Robust and Consistent Real-World Results With NINLARO^® (ixazomib)

Four real-world studies, including REMIX, which is the largest prospective study of NINLARO in the real-world setting, support the effectiveness and safety of the all-oral NINLARO regimen* in patients with relapsed/refractory multiple myeloma.^1-6

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone.

Real-world evidence (RWE) can complement data from clinical trials

Up to 72% of real-world patients with relapsed and/or refractory multiple myeloma receiving routine care in the United States do not meet the eligibility criteria for clinical trials.⁷ RWE can be important in clinical decision-making as it can supplement data generated from clinical trials.^3,8

RWE is clinical evidence derived from analysis of real-world data

RWE should be considered as complementary to data generated from RCTs.⁹

RCTs are designed to demonstrate whether a treatment can improve predefined patient outcomes under ideal, carefully monitored conditions (known as “efficacy”)⁸
RWE assesses whether the results from RCTs are translatable to diverse, real-life settings and broader patient populations (known as “effectiveness”)⁸

Learn more about strengths and limitations of RWE

Strengths and weaknesses of RWE

Strengths^9-11

RWE often has broader generalizability vs RCTs, reflecting the heterogeneity of patients treated in real-world clinical practice, including patients with:

Comorbidities
Advanced age
Reduced performance status

RWE provides information on real-world treatment patterns

Dosing
Treatment duration
Resource use

Data can validate/complement results from RCTs in real-world clinical practice

Effectiveness
Tolerability
Safety profile

Weaknesses^8,9,12

Heterogeneous datasets

Arising from heterogeneous patient population and a variety of dataset resources, e.g. EHRs, healthcare claims
Data may be inconsistently collected or data on key variables may be missed. This can reduce clinical validity

Findings limited to data that are randomly available - susceptible to selection bias

Potential incompatibility of data from different sources
Less scrutiny and less uniformity in reporting or data processing/collection compared with RCTs

Real-world data do not constitute a uniform assessment of efficacy under controlled conditions

Lack of well-characterized, balanced groups of patients in treatment arms
Not blinded or randomized
Potential lack of formal, defined endpoints (e.g., use of time to next therapy as a proxy for PFS due to data availability)

Selection bias

Many positive results that were historically reported for RWE were a result of selection bias
RCTs, through their robust design, limit the role of bias in determining the real efficacy of medicines

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.¹
PFS=progression-free survival; RCTs=randomized controlled trials.

NINLARO REAL-WORLD STUDY DESIGNS AND PATIENT POPULATIONS

The NINLARO regimen was assessed in 4 real-world studies that included some patients who would have not been eligible for the TOURMALINE-MM1 clinical trial.^1,3-6 Real-world studies include a broader range of patients who are more representative of typical patients with relapsed/refractory multiple myeloma.^3,7

Terpos et al, 2020: A multicenter, retrospective analysis of the NINLARO regimen* in 155 patients^† (median age 68 years) with relapsed or refractory multiple myeloma. Patients received a median of 1 prior therapy, the same as the TOURMALINE-MM1 study.³

Hájek et al, 2021: A global retrospective pooled analysis of data from 2 discrete sources or registries^‡ evaluating the NINLARO regimen* in 263 patients^† (median age 68 years) 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.⁴

Minařik et al, 2021: A prospective analysis of NINLARO regimen* vs Rd regimen* in 344 patients^† (median age 66 years) with relapsed or refractory multiple myeloma. Patients received a median of 1 prior therapy, the same as the TOURMALINE-MM1 study.⁵

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. The REMIX study population was older (median age, 71 years) compared with TOURMALINE-MM1 (median age 66 years).⁶

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + 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.^3-7

^‡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

RMG=Registry of Monoclonal Gammopathies.

RWE STUDY RESULTS

Consistent PFS was seen with the NINLARO regimen* across 4
real-world studies^1-6

mPFS in the Tourmaline-MM1 clinical trial was 20.6 months. In real world studies, mPFS was 27.6 in Terpos et al, 21.2 in Hájek et al, 23.1 in Minařik et al, and 19.1 in the REMIX study.

