NCT02181413

A Study of Oral Ixazomib Citrate (MLN9708) Maintenance Therapy in Participants With Multiple Myeloma Following Autologous Stem Cell Transplant

Completed Phase 3 Results posted Last updated 19 November 2024

What this trial tests

Phase 3 trial testing Ixazomib Citrate in Multiple Myeloma in 656 participants. Completed in 8 September 2023.

Timeline

16 July 2014

Primary endpoint
16 April 2018

8 September 2023

Quick facts

Lead sponsor	Takeda
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	656
Start date	16 July 2014
Primary completion	16 April 2018
Estimated completion	8 September 2023
Sites	227 locations across Italy, Colombia, Japan, Taiwan, Poland, South Korea, Denmark, Netherlands

Drugs / interventions tested

• Ixazomib Citrate — full drug profile →
• Placebo

Conditions studied

• Multiple Myeloma — all drugs for Multiple Myeloma →
• Autologous Stem Cell Transplant — all drugs for Autologous Stem Cell Transplant →

Sponsor

Takeda — full company profile →

Who can join

18 and older, any sex, with Multiple Myeloma or Autologous Stem Cell Transplant. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Progression Free Survival (PFS) Primary · Randomization up to End of treatment (EOT) (24 months); thereafter followed up every 4 weeks (up to 45 months)

PFS was defined as the time from the date of randomization to the date of first documentation of PD, as evaluated by an independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurred first. PD was defined as ≥25% increase from lowest value in: serum/urine M component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved free light chain (FLC) levels must be \>10 milligrams per deciliter (mg/dL); participants without measurable serum, urine M-protein le

Group	Value	95% CI
Placebo	21.3	17.97 – 24.67
Ixazomib Citrate	26.5	23.69 – 33.81

Overall Survival (OS) Secondary · Randomization up to end of follow up period (up to 107 months)

OS was measured as the time from the date of randomization to the date of death.

Group	Value	95% CI
Placebo	NA	96.95 – NA
Ixazomib Citrate	NA	104.97 – NA

Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy Secondary · Randomization up to EOT (up to 24 months) and thereafter every 4 weeks until initiation of the next line of therapy (up to 107 months)

Response was assessed according to IMWG criteria. Best response includes partial response (PR), very good partial response (VGPR) and complete response (CR). PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to less than (\<)200 milligrams (mg) per 24 hours. VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hours. CR is negative immunofixation of serum and urine and disappearance of soft tissue plasmacytomas and

PR

Group	Value	95% CI
Placebo	10
Ixazomib Citrate	12

VGPR

Group	Value	95% CI
Placebo	45
Ixazomib Citrate	40

CR

Group	Value	95% CI
Placebo	42
Ixazomib Citrate	44

Time to Progression (TTP) Secondary · Randomization up to PD (up to 107 months)

TTP is defined as the time from the date of randomization to the date of first documentation of PD, using IMWG criteria. PD is defined as ≥25% increase from lowest value in: serum/urine M-component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels must be \>10mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must be ≥10%;new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia develo

Group	Value	95% CI
Placebo	21.4	18.10 – 24.67
Ixazomib Citrate	26.6	23.69 – 33.81

Second Progression Free Survival (PFS2) Secondary · Randomization up to EOT (24 months); thereafter followed up every 4 weeks until initiation of next-line therapy and then every 12 weeks until second progressive disease (PD2) or death (up to 107 months)

PFS2 is defined as the time from the date of randomization to the date of objective disease progression on next line treatment or death from any cause (whichever occurs first). PD is defined as ≥25% increase from lowest value in: serum/urine M-component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels must be \>10 mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must be ≥10%; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/

Group	Value	95% CI
Placebo	80.4	68.7 – NA
Ixazomib Citrate	84.0	67.22 – NA

Time to Start of the Next Line of Therapy Secondary · Randomization up to 107 months

Time to start of the next line of therapy was defined as the time from the date of randomization to the date of initiation dose of the next line of antineoplastic therapy following study treatment or death due to any cause, whichever occurred first. Participants who never took antineoplastic therapy were censored at the date of last contact or death.

