# Safety and efficacy of a dexamethasone-sparing regimen with daratumumab and lenalidomide in patients with frailty and newly diagnosed multiple myeloma (IFM2017-03): a phase 3, open-label, multicentre, randomised, controlled trial

Salomon Manier, Jérôme Lambert, Cyrille Hulin, Margaret Macro, Kamel Laribi, Carla Araujo, Gian Matteo Pica, Cyrille Touzeau, Pascal Godmer, Borhane Slama, et al.

► To cite this version:

Salomon Manier, Jérôme Lambert, Cyrille Hulin, Margaret Macro, Kamel Laribi, et al. Safety and efficacy of a dexamethasone-sparing regimen with daratumumab and lenalidomide in patients with frailty and newly diagnosed multiple myeloma (IFM2017-03): a phase 3, open-label, multicentre, randomised, controlled trial. Lancet Oncology, 2025, 26 (10), pp.1323-1333. 10.1016/S1470-2045(25)00280-3. hal-05319116

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# Safety and efficacy of a dexamethasone-sparing regimen with daratumumab and lenalidomide in patients with frailty and newly diagnosed multiple myeloma (IFM2017-03): a phase 3, open-label, multicentre, randomised, controlled trial

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CrossMark

Salomon Manier, Jérôme Lambert, Cyrille Hulin, Margaret Macro, Kamel Laribi, Carla Araujo, Gian Matteo Pica, Cyrille Touzeau, Pascal Godmer, Borhane Slama, Lionel Karlin, Frédéric Orsini Piocelle, Mamoun Dib, Laurence Sanhes, Pierre Morel, Abderazzak El Yamani, Mourad Tiab, Reza Tabrizi, Valentine Richez, Laurent Garderet, Bruno Royer, Benoit Bareau, Clara Mariette, Emmanuel Fleck, Daniela Robu, Claire Calmettes, Sophie Rigaudeau, Hélène Demarquette, Laurent Frenzel, Olivier Decaux, Mohamad Mohty, Bertrand Arnulf, Noémie Bigot, Aurore Perrot, Jill Corre, Jean-Yves Mary, Hervé Avet-Loiseau, Philippe Moreau, Xavier Leleu, Thierry Façon

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## Summary

**Background** Patients with frailty and newly diagnosed multiple myeloma have worse outcomes due to higher rates of adverse events (AEs) and treatment discontinuation. This study evaluated a dexamethasone-sparing regimen of daratumumab plus lenalidomide versus lenalidomide plus dexamethasone in frail patients with newly diagnosed multiple myeloma.

**Methods** In this prospective, randomised, open-label trial, conducted at 61 active Intergroup Francophone of Myeloma centres, patients aged 65 years or older with newly diagnosed multiple myeloma and an Eastern Cooperative Oncology Group proxy frailty score of 2 or more were randomly assigned 2:1 to receive daratumumab (1800 mg subcutaneously) plus oral lenalidomide (25 mg daily for 21 days of a 28 day cycle) and dexamethasone (20mg weekly) for two cycles (dexamethasone-sparing group) or lenalidomide (25 mg daily) and oral dexamethasone (20 mg weekly; control group), with stratification by International Staging System, age, and centre. The primary endpoint was progression-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in all patients exposed to at least one dose of randomised intervention. This trial is registered with [ClinicalTrials.gov](https://ClinicalTrials.gov), NCT03993912, and is complete.

