Clinical trialPhase 3Multiple myeloma

Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma

N Engl J Med · 2017700 patients

Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. N Engl J Med. 2017. 376:1311-1320

Study type: Clinical trial
Study name: IFM 2009
Phase: Phase 3
Design: Randomised controlled two-arm trial
Sample size: 700 patients
Source: N Engl J Med · 2017
Trial registration: NCT01191060

In plain words

In this study, patients with multiple myeloma received either the RVD drugs alone or the same drugs together with a transplant of their own stem cells. Patients who had a transplant stayed free of disease progression for longer, but overall survival after 4 years was about the same in the two groups. The transplant came with side effects such as a deeper fall in white blood cells, bowel and stomach problems and infections. The decision about a transplant should be made with the treating doctor, taking each patient's circumstances into account.

Key results

50 months vs 36 months (transplantation vs RVD alone)

Median progression-free survival

Adjusted HR for progression or death 0.65; P<0.001

59% vs 48%

Complete response

P=0.03

79% vs 65%

Absence of minimal residual disease (MRD)

P<0.001

81% vs 82%

Overall survival at 4 years

The difference was not significant

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

Dose and schedule cards

VRd followed by autologous transplantation (IFM 2009 trial)

Newly diagnosed myeloma in transplant-eligible patients (age 65 years or younger in IFM 2009); an acceptable option alongside quadruplet regimens in the EHA-EMN guidelineCycle length: Every 21 daysOn the page “Multiple myeloma” · Newly diagnosed myeloma: transplant-eligible patients

Newly diagnosed myeloma in transplant-eligible patients (age 65 years or younger in IFM 2009); an acceptable option alongside quadruplet regimens in the EHA-EMN guideline

Drug	Dose	Route	Schedule
Induction: 3 cycles
Lenalidomide	25 mg once daily	Oral	Days 1–14
Bortezomib	1.3 mg/m²	IV (SC is also acceptable in current practice)	Days 1, 4, 8 and 11
Dexamethasone	20 mg	Oral	Days 1, 2, 4, 5, 8, 9, 11 and 12
Stem cell collection
Cyclophosphamide + G-CSF	Per institutional protocol	IV	—
Transplantation
Melphalan	200 mg/m²	IV	Followed by autologous stem cell infusion
Consolidation: 2 cycles
VRd	Same doses, with dexamethasone 10 mg	—	Same days

Cycle length: Every 21 days
Duration: 3 cycles of induction, transplantation, 2 cycles of consolidation, then lenalidomide maintenance (one year in IFM 2009; until progression per the label)

Doses from the full text of IFM 2009.

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

1RVD-alone group

Induction: three 21-day cycles of RVD comprising lenalidomide 25 mg orally on days 1 to 14, bortezomib 1.3 mg/m² IV on days 1, 4, 8 and 11 and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12; then stem cell collection with cyclophosphamide and G-CSF. Consolidation: five more cycles of RVD with the daily dexamethasone dose reduced to 10 mg (8 cycles in total; 350 patients). Maintenance: lenalidomide 10 mg daily for the first 3 months and 15 mg if tolerated, starting within 3 weeks after consolidation, for 1 year.

2RVD plus transplantation group

Induction: three cycles of RVD at the same doses and stem cell collection with cyclophosphamide and G-CSF; then melphalan 200 mg/m² and autologous stem cell transplantation; then two cycles of RVD with dexamethasone 10 mg (350 patients). Maintenance: lenalidomide 10 mg daily for the first 3 months and 15 mg if tolerated, for 1 year.

Source of the regimen details: Full text of the paper in PMC (PMC6201242), Methods section

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 65 years or younger with symptomatic, measurable, newly diagnosed multiple myeloma.

Endpoints

Primary endpoint: progression-free survival (PFS). The abstract also reports complete response, absence of minimal residual disease (MRD) and overall survival.

Safety and side effects

Grade 3 or 4 neutropenia: 92% in the transplant group versus 47% in the RVD-alone group. Grade 3 or 4 gastrointestinal disorders: 28% versus 7%. Infections: 20% versus 9%. There was no significant difference between the two groups in treatment-related deaths, second primary cancers, thromboembolic events or peripheral neuropathy.

Clinical significance and place in guidelines

This study showed that adding transplantation to RVD prolongs progression-free survival, but in this report overall survival did not differ and grade 3 or 4 adverse events were more frequent. The abstract gives no information on the impact on guidelines or approvals; the current status of guideline recommendations should be checked separately.

Limitations

Based on the abstract, the difference in overall survival at 4 years was not significant, and longer follow-up may be needed. Other limitations should be checked in the full text of the paper.

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.