Observational, retrospective analyses are not intended for direct comparison with clinical trials
Unadjusted, indirect comparison for illustration only; clinical significance is not implied. Cross-trial comparisons are potentially confounded by differences in trial design and study population
Real-world analyses are often nonrandomized, observational, retrospective studies that may have unobserved confounding and 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 data⁴
There is an unknown overlap in study populations across the RWE studies due to inclusion of patients from the same registries^3-5
These RWE studies included patients ineligible for TOURMALINE-MM1 based on refractory status for lenalidomide and/or proteasome inhibitors, frailty, comorbidities, performance status, and median lines of previous therapy. These RWE studies lack adequate controls to establish safety and efficacy in these subgroups^3-5
These RWE studies included analyses of PFS across select patient subgroups. In certain subgroups, the median PFS observed was not consistent with the overall PFS observed. However, these studies were not powered to show significance in PFS across these subgroups^3-5,13

DOWNLOAD RWE BROCHURE

DOWNLOAD REMIX BROCHURE

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone.¹
^†Treatment lines 2-4.⁵
^‡The REMIX study enrolled 376 patients who received the NINLARO regimen*. Of these patients, 1 was lost to follow-up and 17 had not been assessed for disease progression (but were still alive). Therefore, these patients were not included in the PFS analysis.⁶

Consistent response rates were seen across 4 studies in the
real world^1,3-6

Consistent response rates were seen in the clinical trial and clinical practice. Clinical trial saw a response rate of 78% ORR. — Unadjusted, indirect comparison for illustration only; clinical significance is not implied. 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

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone.¹
^†Included CR and stringent CR.
CR=complete response; ORR=overall response rate; PR=partial response; VGPR=very good partial response.

RWE SAFETY PROFILE

Adverse reactions seen in real-world settings were consistent with the known safety profile^4,5,13,14

The majority of patients in the clinical trial and clinical practice remained on therapy at their starting dose^4-6,14

75 percent of patients in the Tourmaline-MM1 trial remained on their starting dose, while 83 percent, 82 percent, and 74 percent of patients remained on their starting dose, respectively, in Hájek et al., Minařik et al., and REMIX real-world studies.

In TOURMALINE-MM1, the median relative dose intensity for NINLARO + Rd and placebo + Rd* was high and similar between both arms: 97.8% and 100%, respectively¹⁴
In TOURMALINE-MM1, relative dose intensity was calculated as: 100 x (total amount of dose taken) ÷ (total prescribed dose of treated cycles)^14‡
In the REMIX study, most patients (90.4%; n=340) initiated NINLARO at the full dosage of 4mg administered orally once a week on Days 1, 8, and 15 of a 28-day cycle.^1,6§

Unadjusted, indirect comparison for illustration only; clinical significance is not implied. 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.

*NINLARO + Rd = NINLARO + lenalidomide + dexamethasone. Rd = placebo + lenalidomide + dexamethasone.¹
^†Median duration of exposure to NINLARO was 457 days (range: 1–2768 days).¹⁴
^‡Total prescribed dose equals (dose prescribed at enrollment × number of prescribed doses per cycle × the number of treated cycles).¹⁴
^§The remaining 9.6% of patients (n=36) were prescribed 3mg or less on Days 1, 8, and 15 of a 28-day cycle.^1,6

In 4 real-world studies, the NINLARO regimen demonstrated a tolerability profile comparable to the NINLARO arm in TOURMALINE-MM1^1-6

Terpos et al, 2020 (N=155)³
Occurrence rates of specific safety aspects of clinical interest: PN (35% vs 27%), PN grade >2 (3% vs 2%), thromboembolism (5% vs 8%), herpes zoster (5% vs 5%), hypertension (4% vs 6%), as reported in the combined study vs TOURMALINE-MM1, respectively.