**Findings** From Oct 18, 2019 to July 20, 2021, 335 patients were screened, of whom 295 patients were randomly assigned (200 to lenalidomide plus daratumumab, 95 to lenalidomide plus dexamethasone). The median age was 81 years (IQR 77–84), with 180 (61%) aged older than 80 years, and 151 (51%) patients were female and 144 (49%) were male. Median follow-up was 46.3 months (IQR 46.0–52.7). Median progression-free survival was 53.4 months (95% CI 35.3–not reached) in the dexamethasone-sparing group versus 22.5 months (16.5–39.0) in the control group (hazard ratio [HR] 0.51, 95% CI 0.37–0.70, p<0.0001). The most common grade 3–5 AEs were neutropenia (110 [55%] of 200 patients in the dexamethasone-sparing group vs 23 [24%] of 95 patients in the control group), and infection (38 [19%] vs 20 [21%]). Serious adverse events occurred in 126 patients (63%) in the dexamethasone-sparing group and 66 patients (69%) in the control group. AEs leading to death occurred in 23 patients (12%) in the dexamethasone-sparing group and 12 patients (13%) in the control group, with 4 (2%) and 2 (2%) grade 5 treatment-emergent adverse events, respectively.

**Interpretation** In the IFM2017-03 trial, use of lenalidomide plus daratumumab, with dexamethasone limited to the first 2 treatment cycles, reduced the risk of progression or death compared with lenalidomide plus dexamethasone, with no additional safety concerns. Lenalidomide plus daratumumab could therefore be considered as a treatment option for older patients with frailty and newly diagnosed multiple myeloma.

**Funding** The study was funded by Johnson & Johnson.

**Copyright** © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

## Introduction

Older patients with newly diagnosed multiple myeloma show variability in their fitness levels and tolerance to treatment, making their management more complex

than younger patients.¹ This heterogeneity necessitates the development of tailored approaches adapted to different patient subgroups.² Patients with frailty have worse outcomes due to higher rates of

Lancet Oncol 2025; 26: 1323-33

See Comment page 1263

Department of Hematology, University Hospital of Lille, Lille, France
(Prof S Manier MD PhD, Prof T Façon MD), Department of Biostatistics and Epidemiology
(Prof J Lambert MD PhD, N Bigot MSc, J-Y Mary PhD), and Department of Hematology
(B Royer MD, Prof B Arnulf MD PhD), University Hospital of Saint-Louis, Paris, France;
Department of Hematology, University Hospital of Bordeaux, Bordeaux, France
(C Hulin MD); Department of Hematology, University Hospital of Caen Normandie, Caen, France (M Macro MD);
Department of Hematology, Le Mans Hospital, Le Mans, France
(K Laribi MD); Department of Hematology, Côte Basque Hospital, Bayonne, France
(C Araujo MD); Department of Hematology, Metropole Savoie Hospital, Chambéry, France
(G M Pica MD); Department of Hematology, University Hospital of Nantes, Nantes, France
(Prof C Touzeau MD PhD, Prof P Moreau MD PhD);
Department of Hematology, Bretagne-Atlantique Hospital, Vannes, France (P Godmer MD);
Department of Hematology, Avignon Hospital, France
(B Slama MD); Department of Hematology, University Hospital of Lyon, Hospices Civils de Lyon, Lyon, France
(L Karlin MD); Department of Hematology, Annecy Genevois Hospital, Annecy, France
(F Orsini Piocelle MD);
Department of Hematology,
University Hospital of Angers,
Angers, France (M Dib MD);
Department of Hematology,
Perpignan Hospital, Perpignan,
France (L Sanhes MD);
Department of Hematology,
University Hospital of Amiens,
Amiens, France
(Prof P Morel MD PhD);
Department of Hematology,
Simone Veil Hospital, Blois,
France (A ElYamani MD);
Department of Hematology, La
Roche-sur-Yon Hospital, La
Roche-sur-Yon, France
(M Tiab MD); Department of
Hematology, Mont-De-Marsan
Hospital, Mont-De-Marsan,
France (R Tabrizi MD);
Department of Hematology,
University Hospital of Nice,
Nice, France (V Richez MD);
Department of Hematology,
University Hospital of Pitié
Salpetriere, Paris, France
(L Garderet MD PhD);
Department of Hematology,
Les Hôpitaux Privés Rennais,
Cesson Sévigné, France
(B Breau MD); Department of
Hematology, University
Hospital of Grenoble, Grenoble,
France (C Mariette MD);
Department of Hematology,
La Rochelle RÉ Aunis Hospital,
La Rochelle, France
(E Fleck MD); Department of
Hematology, Lens Hospital,
Lens, France (D Robu MD);
Department of Hematology,
Périgueux Hospital, Périgueux,
France (C Calmettes MD);
Department of Hématologie,
Versaille Hospital, Le Chesnay-
Rocquencourt, France
(S Rigaudeau MD); Department
of Hématologie, Dunkerque
Hospital, Dunkerque, France
(H Demarquette MD);
Department of Hematology,
University Hospital of Necker,
Paris, France
(L Frenzel MD PhD);
Department of Hematology,
University Hospital of Rennes,
Rennes, France
(Prof O Decaux MD PhD);
Department of Hematology,
Sorbonne University, Saint-
Antoine Hospital, Paris, France
(Prof M Mohty MD PhD);
Department of Hematology
(Prof A Perrot MD PhD) and Unit
for Genomics in Myeloma
(Prof J Corre PharmAD PhD,
Prof H Avet-Loiseau MD PhD),
University Hospital of
Toulouse-Oncopole, Toulouse,
France; Department of
Hematology, University

