Myeloma XIV: Frailty-adjusted Therapy in Transplant Non-Eligible Patients With Newly Diagnosed Multiple Myeloma

Progression-free survival (PFS-R1)

PFS-R1 is defined as the time from R1 to the time of first documented evidence of disease progression or death from any cause. Individuals who are lost to follow-up or progression-free at the time of analysis will be censored at their last known date to be alive and progression-free. Disease progression is defined according to the IMWG Uniform Response Criteria for Multiple Myeloma.

Time frame: The time from the date of Randomisation 1 to the date of first documented evidence of disease progression or death from any cause, up to 120 months

Time to disease progression

Time to disease progression is defined for both Randomisation 1 and Randomisation 2 as the time from randomisation to the date of first documented evidence of disease progression. Participants who die prior to documentation of disease progression will be censored in the analysis at their date of death. Participants not reaching disease progression at the time of analysis will be censored at the last date known to be progression-free. Participants dying from causes not primarily due to progression will also be censored.

Time frame: The time from the date of randomisation to the date of first documented evidence of disease progression, up to 120 months

Progression-free survival two (PFS2)

For both Randomisation 1 and Randomisation 2, progression-free survival two is defined as the time from randomisation to the time of the second documented disease progression. Individuals who are lost to follow-up or second progression-free at the time of analysis will be censored at their last known date to be alive and second progression-free.

Time frame: The time from the date of randomisation to the date of the second documented disease progression, up to 120 months

Overall survival (OS)

Overall survival is defined separately for each randomisation. In each case it is the time from randomisation to the time of death from any cause. Individuals who are lost to follow-up or still alive at the time of analysis will be censored at their last known date to be alive.

Time frame: The time from the date of randomisation to the date of death from any cause, up to 120 months

Survival after progression

Survival after progression is defined from the date of first documented evidence of disease progression to the date of death from any cause. Individuals who are lost to follow-up or alive at the time of analysis will be censored at their last known date to be alive following their first documented evidence of disease progression.

Time frame: The date of first documented evidence of disease progression to the date of death from any cause, up to 120 months

Deaths within 12 months of Randomisation 1 (R1)

Deaths within 12 months of Randomisation 1 is defined as a binary endpoint. Participants will be defined to have experienced an event if they die within 12 months of Randomisation 1.

Time frame: Within 12 months of Randomisation 1

Overall response rate (ORR)

Overall response rate is defined as a categorical outcome consisting of whether a participant had Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Minimal Response (MR), Stable Disease (SD) or Progressive Disease (PD) at the end of induction according to the IMWG Uniform Response Criteria for Multiple Myeloma.

Time frame: From the date of Randomisation 1 to the end of 12 cycles of induction treatment (each induction cycle is 28 days)

Attainment of ≥VGPR

Attainment of ≥VGPR is defined as a binary outcome of whether a participant had ≥VGPR (VGPR, CR, sCR) or \<VGPR (PR, MR, SD, PD) at the end of induction, according to the IMWG Uniform Response Criteria for Multiple Myeloma.

Time frame: From the date of Randomisation 1 to the end of 12 cycles of induction treatment (each induction cycle is 28 days)

Attainment of Minimal Residual Disease (MRD) negativity

Attainment of Minimal Residual Disease (MRD) negativity is defined as a binary endpoint. MRD negativity will be determined at the end of induction therapy and 12 months post Randomisation 2 according to the IMWG MRD criteria.

Time frame: From the date of Randomisation 1 to the end of 12 cycles of induction treatment (each induction cycle is 28 days); and 12 months after the date of Randomisation 2

Duration of response (DoR)

Duration of response is defined as the time from the first observation of response ≥ Partial Response (PR), following Randomisation 1, to the time of first documented evidence of disease progression or death confirmed related to progression. Individuals who are lost to follow-up, or still alive and progression-free at the time of analysis will be censored at their last known date to be alive and progression-free. Individuals whose cause of death is unrelated to disease progression will be censored at their date of death.

Time frame: The time from the date of the first observation of response ≥ Partial Response following Randomisation 1, to the date of first documented evidence of disease progression or death confirmed related to progression, up to 120 months

Time to improved response

Time to improved response is defined as the time from the date of Randomisation 2 to the date the response category is first improved based on the Modified International Uniform Response Criteria for Multiple Myeloma. Subjects without any improvement of the baseline status at Randomisation 2 will be censored at the last date of response assessment.