Hájek et al, 2021 (N=263)⁴
The most common ARs leading to NINLARO discontinuations included: infection (19%), neutropenia (6%), thrombocytopenia (6%), diarrhea (3%), rash (3%), nausea (3%), fatigue (2%), other^† (32%).

Minařik et al, 2021 (n=127)⁵
Grade ≥3 AEs reported in ≥10% of patients with the NINLARO regimen^‡ vs Rd regimen,^‡ respectively, included anemia (12% vs 26%), neutropenia (28% vs 23%), thrombocytopenia (21% vs 23%), infection (21% vs 23%), exanthema/rash (25%^§ vs 0%), and other (19% vs 32%).

REMIX Study, 2023 (N=376)
The most frequently reported AEs >10% (n=294) included diarrhea (26.2%), thrombocytopenia (23.1%), asthenia (15%), neutropenia (11.9%), nausea (11.6%) and anemia (11.2%). The most common SAEs were thrombocytopenia (12.2% of patients with ≥1 AE) and plasma cell myeloma (9.5%).⁶

*Dose reduction rates not available for Terpos et al.
^†More than 1 AE could be assigned to 1 patient; each AE was counted only once for each patient.⁴
^‡The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.¹
^§Grade ≥3 exanthema/rash was reported in 1 patient receiving the NINLARO regimen (n=1/4).⁵
AE=adverse event; PN=peripheral neuropathy.

REMIX REAL-WORLD STUDY DATA

REMIX included some patients who would have not been eligible for TOURMALINE-MM1. In REMIX, the median age of the patient population was 71 years old, which is 5 years older than the median age of the TOURMALINE-MM1 population.^1,6

PFS for overall cohort of patients who received the NINLARO regimen^6,*

mPFS in the overall population in REMIX was 19.1 months. — With a median follow-up of 28.7 months, REMIX demonstrated an mPFS of 19.1 months (95% CI: 15.9–21.5) with NINLARO regimen* in real-world patients with RRMM
In TOURMALINE-MM1, mPFS with the NINLARO regimen* was 20.6 months (95% CI: 17.0–NE) after a median follow-up of 14.8 months, which is consistent with the mPFS reported in the REMIX study ^2,6

Median PFS was similar in patients <80 years and ≥80 years who received the NINLARO regimen^6,*

mPFS in patients 80 years or older was 17.4 months. For patients under 80, mPFS was 19.1 months. — The REMIX study was not powered to detect statistical significance in subgroup analyses. A sample size of 250 patients per subgroup (including age group) would provide an accuracy of 6.2% in describing the study results.⁶

MEDIAN PFS WAS LONGER IN NON-FRAIL VS FRAIL^† PATIENTS RECEIVING THE NINLARO REGIMEN⁶

mPFS in frail patients was 14.6 months. mPFS in non-frail patients was 21.5 months. — This study was not powered to detect statistical significance in subgroup analyses. A sample size of 250 patients per subgroup (including age group) would provide an accuracy of 6.2% in describing the study results.⁶
*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.¹
^†Frailty was evaluated using the simplified frailty score based on age, Charlson’s Comorbidity Index and ECOG PS. Frailty score calculation was based on ECOG PS if patients were ≤ 80 years. Due to missing data on ECOG PS, the simplified frailty score was only available for 283 patients (75.0%).⁶
CI=confidence interval; ECOG PS=Eastern Cooperative Oncology Group Performance Status; mPFS=median progression-free survival; PFS=progression-free survival.

NINLARO clinical trial data

The TOURMALINE-MM1 clinical trial evaluated efficacy and safety of the all-oral NINLARO regimen vs Rd regimen in relapsed patients with multiple myeloma.

Find Trial Results

NINLARO patient profiles

Different patient types with relapsed multiple myeloma may benefit from the NINLARO triplet regimen.

Discover Appropriate Patients

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.

Robust and Consistent Real-World Results With NINLARO^® (ixazomib)

Real-world evidence (RWE) can complement data from clinical trials