Ruemu E. Birhiray

BACKGROUND: Randomized clinical trials (RCTs) typically enroll highly selected populations. Oncology RCTs have an average of 16 eligibility criteria (Unger JNCI 2014). Registry analyses indicate that up to ~40% of ‘real-world’ MM patients are ineligible for RCTs based on common criteria (Shah CLML 2017).

PURPOSE: US MM-6 (NCT03173092) is evaluating iCT from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) in MM patients treated at US community oncology centers. Eligibility criteria are less stringent than RCTs, to enroll patients more representative of the real-world MM population.

METHODS: Non-transplant-eligible newly-diagnosed MM patients with stable disease or better after 3 cycles of bortezomib-based induction are being enrolled at 22 US community sites (including three Veterans Affairs hospitals) to receive ixazomib-Rd for up to 39 28- day cycles or until progression/toxicity.

DATA ANALYSIS: We reviewed 84 consecutively enrolled patients using standard RCT eligibility criteria. Initially, six criteria were explored to determine the proportion of patients who might have been RCT-ineligible: renal dysfunction, congestive heart failure (CHF), stroke, prior malignancies, chronic obstructive pulmonary disease (COPD), and memory loss. Dosing information was evaluated to determine any correlation between dose modifications and eligibility status.

RESULTS: Based on six criteria, 24/84 patients (29%) may have been RCT-ineligible: 12% (n=10) had renal dysfunction, 7% (n=6) CHF, 6% (n=5) stroke, 5% (n=4) each other prior malignancies and COPD, and 2% (n=2) memory loss; 6% (n=5) had >1 criterion. Among the 24 RCT-ineligible patients, 75% (n=18), 42% (n=10), and 54% (n=13) received the highest starting doses of ixazomib (4mg), lenalidomide (25mg), and dexamethasone (40mg), respectively. Ixazomib, lenalidomide, and dexamethasone dose reductions were required in 29% (n=7), 25% (n=6), and 21% (n=5), respectively (due to adverse events [AEs]: 21% [n=5], 21% [n=5], 4% [n=1]). 50% (n=12) discontinued treatment (consent withdrawal/patient decision, n=7; disease progression, n=2; sufficient response, AE, death, each n=1); n=3/2/2 discontinued ixazomib/lenalidomide/ dexamethasone due to AEs.

IMPLICATIONS: US MM-6 is enrolling real-world, community- based MM patients, including those who may be ineligible for RCTs based on standard inclusion criteria. Our analysis indicates that iCT to ixazomib- Rd appears to be feasible in these RCT-ineligible US MM-6 patients. Further criteria will be analyzed and presented.

BACKGROUND: Randomized clinical trials (RCTs) typically enroll highly selected populations. Oncology RCTs have an average of 16 eligibility criteria (Unger JNCI 2014). Registry analyses indicate that up to ~40% of ‘real-world’ MM patients are ineligible for RCTs based on common criteria (Shah CLML 2017).

PURPOSE: US MM-6 (NCT03173092) is evaluating iCT from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) in MM patients treated at US community oncology centers. Eligibility criteria are less stringent than RCTs, to enroll patients more representative of the real-world MM population.

METHODS: Non-transplant-eligible newly-diagnosed MM patients with stable disease or better after 3 cycles of bortezomib-based induction are being enrolled at 22 US community sites (including three Veterans Affairs hospitals) to receive ixazomib-Rd for up to 39 28- day cycles or until progression/toxicity.

DATA ANALYSIS: We reviewed 84 consecutively enrolled patients using standard RCT eligibility criteria. Initially, six criteria were explored to determine the proportion of patients who might have been RCT-ineligible: renal dysfunction, congestive heart failure (CHF), stroke, prior malignancies, chronic obstructive pulmonary disease (COPD), and memory loss. Dosing information was evaluated to determine any correlation between dose modifications and eligibility status.

