**The NINLARO^® (ixazomib) Regimen* Prolonged Progression-Free Survival vs Rd Regimen*^1,2**

TOURMALINE-MM1 was a global, phase 3, randomized, double-blind, placebo-controlled study of patients with relapsed and/or refractory multiple myeloma who had received at least one prior line of therapy (N=722).^1,2

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

TOURMALINE-MM1 CLINICAL TRIAL DESIGN AND PATIENT CHARACTERISTICS

TOURMALINE-MM1 clinical trial evaluated the efficacy and safety of NINLARO (ixazomib) + lenalidomide + dexamethasone vs placebo + lenalidomide + dexamethasone in patients with relapsed and/or refractory multiple myeloma (N=722).^1,2

TRIAL DESIGN

TOURMALINE-MM1 was a global, phase 3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of the all-oral NINLARO regimen* vs Rd regimen in patients with relapsed and/or refractory multiple myeloma who had received at least one prior multiple myeloma treatment.^1,2

TOURMALINE-MM1 clinical trial study design.

Primary endpoint: PFS, according to 2011 IMWG criteria, was assessed every 4 weeks until disease progression by a blinded IRC and was based on central laboratory results¹
Key secondary endpoints: OS and OS in del(17p)²
Other secondary endpoints: ORR and PFS in patients with high-risk cytogenetics^‡ and safety²

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

†Stratification: 1 vs 2 or 3 prior therapies; PI exposed vs PI naive; and ISS stage I or II vs III.^1

‡Defined as patients with del(17p), t(4;14), and/or t(14;16).¹

PATIENT CHARACTERISTICS

TOURMALINE-MM1 included difficult-to-treat patients—including patients with primary refractory disease*, high-risk cytogenetics, free-light chain disease, and renal impairment.^1,2

Baseline characteristics of participants in TOURMALINE-MM1 clinical trial. — *Primary refractory, defined as best response of stable disease or disease progression on all prior lines of therapy, was documented in 7% and 6% of patients in the NINLARO regimen and Rd regimens, respectively.¹
^†The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.¹
^‡Stratification factor.¹
ECOG=Eastern Cooperative Oncology Group performance status; IMWG=International Myeloma Working Group; IRC=independent review committee; ISS=International Staging System; MM=multiple myeloma; ORR=overall response rate; OS=overall survival; PI=proteasome inhibitor.

Cutoff values for high-risk cytogenetic markers, including del(17p), t(4;14), and t(14;16), were performed by a central laboratory²
Positivity for del(17p) was defined by a percentage of positive cells that were above the technical background cutoff of 5%²
22%-27% of patients had renal impairment¹
23% of patients had light chain disease and 12% of patients had free light chain-measurable only disease¹
Primary refractory was defined as best response of stable disease or disease progression on all prior lines of therapy. Primary refractory status was documented in 7% and 6% of patients in the NINLARO regimen and the Rd regimen, respectively¹

21% of patients had high-risk cytogenetics. 69% of patients were previously treated with VELCADE® (bortezomib).

Learn more about patients who may be appropriate for NINLARO

DISCOVER PATIENT PROFILES

Joe, a real patient with indolent first relapse, pictured outside.

*Joe is a real patient taking the NINLARO regimen (NINLARO + lenalidomide + dexamethasone).
Individual results may vary.

"I've now been on NINLARO for 5 years." – Joe, a real patient taking the NINLARO regimen*

Discover Joe's Story

TOURMALINE-MM1 CLINICAL TRIAL RESULTS

In the TOURMALINE-MM1 pivotal clinical trial, the NINLARO regimen was shown to significantly extend PFS compared to the Rd regimen.^1,2

Primary PFS analysis^1,2

Median PFS of 20.6 months achieved with NINLARO® (ixazomib) regimen vs 14.7 months with Rd regimen.

Final OS Analysis

With a median follow-up of ~85 months, median OS in the ITT population was 53.6 months for patients receiving the NINLARO regimen* and 51.6 months for patients receiving the Rd regimen* (HR=0.94 [95% CI, 0.78-1.13])¹

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.¹
CI=confidence interval; HR=hazard ratio; ITT=intention-to-treat; mPFS=median progression-free survival; NE=not evaluable; OS=overall survival; PFS=progression-free survival.

