NINLARO® (ixazomib) Real-world Evidence

NINLARO has been investigated in patients with relapsed/refractory multiple myeloma in both randomized controlled trials and real-world studies.1-5

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.6 RWE can be important in clinical decision-making as it can supplement data generated from clinical trials.3,7

Learn more about RWE and why it matters

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

RWE should be considered as complementary to data generated from RCTs.8 

  • RCTs are designed to demonstrate whether a treatment can improve pre-defined patient outcomes under ideal, carefully monitored conditions (known as “efficacy”)7
  • RWE assesses whether the results from RCTs are translatable to diverse, real-life settings and broader patient populations (known as “effectiveness”)7

Strengths and weaknesses of RWE

Strengths8-10

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
     

Weaknesses7,8,11

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

RWE STUDY DESIGN AND PATIENT POPULATION

The NINLARO regimen was assessed in real-world trials to evaluate study results of patients taking NINLARO outside of clinical trials. Real-world studies include a broader range of patients who are more representative of typical patients with relapsed/refractory multiple myeloma.3,7

Study Design
The real-world effectiveness and safety of the all-oral NINLARO regimen for patients with relapsed/refractory multiple myeloma was evaluated in three different studies.1,3-5 

Terpos et al: A multicenter, retrospective analysis of NINLARO+Rd in relapsed or refractory multiple myeloma. Patients received a median of 1 prior therapy, the same as the TOURMALINE-MM1 study. 

Hájek et al: A global retrospective analysis of NINLARO+Rd in patients with relapsed or refractory multiple myeloma who had received a median of 2 prior therapies vs a median of 1 prior therapy in the TOURMALINE-MM1 study.

Minařik et al: A prospective analysis of NINLARO+Rd vs Rd in relapsed or refractory multiple myeloma. Patients received a median of 1 prior therapy, the same as the TOURMALINE-MM1 study.

Terpos et al, 20203
Multicenter, retrospective study

Study group/duration

  • 12 clinical centers from December 2015 and October 2017

Treatment regimen

  • NINLARO regimen through early access program

Key study endpoints

  • ORR
  • CBR (clinical benefit rate)
  • DCR (disease control rate)
  • Safety
     

Hájek et al, 20214
Retrospective study

Study group/duration

  • Pooled analysis of data from 2 discrete sources or registries*: July 2016-September 2019 (15 countries) and May 2007-February 2020

Treatment regimen

  • NINLARO regimen used in INSIGHT MM (n=132) and Czech RMG (n=131)

Key study endpoints

  • Best response to therapy
  • DOT
  • TTNT
  • PFS
  • OS
     

Minařik et al, 20215
Prospective study

Study group/duration

  • Comparative study of patients treated with NINLARO regimen vs Rd regimen between 2016 and 2018

Treatment regimen

  • NINLARO regimen (n=127) vs Rd regimen (n=217) as part of Named Patient Program

Key study endpoints

  • PFS
  • Response rates
  • OS
     
STUDY POPULATION
The efficacy and safety of the all-oral NINLARO regimen was evaluated in three different studies with real-world patients with relapsed/refractory multiple myeloma.3-5

Terpos et al, 20203
Multicenter, retrospective study

Patient population

  • 155 patients
  • Relapsed/refractory multiple myeloma
  • Median of 1 prior line of therapy
  • Some patients would not have been eligible for TOURMALINE-MM1
     

Hájek et al, 20214
Retrospective study

Patient population

  • 263 patients
  • Relapsed/refractory multiple myeloma
  • Median of 2 prior lines of therapy
  • Some patients would not have been eligible for TOURMALINE-MM1
     

Minařik et al, 20215
Prospective study

Patient population

  • 344 patients
  • Relapsed/refractory multiple myeloma
  • Median of 1 prior line of therapy
  • Some patients would not have been eligible for TOURMALINE-MM1

*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
The NINLARO regimen included NINLARO+lenalidomide+dexamethasone. The Rd regimen included placebo+lenalidomide+dexamethasone.1
Key exclusion criteria for Minařik et al included: active 1L therapy; patients with missing data for primary endpoints; patients in clinical trials; patients who switched combination regimens. In Hájek et al, 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, no exclusion criteria were identified.3-5
1L=first line; DOT=duration of treatment; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; RMG=Registry of Monoclonal Gammopathies; TTNT=time to next therapy.

RWE STUDY RESULTS

Consistent PFS was seen with the NINLARO regimen* in the real-world1-5

The NINLARO® (ixazomib) regimen demonstrated comparable PFS between clinical trial and clinical practice, with a median PFS of 20.6 in TOURMALINE MM1 clinical trial and similar results in real‐world studies.
  • 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 base 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 registries3-5
  • These RWE studies included patients ineligible for TOURMALINE-MM1 based on refractory status for lenalidomide and/or proteasome inhibitors, comorbidities, performance status, and median lines of previous therapy. These RWE studies lack adequate controls to establish safety and efficacy in these subgroups3-5
  • 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 subgroups3-5,12
*The NINLARO (ixazomib) regimen included NINLARO+lenalidomide+dexamethasone.1
Treatment lines 2-4.5
Discover PFS in the relapsed setting

In 2 real-world studies, the NINLARO regimen* demonstrated longer PFS in patients who had not been heavily pre-treated vs heavily pre-treated patients3,4,12,13

PFS from 2 real-world studies3,4,12

PFS rates from 2 real‐world studies. Hajek et al saw a median PFS of 26 months as a 2nd line, 23.8 months as a 3rd line, 13.6 months as a 4th line, and 6.7 months as a greater than 4th line treatment. Terpos et al saw a median PFS of 27.6 months as a 2nd line, and 19.9 months as a 3rd line or greater treatment.
Statistical significance is not implied when comparing across MM1 and real-world evidence. Cross-trial comparisons are potentially confounded by differences in trial design and study population. When interpreting the data from the Hájek, Minařik, and Terpos studies, it is important to consider that they may include overlap in patient populations.
*The NINLARO regimen included NINLARO+lenalidomide+dexamethasone.1
In 4L+.

Consistent response rates were seen in the real world1,3-5

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
Includes 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 profile4,5,12,14

The majority of patients in the clinical trial and clinical practice remained on therapy at their starting dose4,5,14

In clinical trials 80% of patients remained on dose, while in real world studies 90% of patients remained on dose in Hajek et al and 82% remained on dose in Minarik et al.

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.

*Dose reduction rates not available for Terpos et al.

In real-word studies, the NINLARO regimen demonstrated a safety profile comparable to the NINLARO arm in TOURMALINE-MM11-5

Terpos et al (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 MM1, respectively.

Hájek et al (N=263)12
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 (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%).

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.

NINLARO clinical trial data

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

NINLARO patient profiles

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