Clinical trialPhase 3Multiple myeloma

Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

N Engl J Med · 2024446 patients (265 Isa-VRd, 181 VRd)

Facon T, Dimopoulos MA, Leleu XP, et al. N Engl J Med. 2024. 391:1597-1609

Study type: Clinical trial
Study name: IMROZ
Phase: Phase 3
Design: Randomised (3:2), open-label, international trial
Sample size: 446 patients (265 Isa-VRd, 181 VRd)
Source: N Engl J Med · 2024
Trial registration: NCT03319667

In plain words

This study was done in people with myeloma (up to 80 years old) for whom a stem cell transplant was not suitable. Adding the antibody isatuximab to the three-drug VRd regimen meant that after 5 years about 63% of patients were living without their disease getting worse, compared with about 45% with the three-drug treatment. Serious side effects were similar in the two groups, although this regimen is not suitable for very frail patients.

Key results

63.2% vs 45.2%

60-month progression-free survival

HR 0.60 (98.5% CI 0.41–0.88); P<0.001; median follow-up 59.7 months

74.7% vs 64.1%

Complete response or better

P = 0.01

55.5% vs 40.9%

MRD negativity with complete response

P = 0.003

Drugs in this study:Bortezomib (Velcade)Lenalidomide (Revlimid)

Dose and schedule cards

Isa-VRd (IMROZ trial)

Transplant-ineligible newly diagnosed myeloma, age 18–80 yearsOn the page “Multiple myeloma” · Newly diagnosed myeloma: transplant-ineligible patients

Transplant-ineligible newly diagnosed myeloma, age 18–80 years

Drug	Dose	Route	Schedule
Induction: Cycles 1–4 (42-day)
Isatuximab	10 mg/kg	IV	Cycle 1: Days 1, 8, 15, 22 and 29; Cycles 2–4: Days 1, 15 and 29
Bortezomib	1.3 mg/m²	SC	Days 1, 4, 8, 11, 22, 25, 29 and 32
Lenalidomide	25 mg once daily	Oral	Days 1–14 and 22–35
Dexamethasone	20 mg	IV on isatuximab days, oral on other days	Days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32 and 33
Continuation: from Cycle 5 (28-day)
Isatuximab	10 mg/kg	IV	Cycles 5–17: Days 1 and 15; from Cycle 18: Day 1
Lenalidomide	25 mg once daily	Oral	Days 1–21
Dexamethasone	20 mg	IV or oral	Days 1, 8, 15 and 22

Cycle length: Induction every 42 days; then every 28 days
Duration: 4 cycles of induction, then Isa-Rd until progression or intolerance

Doses from the FDA label for SARCLISA (IMROZ section); results from IMROZ. Premedication 15–60 minutes before isatuximab: dexamethasone (part of the regimen), acetaminophen 650–1,000 mg, an H2 antagonist and diphenhydramine 25–50 mg; antibacterial and antiviral prophylaxis (e.g., against herpes zoster) according to guidelines; isatuximab dose reductions are not recommended. In IMROZ, with 60 months of follow-up, second primary malignancies occurred in 16% vs 9%.

On the page “Multiple myeloma” · Newly diagnosed myeloma: transplant-ineligible patients

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Isatuximab + VRd (Isa-VRd)

Induction (4 cycles of 42 days): isatuximab 10 mg/kg IV on days 1, 8, 15, 22 and 29 of cycle 1 and days 1, 15 and 29 of cycles 2 to 4; bortezomib 1.3 mg/m² subcutaneously on days 1, 4, 8, 11, 22, 25, 29 and 32; lenalidomide 25 mg daily orally on days 1 to 14 and 22 to 35; dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32 and 33.

Continuous treatment (28-day cycles from cycle 5): isatuximab 10 mg/kg on days 1 and 15 of cycles 5 to 17 and on day 1 from cycle 18 onwards; lenalidomide 25 mg days 1 to 21; dexamethasone 20 mg days 1, 8, 15 and 22; until disease progression or unacceptable toxicity.

2VRd

The same induction schedule with bortezomib, lenalidomide and dexamethasone (4 cycles of 42 days), followed by continuous lenalidomide and dexamethasone (Rd) in 28-day cycles until disease progression.

Source of the regimen details: FDA label for SARCLISA (intravenous formulation), Clinical Studies (IMROZ) and Dosage and Administration sections

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 to 80 years with newly diagnosed multiple myeloma who were not transplant candidates (median age 72 years).

Endpoints

Primary endpoint: progression-free survival.

Key secondary endpoints: complete response or better, and MRD negativity in patients with a complete response.

Safety and side effects

No new safety signal was observed with Isa-VRd. The incidence of serious treatment-emergent adverse events and of adverse events leading to discontinuation was similar in the two groups.

Clinical significance and place in guidelines

Based on this study, the FDA in September 2024 approved isatuximab (Sarclisa) with VRd for induction, followed by Isa-Rd, for newly diagnosed transplant-ineligible patients, and the EMA has also approved it. Isa-VRd is the first four-drug regimen approved for transplant-ineligible patients and is recommended in guidelines for non-frail patients under 80 years.

Limitations

The study was open-label. Patients over 80 years and frail patients were not enrolled, so the results cannot be generalised to these groups. Overall survival data at the time of this report were insufficient for a definitive conclusion.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.