.2). Median progression-free survival was 7 months with VAD alone and 4.9 months with valspodar (P 0.50). Subjective response was 19% with VAD alone and 17% with valspodar (P 1.0). Median survival with VAD alone was 18.5 months and 15.3 with the addition of valspodar (P 0.055). Toxicity of Grade 3 or greater was higher (P 0.0001) in the valspodar arm (89%) compared with the VAD-alone arm (58%). The reduction of doxorubicin dose reduced toxicity but not significantly (P 0.11). CONCLUSION. The addition of the MDR-modulating agent valspodar to VAD did not improve treatment outcome. Toxicity was increased in the valspodar-treated group compared with VAD alone

Phase 3 trial of ibrutinib plus rituximab in Waldenström's macroglobulinemia

En este estudio se evaluó el efecto de la adición de ibrutinib a rituximab en pacientes con macro-globulinemia de Waldenström, tanto en paciente que no habían recibido tratamiento previo como en aquellos con recidiva de la enfermedad. Se asignaron aleatoriamente 150 pacientes sintomá-ticos para recibir ibrutinib más rituximab o placebo más rituximab. El criterio principal de valoración fue la supervivencia libre de progresión, evaluada por un comité de revisión independiente. Los criterios de valoración secundarios clave fueron las tasas de respuesta, la mejoría hematológica sostenida desde el inicio y la seguridad. Se evaluó el estado mutacional de MYD88 y CXCR4 en muestras de médula ósea. A los 30 meses de seguimiento, la de supervivencia libre de progre-sión fue del 82% con ibrutinib-rituximab frente al 28% con placebo-rituximab (Hazard Ratio 0,20; P<0,001). El beneficio en el grupo de ibrutinib-rituximab sobre el grupo de placebo-rituximab fue independiente del genotipo MYD88 o CXCR4. La proporción de respuestas mayores fue más alta con ibrutinib-rituximab que con placebo-rituximab (72% vs. 32%, P<0,001). Hubo más pacientes con aumentos sostenidos en la concentración de hemoglobina con ibrutinib-rituximab que con placebo-rituximab (73% vs. 41%, P<0,001). Los efectos adversos más comunes (cualquier grado) con ibrutinib-rituximab, en especial reacciones relacionadas con la infusión, diarrea, artralgia y náuseas. Los efectos adversos grado ≥3 que fueron más frecuentes con ibrutinib-rituximab que con placebo-rituximab incluyeron fibrilación auricular (12% vs. 1%) e hipertensión (13% vs. 4%); los que ocurrieron con menos frecuencia incluyeron reacciones a la infusión (1% vs. 16%) y cual-quier grado de flare de IgM (8% vs. 47%). La tasa de hemorragia mayor fue la misma en los dos grupos de ensayo (4%). Gracias a este ensayo, que mostró beneficios en los pacientes con macroglobulinemia de Wal-denström para la combinación ibrutinib-rituximab frente a rituximab sólo (mejor supervivencia libre de progresión), tanto en pacientes de nuevo diagnóstico como en segunda línea, el fármaco se aprobó por la FDA. La EMA y la AEMPS, convirtiéndose en un estándar de tratamiento para la MW, con gran aceptación entre médicos y pacientes. Además se advirtió de la necesidad de to-mar actitudes activas frente a efectos secundarios relevantes como fibrilación auricular e hiperten-sión fueron más frecuentes con ibrutinib-rituximab, aunque el nuevo fármaco se vio favorecido por una menor frecuencia de reacciones a la perfusión y el fenómeno flare que sin dicho fármaco. El ensayo fue financiado por Pharmacyclics y Janssen Research and Development y se registró en ClinicalTrials.gov: NCT02165397.[EN]Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence. We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples. At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%); those that occurred less frequently included infusion reactions (1% vs. 16%) and any grade of IgM flare (8% vs. 47%). The major hemorrhage rate was the same in the two trial groups (4%). Among patients with Waldenström's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .).Janssen Research and Development PharmacyclicsJanssen Research and Developmen