A Study to Evaluate the Efficacy and Safety of Ixazomib in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma Initially Treated With an Injection of Proteasome Inhibitor-Based Therapy

Browse trials for

• Multiple Myeloma 3,627
• Neoplasms, Plasma Cell 2,308

Study arms

• Experimental
  Combination Therapy + Ixazomib Therapy

  Bortezomib + Lenalidomide + Dexamethasone, or Carfilzomib + Lenalidomide + Dexamethasone, standard recommended dose according to the package insert of each drug (Treatment Period I), followed by Ixazomib (4.0 mg) on Days 1, 8 and 15, plus Lenalidomide (25 mg) on Days 1 to 21, and Dexamethasone (40 mg) on Days 1, 8, 15 and 22, of a 28-day cycle (Treatment Period II)

  Drug: Ixazomib · Drug: Bortezomib · Drug: Carfilzomib · Drug: Lenalidomide · Drug: Dexamethasone

Interventions

• DrugIxazomib

  Ixazomib capsules

• DrugBortezomib

  Bortezomib injections

• DrugCarfilzomib

  Carfilzomib intravenous infusions

• DrugLenalidomide

  Lenalidomide capsules

• DrugDexamethasone

  Dexamethasone tablets

Primary outcomes

1. Progression-Free Survival (PFS) Rate at 12 Months From the Start of Study Treatment

   PFS rate was defined as the percentage of participants who were alive and have not had disease progression at 12 months after the date of first dose of treatment in Treatment Period I. PFS was assessed by International Myeloma Working Group (IMWG) Criteria (2014 version). Per IMWG criteria, progressive disease (PD): serum M-component increase ≥0.5 g/dl or urine M-component increase ≥200 mg/24-hour/ difference between involved and uninvolved free light chain (FLC) levels increase \>10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.

   Time frame: Up to 12 months

Secondary outcomes

1. Overall Survival (OS) From the Start of Study Treatment

   OS was defined as the period from the first dose of treatment in Treatment Period I to the time when death (regardless of the cause of death) was confirmed. Participants who were still alive were censored at the last confirmed date of survival or the date of data cut-off, whichever was earlier.

   Time frame: Up to 39 months as a maximum

2. PFS From the Start of Study Treatment

   PFS was defined as the period from the first dose of treatment in Treatment Period I to the time of confirmed PD or confirmed death (regardless of the cause of death), whichever is earlier. PFS was assessed by IMWG Criteria.

   Time frame: Up to 39 months as a maximum

3. Percentage of Participants Who Achieved VGPR or Better (CR + VGPR)

   VGPR or better (CR + VGPR) were assessed by IMWG Criteria. Per IMWG criteria, PR (partial response): ≥50% reduction of serum M protein+reduction in 24-hour urinary M protein by ≥90%/ to \<200 mg/24-hour or ≥50% decrease in difference between involved and uninvolved free light chain (FLC) levels/ ≥50% reduction in bone marrow plasma cells, if ≥30% at baseline/ ≥50% reduction in size of soft tissue plasmacytomas. VGPR (very good PR): serum+urine M-protein detectable by immunofixation but not on electrophoresis/ ≥90% reduction in serum M-protein+urine Mprotein level \<100 mg/24-hour. CR (complete response): negative immunofixation on serum+urine+disappearance of soft tissue plasmacytomas+\<5% plasma cells in bone marrow.

   Time frame: Up to 39 months as a maximum

4. Number of Participants With Minimal Residual Disease (MRD) Positive or Negative in Bone Marrow in Participants Who Achieved CR

   MRD was measured by the flow cytometry method using bone marrow aspiration. Reported data were numbers of participants with MRD positive and negative in bone marrow in participants who achieved CR. MRD positive was categorized into three sensitivity levels with the numbers of cells counted (10\^-4 to - Max; 10\^-5 to 10\^-4; 10\^-6 to 10\^-5). MRD negativity is defined as absence of MRD and MRD positivity is defined as presence of MRD. If a participant is MRD-positive at their first evaluation and MRD-negative after re-examination, the participant will be considered to be MRD-negative. CR will be assessed by IMWG Criteria.

   Time frame: Up to 39 months as a maximum

5. Percentage of Participants Who Achieve or Maintain Any Best Response

   Best response is defined as the cumulative numbers of participants who achieve each level of best response including PR, VGPR and CR assessed with IMWG Criteria, after each cycle of treatment. Per IMWG criteria, PR (partial response): ≥50% reduction of serum M protein+reduction in 24-hour urinary M protein by ≥90%/ to \<200 mg/24-hour or ≥50% decrease in difference between involved and uninvolved free light chain (FLC) levels/ ≥50% reduction in bone marrow plasma cells, if ≥30% at baseline/ ≥50% reduction in size of soft tissue plasmacytomas. VGPR (very good PR): serum+urine M-protein detectable by immunofixation but not on electrophoresis/ ≥90% reduction in serum M-protein+urine Mprotein level \<100 mg/24-hour. CR (complete response): negative immunofixation on serum+urine+disappearance of soft tissue plasmacytomas+\<5% plasma cells in bone marrow.