Group	Value	95% CI
Placebo	27.6	24.48 – 31.61
Ixazomib Citrate	33.1	29.14 – 36.34

Time to End of the Next Line of Therapy Secondary · Randomization up to 107 months

Time to end of the next line of therapy was defined as the time from the date of randomization to the date of last dose of the next line of antineoplastic therapy following study treatment or death due to any cause, whichever occurred first or date of last contact for participants who never took antineoplastic therapy.

Group	Value	95% CI
Placebo	50.4	42.84 – 61.01
Ixazomib Citrate	55.9	49.61 – 61.86

Duration of the Next Line of Therapy Secondary · Up to 107 months

Duration of the next line of therapy was defined as the time from the date of the first dose of the next line of therapy to the date of the last dose of the next antineoplastic therapy following study treatment or death due to any cause, whichever occurred first. Duration of the next line of therapy was analyzed on those participants who received the next line of therapy following the study treatment and duration was summarized using Kaplan-Meier method.

Group	Value	95% CI
Placebo	12.3	9.82 – 16.53
Ixazomib Citrate	9.6	7.49 – 12.06

Percentage of Participants Who Develop a New Primary Malignancy Secondary · Up to 107 months

The decimal values of percentages were subjected to rounding off.

Group	Value	95% CI
Placebo	8
Ixazomib Citrate	7

Number of Participants With Conversion to Minimal Residual Disease (MRD) Negative Secondary · Baseline up to EOT (up to 24 months)

MRD negativity (MRD-) is defined as absence of MRD and MRD positivity (MRD+) is defined as presence of MRD. The conversion rate from MRD positive to MRD negative was assessed and reported. Bone marrow aspirates and blood samples were sent to a central laboratory and were assessed for MRD using flow cytometry and a sequencing methodology.

Group	Value	95% CI
Placebo	27
Ixazomib Citrate	39

Number of Participants With Maintenance of MRD Negativity Secondary · Up to EOT (up to 24 months)

MRD negativity is defined as absence of MRD and MRD positivity is defined as presence of MRD. The maintenance of MRD negativity up to the end of treatment was assessed and reported in participants converting from MRD+ at Baseline to MRD negative. Bone marrow aspirates and blood samples were sent to a central laboratory and were assessed for MRD using flow cytometry and a sequencing methodology.

Group	Value	95% CI
Placebo	25
Ixazomib Citrate	37

Correlation Between MRD Status and Progression Free Survival (PFS) Secondary · From randomization up to 107 months

PFS is defined as the time from the date of randomization to the date of first documentation of PD as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurred first, assessed for up to 107 months in this outcome measure.

MRD- at Study Entry

Group	Value	95% CI
Placebo	32.5	19.32 – NA
Ixazomib Citrate	38.6	33.81 – NA

MRD+ at Study Entry

Group	Value	95% CI
Placebo	18.5	15.70 – 21.91
Ixazomib Citrate	23.1	20.24 – 25.69

Adverse events — posted to ClinicalTrials.gov

Time frame: Randomization up to end of follow up period (107 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 51/259 (20%)

Deaths: 93/261

Ixazomib Citrate

Serious: 108/394 (27%)

Deaths: 144/395

Serious adverse events (127 terms)

Reaction	System	Placebo	Ixazomib Citrate
Pneumonia	Infections and infestations	—	—
Pyrexia	General disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Herpes zoster	Infections and infestations	—	—
Influenza	Infections and infestations	—	—
Pathological fracture	Musculoskeletal and connective tissue disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Bronchitis	Infections and infestations	—	—
Lower respiratory tract infection	Infections and infestations	—	—
Osteonecrosis of jaw	Musculoskeletal and connective tissue disorders	—	—
Sinusitis	Infections and infestations	—	—
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Cellulitis	Infections and infestations	—	—
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—
Gastroenteritis	Infections and infestations	—	—
Meniscus injury	Injury, poisoning and procedural complications	—	—
Metapneumovirus infection	Infections and infestations	—	—
Myocardial ischaemia	Cardiac disorders	—	—
Plasma cell myeloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—
Adenocarcinoma of colon	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Alanine aminotransferase increased	Investigations	—	—
Anaemia	Blood and lymphatic system disorders	—	—

