**Discover how real-world evidence (RWE) for the NINLARO^® (ixazomib) regimen* can complement clinical trial results^1-6**

Four real-world studies, including REMIX, which is the largest prospective study of NINLARO in the real-world setting, provide additional data for the all-oral NINLARO regimen* as early as first multiple myeloma relapse.

EXPLORE NINLARO RWE

^*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone.¹

RWE PROVIDES DATA ABOUT PATIENT OUTCOMES FROM ROUTINE CLINICAL PRACTICE

Randomized, controlled trials are the gold standard for measuring efficacy and safety; however, up to 72% of real-world patients with relapsed and/or refractory multiple myeloma (RRMM)* do not meet eligibility criteria for clinical trials⁷

*Range: 47.9%-72.3%. Based on US EHR data from 600+ hospitals and 6,500 clinics.⁷

"In general, real-world evidence trials often include patients who are excluded from clinical trials and tend to experience worse outcomes,^3,7,9 perhaps because of comorbidities, concomitant medication use, or frailness."

– Saulius K. Girnius, MD

Real-world studies include a broader range of patients with RRMM who are underrepresented in clinical trials^3-6,8

"In addition to clinical trials, prospective or retrospective real-world studies are critical to help providers determine how treatments can help patients in their clinical practice.^3,8,9"

– Mihir Raval, MD, MPH

MEET BRUCE, A PATIENT EXPERIENCING AN INDOLENT FIRST RELAPSE

DISCOVER BRUCE'S VIDEO

THE TOURMALINE-MM1 PIVOTAL TRIAL EVALUATED EFFICACY AND SAFETY FOR THE NINLARO REGIMEN*

TOURMALINE-MM1 was a global, phase 3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of NINLARO + lenalidomide + dexamethasone vs placebo + lenalidomide + dexamethasone in patients with RRMM who had received at least one prior line of therapy (N=722).^1,2Explore MM1 efficacy Explore MM1 safety

CONSISTENT EFFICACY AND SAFETY WERE DEMONSTRATED WITH THE NINLARO REGIMEN*IN 4 REAL-WORLD STUDIES^1-6

Real-world study designs^3-6

REMIX Study, 2023: A multicenter, non-interventional, prospective study conducted at 60 sites in France that evaluated the effectiveness and safety of the NINLARO regimen* in 376 real-world patients^† with RRMM who initiated the regimen after ≥1 prior therapies. In the study population, 48.8% of patients were frail and 62.8% had at least 1 comorbidity.

Minařik et al, 2021: A prospective analysis of NINLARO regimen* vs Rd regimen* in 344 patients^† with relapsed or refractory multiple myeloma. Patients received a median of 1 prior therapy, the same as the TOURMALINE-MM1 study.

Hájek et al, 2021: A global retrospective pooled analysis of data from 2 discrete sources or registries^‡ evaluating the NINLARO regimen* in 263 patients^† with relapsed or refractory multiple myeloma. Patients had received a median of 2 prior therapies vs a median of 1 prior therapy in the TOURMALINE-MM1 study.

Terpos et al, 2020: A multicenter, retrospective analysis of the NINLARO regimen* in 155 patients^† with relapsed or refractory multiple myeloma. Patients received a median of 1 prior therapy, the same as the TOURMALINE-MM1 study.

Explore RWE Study Designs

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone.¹
^†Key exclusion criteria for Minařik et al, 2021, included: active first-line therapy; patients with missing data for primary endpoints; patients in clinical trials; patients who switched combination regimens. In Hájek et al, 2021, patients from INSIGHT MM were excluded if they had missing or incomplete data or had signed the study informed consent form more than 3 months after starting the NINLARO regimen. This analysis also excluded patients from RMG with missing or incomplete data. In Terpos et al, 2020, no exclusion criteria were identified. In REMIX 2023, patients who received lenalidomide more than 6 weeks before NINLARO + Rd were excluded from the study.^3-6
^‡Many of the patients included in the analysis were treated at academic centers; therefore these results may not be representative of the community practice setting.⁴

Important findings from the 2023 REMIX study

Real-world results from REMIX include PFS, disease control rate, discontinuation rates, and subgroup data based on frailty status and age.⁶

DISCOVER REMIX DATA

**Consistent PFS was seen with the NINLARO regimen* in the real
world^1-6**

Discover results from 4 real-world studies that evaluated RRMM patients outside of clinical trials.

Explore RWE Efficacy

ARs seen in real-world settings were consistent with the known safety
profile^4-6

The NINLARO regimen* demonstrated a safety profile comparable to the NINLARO arm in TOURMALINE-MM1 for patients with relapsed/refractory multiple myeloma.^1-6

Explore RWE Safety

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone; the Rd regimen included placebo + lenalidomide + dexamethasone.¹

ARs=adverse reactions; PFS=median progression-free survival; Rd=lenalidomide + dexamethasone; EHR=Electronic Health Record.

Cross-trial comparisons are potentially confounded by differences in trial design and study population. Observational, retrospective analyses are not intended for direct comparison with clinical trials.⁷

REAL-WORLD STUDY LIMITATIONS

Real-world analyses are often nonrandomized, observational, retrospective studies that may have unobserved treatment-selection biases as well as other limitations that should be considered when comparing results with clinical trials. Outcomes should be interpreted with caution because of small sample size, limited follow-up, and limited maturity of data.⁴ Learn more about study limitations

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with NINLARO. Platelet nadirs typically occurred between Days 14-21 of each 28-day cycle and recovered to baseline by the start of the next cycle. Grade 3 thrombocytopenia was reported in 17% of patients in the NINLARO regimen and Grade 4 thrombocytopenia was reported in 13% in the NINLARO regimen. During treatment, monitor platelet counts at least monthly, and consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications and platelet transfusions as per standard medical guidelines.