PFS IN SELECT PATIENT POPULATIONS

Positive PFS trends across selected prespecified subgroups.^2-4

PFS analysis in selected patients

NINLARO® (ixazomib) regimen: PFS subgroup analysis.

Study limitations

This study was not powered to show significance in PFS across these prespecified subgroups.⁴
Cytogenetic risk data were not available for 24% of patients in the study.²

Other prespecified subgroups not included in this figure were gender, race, region, Western countries, prior bortezomib exposure, thalidomide refractory, and creatinine clearance at baseline.⁴

The PFS results in the above subgroups were consistent with those represented in the figure above.⁴

*Median PFS (months).
^†Defined as patients with del(17p), t(4;14), and/or t(14;16).²
^‡The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.¹
ECOG=Eastern Cooperative Oncology Group; ISS=International Staging System; PI=proteasome inhibitor.

Median PFS in overall population and cytogenetic-risk subgroups^1-3

Chart showing the median PFS in the overall study population and cytogenetic-risk subgroups. Median PFS was 20.6 with the NINLARO® (ixazomib) regimen. Rd regimen had a median PFS of 14.7.

Study limitations

This study was not powered to show significance in PFS across these prespecified subgroups
Cytogenetic-risk data were not available for 24% of patients in the study²

*Defined as patients with del(17p), t(4;14), and/or t(14;16).²
^†The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.¹
CI=confidence interval; HR=hazard ratio; mPFS=median progression-free survival; PFS=progression-free survival.

RESPONSE RATES

The NINLARO regimen* achieved rapid responses^† that deepened with long-term^‡treatment.^1,5

Depth of response¹

Depth of response: ORR was 78% for the NINLARO® (ixazomib) regimen vs 72% for Rd regimen.

Study limitation: The study was not powered to detect differences in response rates between arms

*The NINLARO (ixazomib) regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.¹
^†Versus the Rd regimen.
^‡Used herein to refer to treatment to disease progression or unacceptable toxicity.¹
CR=complete response; ORR=overall response rate; PR=partial response; VGPR=very good partial response.

The NINLARO regimen* achieved rapid responses vs the Rd regimen*¹

Median time to initial response¹

Median time to initial response: 1.1 months for NINLARO® (ixazomib) regimen vs 1.9 months for Rd regimen. — *The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.¹

The NINLARO regimen* responses deepened with long-term^† treatment⁵

NINLARO regimen: cumulative best responses over time in the intent-to-treat population⁵

NINLARO® (ixazomib) arm: cumulative best responses over time in the intent‐to-treat population. — Depth of response for the NINLARO vs Rd regimens, respectively: ORR^‡: 78% vs 72%; CR: 12% vs 7%; VGPR+CR: 48% vs 39%; PR: 30% vs 33%¹

**Study limitation: The study was not powered to detect differences in response rates between arms**

Responses improved over time in both arms of the study⁵

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.¹
^†Used herein to refer to treatment to disease progression or unacceptable toxicity.¹
^‡ORR=CR+VGPR+PR.
CR=complete response; PR=partial response; VGPR=very good partial response.

NINLARO dosing

Find the dosing schedule for the NINLARO all-oral triplet regimen and information on dosage modifications.

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NINLARO real-world studies

Real-world evidence can help provide a better understanding of patient outcomes in routine clinical practice.

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NINLARO safety profile

The NINLARO regimen: a PI triplet with safety similar to the Rd regimen.

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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.

**The NINLARO^® (ixazomib) Regimen* Prolonged Progression-Free Survival vs Rd Regimen*^1,2**

TOURMALINE-MM1 CLINICAL TRIAL DESIGN AND PATIENT CHARACTERISTICS

Learn more about patients who may be appropriate for NINLARO

"I've now been on NINLARO for 5 years." – Joe, a real patient taking the NINLARO regimen*