Other adverse events (43 terms — click to expand)

Reaction	System	Placebo	Ixazomib Citrate
Nausea	Gastrointestinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Nasopharyngitis	Infections and infestations	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Fatigue	General disorders	—	—
Pyrexia	General disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Headache	Nervous system disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Peripheral sensory neuropathy	Nervous system disorders	—	—
Bronchitis	Infections and infestations	—	—
Neuropathy peripheral	Nervous system disorders	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—
Influenza	Infections and infestations	—	—
Bone pain	Musculoskeletal and connective tissue disorders	—	—
Herpes zoster	Infections and infestations	—	—
Influenza like illness	General disorders	—	—
Muscle spasms	Musculoskeletal and connective tissue disorders	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—
Oedema peripheral	General disorders	—	—
Dizziness	Nervous system disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Insomnia	Psychiatric disorders	—	—
Asthenia	General disorders	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Conjunctivitis	Infections and infestations	—	—
Paraesthesia	Nervous system disorders	—	—
Productive cough	Respiratory, thoracic and mediastinal disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Pneumonia	Infections and infestations	—	—
Rash macular	Skin and subcutaneous tissue disorders	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Hypertension	Vascular disorders	—	—
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	—	—

Most-reported serious reactions: Pneumonia, Pyrexia, Diarrhoea, Herpes zoster, Influenza, Pathological fracture, Back pain, Bronchitis.

Data from ClinicalTrials.gov NCT02181413 adverse events section.

Sponsor's own description

The purpose of this study is to determine the effect of ixazomib citrate maintenance therapy on progression-free survival (PFS), compared to placebo, in participants with newly diagnosed multiple myeloma (NDMM) who have had a response (complete response \[CR\], very good partial response \[VGPR\], or partial response \[PR\]) to induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplant (ASCT).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Proteasome inhibitors in cancer therapy.
   Manasanch EE, Orlowski RZ. · · 2017 · cited 743× · PMID 28117417 · DOI 10.1038/nrclinonc.2016.206
2. The role of ubiquitination in tumorigenesis and targeted drug discovery.
   Deng L, Meng T, Chen L, Wei W, et al · · 2020 · cited 586× · PMID 32296023 · DOI 10.1038/s41392-020-0107-0
3. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial.
   Dimopoulos MA, Gay F, Schjesvold F, Beksac M, et al · · 2019 · cited 178× · PMID 30545780 · DOI 10.1016/s0140-6736(18)33003-4
4. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis.
   Sanchorawala V, Palladini G, Kukreti V, Zonder JA, et al · · 2017 · cited 97× · PMID 28550039 · DOI 10.1182/blood-2017-03-771220
5. Spotlight on ixazomib: potential in the treatment of multiple myeloma.
   Muz B, Ghazarian RN, Ou M, Luderer MJ, et al · · 2016 · cited 87× · PMID 26811670 · DOI 10.2147/dddt.s93602
6. The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.
   Tundo GR, Sbardella D, Santoro AM, Coletta A, et al · · 2020 · cited 78× · PMID 32442437 · DOI 10.1016/j.pharmthera.2020.107579
7. Emerging agents and regimens for multiple myeloma.
   Yang Y, Li Y, Gu H, Dong M, et al · · 2020 · cited 57× · PMID 33168044 · DOI 10.1186/s13045-020-00980-5
8. Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration.
   Anderson KC, Auclair D, Adam SJ, Agarwal A, et al · · 2021 · cited 44× · PMID 34321279 · DOI 10.1158/1078-0432.ccr-21-1059