Randomized Phase III Trial of Bortezomib, Lenalidomide, and Dexamethasone (VRd) Versus Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Followed by Limited or Indefinite Duration Lenalidomide Maintenance in Patients With Newly Diagnosed Symptomatic Multiple Myeloma (ENDURANCE)

Brief Summary

Detailed Description

PRIMARY OBJECTIVES: I. To compare the overall survival between two strategies of lenalidomide maintenance following induction with a proteasome inhibitor? immunomodulatory drug (IMiD) combination: limited duration of maintenance (24 months) versus indefinite maintenance therapy until disease progression. II. To compare progression-free survival between bortezomib, lenalidomide, and dexamethasone (VRd) and carfilzomib, lenalidomide, and dexamethasone (CRd) induction followed by lenalidomide maintenance in patients with newly diagnosed symptomatic multiple myeloma. SECONDARY OBJECTIVES: I. To compare the progression-free survival between two strategies of lenalidomide maintenance following induction with a proteasome inhibitor?IMiD combination: limited duration of maintenance (24 months) or indefinite maintenance therapy until disease progression. II. To compare induction rates of response between VRd and CRd arms. III. To evaluate time to progression, duration of response and overall survival between VRd and CRd induction therapy. IV. To compare induction rates of toxicity between VRd and CRd arms. V. To evaluate toxicity during lenalidomide maintenance. VI. To compare minimal residual disease (MRD) negative rates between VRd and CRd arms at end of induction therapy. TERTIARY OBJECTIVES: I. To compare the short and long-term health-related quality of life impact between the two strategies of lenalidomide maintenance. II. To compare the impact on health-related quality of life between VRd and CRd induction therapy. III. To evaluate the association between early induction response and change in health-related quality of life. IV. To describe changes in health-related quality of life during the induction, active maintenance and observation phases. V. To evaluate correlation between treatment adherence during maintenance and health-related quality of life. VI. To compare MRD negative rates between the two strategies of lenalidomide maintenance. VII. To compare MRD negative rates between VRd and CRd arms during induction therapy. VIII. To examine patterns of change in MRD levels over time and examine conversion from detectable to MRD negative status. IX. To evaluate agreement and association between International Myeloma Working Group (IMWG) and MRD based disease-free status. X. To describe the mutational profile of newly diagnosed multiple myeloma. XI. To identify mutations associated with resistance to VRd and CRd induction therapy. XI. To identify expression profiles associated with MRD negative status with each induction therapy. XII. To determine the ability of MRD status at induction end to predict short-term and long-term overall and progression-free survival. XIII. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity (adverse events \[both clinical and hematologic\] and dose modifications). XIV. To determine the effects of tobacco on patient-reported physical symptoms and psychological symptoms. XV. To examine quitting behaviors and behavioral counseling/support and cessation medication utilization. XVI. To explore the effect of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit. OUTLINE: INDUCTION: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) on days 1, 4, 8, and 11 of courses 1-8 and days 1 and 8 of courses 9-12; lenalidomide orally (PO) daily on days 1-14; and dexamethasone PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of courses 1-8 and days 1, 2, 8, and 9 of courses 9-12. Treatment repeats every 3 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16; lenalidomide PO daily on days 1-21; and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for 9 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE: After completion of induction therapy (or completion of at least 6 courses in Arm A but stopped early due to unacceptable toxicity, or at least 4 courses in Arm B but stopped early due to unacceptable toxicity), patients are then randomized to 1 of 2 maintenance treatment arms. ARM C: Patients receive lenalidomide PO daily on days 1-21. Treatment repeats every 4 weeks for 24 courses in the absences of disease progression or unacceptable toxicity. ARM D: Patients receive lenalidomide PO daily on days 1-21. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 10 years.

Primary Outcomes

Secondary Outcomes

• Overall survival for the induction analysis(From induction randomization to death due to any cause, or censored at the date last known alive, assessed up to 15 years)
• Progression-free survival for the maintenance analysis(From the maintenance randomization until the earlier of progression or death due to any cause, assessed up to 15 years)
• Incidence of overall grade 3 or higher non-hematologic toxicity and grade 3 or higher toxicity by type during induction, active maintenance and observation phases using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0(Up to 15 years)
• Change in the FACT-Ntx TOI for the short-term maintenance analysis(From the end of 2 years of maintenance to 3 years post maintenance randomization)
• Change in the FACT-Ntx TOI for the early induction analysis(From baseline (induction randomization) to 2.8 months of induction therapy)
• Response rates including partial response (PR), very good partial response (VGPR), immunofixation negative complete response (IF-CR) and complete response (CR)(At 2.8 months)
• Response rates including PR, VGPR, IF-CR and CR(At 8.3 months)
• Time to progression (TTP) for the induction analysis(From the induction randomization to progression, or censored at the date of last disease evaluation for those without progression reported, assessed up to 15 years)
• Duration of response (DOR) for the induction analysis(From first objective response (partial response or better) since induction randomization until the earlier of progression or death due to any cause, or censored at date of last disease evaluation for those without events reported, assessed up to 15 years)
• Incidence of grade 2 or higher peripheral neuropathy and cardiac toxicity during induction phase assessed using CTCAE version 5.0(Up to 36 weeks)
• Minimal residual disease (MRD) negative rates(At 8.3 months after induction randomization)
• Change in the Functional Assessment of Cancer Therapy-Neurotoxicity Trial Outcome Index (FACT-Ntx TOI) for the transition to maintenance analysis(From week 36 (the end) of induction therapy to week 24 (end of course 6) of maintenance therapy)
• Change in the FACT-Ntx TOI for the long-term maintenance analysis(From the end of 2 years of maintenance to 5 years post maintenance randomization)
• Change in the FACT-Ntx TOI for the end of induction analysis(From baseline (induction randomization) to 36 weeks (end) of induction therapy)
• Levels and changes in the FACT-Ntx TOI and Functional Assessment of Cancer Therapy- Multiple Myeloma (FACT-MM) during induction, active maintenance and observation phases(Up to 15 years)
• Time to worsening of FACT-Ntx TOI for the induction analysis(From the baseline assessment at induction randomization to a decrease of 7 points, assessed up to 15 years)
• Time to worsening of FACT-MM for the maintenance analysis(From the baseline assessment at maintenance randomization to a decrease of 4 points, assessed up to 15 years)