Gastrointestinal Toxicities, including diarrhea, constipation, nausea and vomiting were reported with NINLARO and may occasionally require the use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea resulted in the discontinuation of one or more of the three drugs in 3% of patients in the NINLARO regimen and 2% of patients in the placebo regimen. Adjust dosing for Grade 3 or 4 symptoms.

Peripheral Neuropathy was reported with NINLARO. The most commonly reported reaction was peripheral sensory neuropathy (24% and 17% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (<1%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 4% of patients in the NINLARO regimen and <1% of patients in the placebo regimen. During treatment, monitor patients for symptoms of neuropathy and consider adjusting dosing for new or worsening peripheral neuropathy.

Peripheral Edema was reported with NINLARO. Evaluate for underlying causes and provide supportive care, as necessary. Adjust dosing of NINLARO for Grade 3 or 4 symptoms or dexamethasone per its prescribing information.

Cutaneous Reactions. Stevens-Johnson syndrome and toxic epidermal necrolysis, including fatal cases, have been reported with NINLARO. If Stevens-Johnson syndrome or toxic epidermal necrolysis occurs, discontinue NINLARO and manage as clinically indicated. Rash, most commonly maculo-papular and macular rash, was reported with NINLARO. Rash resulted in discontinuation of one or more of the three drugs in <1% of patients in both regimens. Manage rash with supportive care or with dose modification if Grade 2 or higher.

Thrombotic Microangiopathy has been reported with NINLARO. Fatal cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop NINLARO and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TTP/HUS is not known.

Hepatotoxicity has been reported with NINLARO. Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in <1% of patients treated with NINLARO. Hepatotoxicity has been reported (10% in the NINLARO regimen and 9% in the placebo regimen). Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms.

Embryo-fetal Toxicity: NINLARO can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with NINLARO and for 90 days following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days following the last dose.

Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting: In two prospective randomized clinical trials in multiple myeloma in the maintenance setting, treatment with NINLARO resulted in increased deaths. Treatment of patients with NINLARO for multiple myeloma in the maintenance setting is not recommended outside of controlled trials.

ADVERSE REACTIONS

The most common adverse reactions (≥ 20%) in the NINLARO regimen compared to placebo in combination with lenalidomide plus dexamethasone, respectively were thrombocytopenia (85%, 67%; pooled from adverse event and laboratory data), neutropenia (74%, 70%; pooled from adverse event and laboratory data), diarrhea (52%, 43%), constipation (35%, 28%), peripheral neuropathy (32%, 24%), nausea (32%, 23%), edema peripheral (27%, 21%), rash (27%, 16%), vomiting (26%, 13%), and bronchitis (22%, 17%). Serious adverse reactions reported in ≥ 2% of patients in the NINLARO regimen included diarrhea (3%), thrombocytopenia (2%), and bronchitis (2%).

DRUG INTERACTIONS:

Avoid concomitant administration of NINLARO with strong CYP3A inducers.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during treatment with NINLARO and for 90 days after the last dose.

Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. NINLARO is not dialyzable.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-217-6468 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

**Discover how real-world evidence (RWE) for the NINLARO^® (ixazomib) regimen* can complement clinical trial results^1-6**

RWE PROVIDES DATA ABOUT PATIENT OUTCOMES FROM ROUTINE CLINICAL PRACTICE

MEET BRUCE, A PATIENT EXPERIENCING AN INDOLENT FIRST RELAPSE

THE TOURMALINE-MM1 PIVOTAL TRIAL EVALUATED EFFICACY AND SAFETY FOR THE NINLARO REGIMEN*

CONSISTENT EFFICACY AND SAFETY WERE DEMONSTRATED WITH THE NINLARO REGIMEN*IN 4 REAL-WORLD STUDIES^1-6

Real-world study designs^3-6

Important findings from the 2023 REMIX study

**Consistent PFS was seen with the NINLARO regimen* in the real
world^1-6**

ARs seen in real-world settings were consistent with the known safety
profile^4-6

IMPORTANT SAFETY INFORMATION, INDICATION, AND USAGE

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

DRUG INTERACTIONS:

USE IN SPECIFIC POPULATIONS

INDICATION AND USAGE

RWE PROVIDES DATA ABOUT PATIENT OUTCOMES FROM ROUTINE CLINICAL PRACTICE

MEET BRUCE, A PATIENT EXPERIENCING AN INDOLENT FIRST RELAPSE

THE TOURMALINE-MM1 PIVOTAL TRIAL EVALUATED EFFICACY AND SAFETY FOR THE NINLARO REGIMEN*

CONSISTENT EFFICACY AND SAFETY WERE DEMONSTRATED WITH THE NINLARO REGIMEN* IN 4 REAL-WORLD STUDIES1-6

Real-world study designs3-6

Important findings from the 2023 REMIX study

Consistent PFS was seen with the NINLARO regimen* in the realworld1-6

ARs seen in real-world settings were consistent with the known safetyprofile4-6

IMPORTANT SAFETY INFORMATION, INDICATION, AND USAGE

CONSISTENT EFFICACY AND SAFETY WERE DEMONSTRATED WITH THE NINLARO REGIMEN*IN 4 REAL-WORLD STUDIES^1-6

Real-world study designs^3-6

**Consistent PFS was seen with the NINLARO regimen* in the real
world^1-6**

ARs seen in real-world settings were consistent with the known safety
profile^4-6