   Time frame: Up to 39 months as a maximum

6. Overall Response Rate (ORR)

   ORR is defined as the percentage of participants who achieve a best response of PR or better including stringent complete response (sCR), VGPR and PR assessed with IMWG Criteria, after the start of the study treatment. Per IMWG criteria, PR (partial response): ≥50% reduction of serum M protein+reduction in 24-hour urinary M protein by ≥90%/ to \<200 mg/24-hour or ≥50% decrease in difference between involved and uninvolved free light chain (FLC) levels/ ≥50% reduction in bone marrow plasma cells, if ≥30% at baseline/ ≥50% reduction in size of soft tissue plasmacytomas. VGPR (very good PR): serum+urine M-protein detectable by immunofixation but not on electrophoresis/ ≥90% reduction in serum M-protein+urine Mprotein level \<100 mg/24-hour. CR (complete response): negative immunofixation on serum+urine+disappearance of soft tissue plasmacytomas+\<5% plasma cells in bone marrow.

   Time frame: Up to 39 months as a maximum

7. Percentage of Participants Continuing Treatment With Ixazomib at 12 Months From the Start of Study Treatment

   Time frame: 12 months

8. Duration of Response (DOR)

   DOR is defined as the time from the date of first documentation of response ≥PR to the date of first documentation of PD or death due to any cause. PR and PD will be assessed with IMWG Criteria. Per IMWG criteria, PR (partial response): ≥50% reduction of serum M protein+reduction in 24-hour urinary M protein by ≥90%/ to \<200 mg/24-hour or ≥50% decrease in difference between involved and uninvolved free light chain (FLC) levels/ ≥50% reduction in bone marrow plasma cells, if ≥30% at baseline/ ≥50% reduction in size of soft tissue plasmacytomas. VGPR (very good PR): serum+urine M-protein detectable by immunofixation but not on electrophoresis/ ≥90% reduction in serum M-protein+urine Mprotein level \<100 mg/24-hour. CR (complete response): negative immunofixation on serum+urine+disappearance of soft tissue plasmacytomas+\<5% plasma cells in bone marrow.

   Time frame: Up to 39 months as a maximum

9. Time to Next Treatment (TTNT)

   TTNT is defined as the period from the start of study treatment Period I to the start of next line treatment.

   Time frame: Up to 39 months as a maximum

10. Duration of Therapy (DOT)

    DOT is defined as the treatment duration of study drug at study treatment Period I.

    Time frame: Up to 39 months as a maximum

11. Patient-Reported Outcome Health-Related Quality of Life (HRQoL) Based on Global Health Status Scale of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (EORTC QLQ-C30)

    EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale (Global Health Status). EORTC QLQ-C30 contains 28 questions (4-point scale where 1=Not at all \[best\] to 4=Very Much \[worst\]) and 2 questions (7-point scale where 1=Very poor \[worst\] to 7= Excellent \[best\]). Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QOL scale, higher scores represent better QOL; for the symptom scales, lower scores represent better QOL.

    Time frame: Baseline and End of Treatment (Up to 23 cycles for VRd Group, Up to 32 cycles for KRd and Overall Group, each cycle was of 28 days)

12. Patient-Reported Outcome HRQoL Based on EORTC Multiple Myeloma Module (EORTC QLQ-MY20) Score

    EORTC QLQ-MY20 has 20 items across 4 independent subscales, 2 functional subscales (body image, future perspective), and 2 symptoms scales (disease symptoms, and side effects of treatment). Scores are averaged, and transformed to 0-100 scale. For the functional scales, high scores represent improvement. For the symptom scales, higher scores represent worsening.

    Time frame: Baseline and End of Treatment (Up to 23 cycles for VRd Group, Up to 32 cycles for KRd and Overall Group, each cycle was of 28 days)

13. Evaluation of Modified Quality-Adjusted Life-Years (QALYs)

    Modified QALYs was calculated from the score of EORTC QLQ-C30. The health-related quality of life scale score of EORTC QLQ-C30 was converted into a utility value ranging from 0 (dead) to 1 (perfect health), and used to adjust the value of survival years; this value was assessed as the modified QALY.

    Time frame: Up to 39 months as a maximum

14. Healthcare Resource Utilization (HCRU): Number of Events With Hospitalization Per Participants-Month

    HCRU was calculated from Exposure-adjusted rate of hospitalization events (per participants-months) and the duration of hospitalization among participants in Treatment Period I and Treatment Period II. Number of events with hospitalization per participants-month in Treatment Period I and Treatment Period II was reported.

    Time frame: Up to 39 months as a maximum

15. Healthcare Resource Utilization (HCRU): Duration of Hospital Stay Per Participants

    HCRU was calculated from Exposure-adjusted rate of hospitalization events (per participants-months) and the duration of hospitalization among participants in Treatment Period I and Treatment Period II. Duration of hospital stay per participants in Treatment Period I and Treatment Period II was reported.

    Time frame: Up to 39 months as a maximum

16. Relative Dose Intensity (RDI)

    RDI for each study drug is defined as 100\*(Total amount of dose taken)/(Total prescribed dose of treated cycles), where total prescribed dose equals \[dose prescribed at enrollment\* number of prescribed doses per cycle\* the number of treated cycles\].

    Time frame: Up to 39 months as a maximum

17. Percentage of Participants With Bone Lesions (Bone Evaluation)

    Time frame: Up to 39 months as a maximum

18. Number of Participants Reporting One or More Treatment-Emergent AEs (TEAEs)

    An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

    Time frame: Up to 39 months as a maximum

Baseline characteristics

3 further baseline measures are reported on the registry.

Related links

• To obtain more information on the study, click here/on this link ↗

Study documents

• Study protocol · May 30, 2019
• Statistical analysis plan · Nov 1, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Supporting information: Study protocol, Sap, Icf, Csr