Time frame: The time from the date of Randomisation 2 to the date the response category is first improved, up to 120 months

Time to next treatment

Time to next treatment is defined as the time from Randomisation 1 to the start date of the next line of treatment or death from any cause.

Time frame: The time from the date of Randomisation 1 to the start date of the next line of treatment or death from any cause, up to 120 months

Treatment compliance and total amount of therapy delivered

In the first instance treatment compliance is defined as a binary outcome i.e. did the participant receive 12 cycles of induction treatment. The total amount of therapy delivered will be first defined as the number of induction and maintenance cycles which the participant received. This may be extended to consider the percentage of protocol dose delivered. For each treatment (ixazomib, lenalidomide, dexamethasone) this will be defined as the total dose received in a cycle compared to the total dose the participant should have received in the cycle without modifications, averaged across all cycles of treatment.

Time frame: Number of induction and maintenance cycles a participant received (each cycle of induction or maintenance is 28 days), until disease progression, up to 120 months

Incidence of treatment-emergent adverse events (Toxicity and safety, including incidence of second malignancies)

Toxicity \& safety, including incidence of second malignancies Toxicity and safety will be reported based on the adverse events, as graded by CTCAE V5 and determined by routine clinical assessments at each centre. The number of SAEs will be reported according to MedDRA System Organ Class. All second primary malignancies will be reported based on information collected on the Case Report Form.

Time frame: Baseline, end of each induction cycle (each induction cycle is 28 days), end of each maintenance cycle (each maintenance cycle is 28 days), until disease progression, up to 120 months

EORTC QLQ-C30_questionnaire

European Organization for the Research \& Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) is used to measure patient-assessed quality of life (QoL) at R1, after cycles 2, 4, 6 \& 12 of induction, and after cycles 6 and 12 of maintenance (all cycles are 28 days). The QLQ-C30 comprises multi-item scales \& single-item measures: 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, pain, nausea \& vomiting), a global health status/QoL scale, \& 6 single items assessing additional symptoms (dyspnoea, loss of appetite, insomnia, constipation \& diarrhoea). All scales \& single-item measures range in score from 0 to 100. A high scale score represents a higher response level: a high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/QoL represents a high quality of life, but a high score for a symptom scale/item represents a high level of symptomatology/problems.

Time frame: Randomisation 1; after cycles 2, 4, 6 and 12 of induction treatment (each induction cycle is 28 days); after cycles 6 and 12 of maintenance treatment (each maintenance cycle is 28 days)

EORTC QLQ-MY20_questionnaire

The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) is used to measure patient-assessed quality of life (QoL) at Randomisation 1, after cycles 2, 4, 6 and 12 of induction treatment (each induction cycle is 28 days), and after cycles 6 and 12 of maintenance treatment (each maintenance cycle is 28 days). The EORTC QLQ-MY20 comprises 20 questions that address four myeloma-specific QoL domains: Disease Symptoms, Side Effects of Treatment, Future Perspectives, and Body Image. Disease Symptoms, Side Effects of Treatment, and Future Perspectives are all multi-item scales, and Body Image is a single-item scale. Domain scores are averaged and transformed linearly to a score ranging from 0-100. A high score for Disease Symptoms and Side Effects of Treatment represents a high level of symptomatology or problems, whereas a high score for Future Perspective and Body Image represents better outcomes.

Time frame: Randomisation 1; after cycles 2, 4, 6 and 12 of induction treatment (each induction cycle is 28 days); after cycles 6 and 12 of maintenance treatment (each maintenance cycle is 28 days)

EQ-5D-3L_questionnaire

The EuroQol 5 Dimension 3 Level questionnaire (EQ-5D-3L) will be used to measure participant-assessed quality of life at Randomisation 1, after cycles 2, 4, 6 and 12 of induction treatment (each induction cycle is 28 days), and after cycles 6 and 12 of maintenance treatment (each maintenance cycle is 28 days). The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results into a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.

Time frame: Randomisation 1; after cycles 2, 4, 6 and 12 of induction treatment (each induction cycle is 28 days); after cycles 6 and 12 of maintenance treatment (each maintenance cycle is 28 days)