RESULTS: Based on six criteria, 24/84 patients (29%) may have been RCT-ineligible: 12% (n=10) had renal dysfunction, 7% (n=6) CHF, 6% (n=5) stroke, 5% (n=4) each other prior malignancies and COPD, and 2% (n=2) memory loss; 6% (n=5) had >1 criterion. Among the 24 RCT-ineligible patients, 75% (n=18), 42% (n=10), and 54% (n=13) received the highest starting doses of ixazomib (4mg), lenalidomide (25mg), and dexamethasone (40mg), respectively. Ixazomib, lenalidomide, and dexamethasone dose reductions were required in 29% (n=7), 25% (n=6), and 21% (n=5), respectively (due to adverse events [AEs]: 21% [n=5], 21% [n=5], 4% [n=1]). 50% (n=12) discontinued treatment (consent withdrawal/patient decision, n=7; disease progression, n=2; sufficient response, AE, death, each n=1); n=3/2/2 discontinued ixazomib/lenalidomide/ dexamethasone due to AEs.

IMPLICATIONS: US MM-6 is enrolling real-world, community- based MM patients, including those who may be ineligible for RCTs based on standard inclusion criteria. Our analysis indicates that iCT to ixazomib- Rd appears to be feasible in these RCT-ineligible US MM-6 patients. Further criteria will be analyzed and presented.

BACKGROUND: Randomized clinical trials (RCTs) typically enroll highly selected populations. Oncology RCTs have an average of 16 eligibility criteria (Unger JNCI 2014). Registry analyses indicate that up to ~40% of ‘real-world’ MM patients are ineligible for RCTs based on common criteria (Shah CLML 2017).

PURPOSE: US MM-6 (NCT03173092) is evaluating iCT from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) in MM patients treated at US community oncology centers. Eligibility criteria are less stringent than RCTs, to enroll patients more representative of the real-world MM population.

METHODS: Non-transplant-eligible newly-diagnosed MM patients with stable disease or better after 3 cycles of bortezomib-based induction are being enrolled at 22 US community sites (including three Veterans Affairs hospitals) to receive ixazomib-Rd for up to 39 28- day cycles or until progression/toxicity.

DATA ANALYSIS: We reviewed 84 consecutively enrolled patients using standard RCT eligibility criteria. Initially, six criteria were explored to determine the proportion of patients who might have been RCT-ineligible: renal dysfunction, congestive heart failure (CHF), stroke, prior malignancies, chronic obstructive pulmonary disease (COPD), and memory loss. Dosing information was evaluated to determine any correlation between dose modifications and eligibility status.

RESULTS: Based on six criteria, 24/84 patients (29%) may have been RCT-ineligible: 12% (n=10) had renal dysfunction, 7% (n=6) CHF, 6% (n=5) stroke, 5% (n=4) each other prior malignancies and COPD, and 2% (n=2) memory loss; 6% (n=5) had >1 criterion. Among the 24 RCT-ineligible patients, 75% (n=18), 42% (n=10), and 54% (n=13) received the highest starting doses of ixazomib (4mg), lenalidomide (25mg), and dexamethasone (40mg), respectively. Ixazomib, lenalidomide, and dexamethasone dose reductions were required in 29% (n=7), 25% (n=6), and 21% (n=5), respectively (due to adverse events [AEs]: 21% [n=5], 21% [n=5], 4% [n=1]). 50% (n=12) discontinued treatment (consent withdrawal/patient decision, n=7; disease progression, n=2; sufficient response, AE, death, each n=1); n=3/2/2 discontinued ixazomib/lenalidomide/ dexamethasone due to AEs.

IMPLICATIONS: US MM-6 is enrolling real-world, community- based MM patients, including those who may be ineligible for RCTs based on standard inclusion criteria. Our analysis indicates that iCT to ixazomib- Rd appears to be feasible in these RCT-ineligible US MM-6 patients. Further criteria will be analyzed and presented.