Research in Context

Evidence before this study

We searched PubMed on Feb 23, 2025, using the keywords "myeloma" and "frail" to identify studies focused on patients with frailty who had newly diagnosed multiple myeloma. The majority of relevant literature emerged after the publication of the International Myeloma Working Group (IMWG) frailty score in 2015, which provided a standardised approach for assessing frailty in myeloma. Several phase 2 trials have explored treatment strategies for patients with frailty and newly diagnosed multiple myeloma, including low-dose intensity bortezomib-based regimens and ixazomib, daratumumab, and dexamethasone in the HOVON 143 trial, both showing favourable efficacy and safety profiles. In addition, retrospective subgroup analyses of patients with frailty in phase 3 trials, such as ALCYONE (daratumumab plus bortezomib, melphalan, and prednisone vs bortezomib, melphalan, and prednisone) and MAIA (daratumumab, lenalidomide, and dexamethasone vs lenalidomide plus dexamethasone), have provided further insights into the outcomes in these patients. However, we identified no randomised phase 3 trials conducted in older patients with frailty and newly diagnosed multiple myeloma, highlighting an unmet need for frailty-adapted treatment strategies.

Added value of this study

To our knowledge, the IFM2017-03 trial is the first phase 3
randomised trial focused specifically on older patients with
frailty and newly diagnosed multiple myeloma. The study
shows the superiority of a dexamethasone-sparing strategy
with lenalidomide plus daratumumab compared with
lenalidomide plus dexamethasone, with a notable median
progression free survival for this population with frailty.
Importantly, in the context of prolonged removal of
dexamethasone, the addition of daratumumab did not lead to
an increased risk of infections, including pneumonia. These
results suggest that a dexamethasone-sparing strategy can
mitigate toxicity risks while maintaining the benefits of
anti-CD38 antibody therapy.

Implications of all the available evidence

The IFM2017-03 trial supports the integration of a dexamethasone-sparing regimen into clinical practice for older patients with frailty and newly diagnosed multiple myeloma. The strategy has been included in the European Hematology Association-European Myeloma Network evidence-based guidelines for diagnosis, treatment and follow-up of patients with multiple myeloma.

non-haematological adverse events (AEs) and
treatment discontinuations.

Several frailty scores have been developed to evaluate the fitness of patients with multiple myeloma. Among them, the International Myeloma Working Group (IMWG) frailty score is considered as the gold standard.¹ However, its complexity limits its utility in routine clinical practice. To address this, the Intergroup Francophone of Myeloma (IFM) has developed a simplified frailty score called the Eastern Cooperative Oncology Group (ECOG)-proxy frailty score that is based on age, ECOG performance status, and Charlson Comorbidity Index (CCI).³

The combination of lenalidomide and dexamethasone has, until recently, been a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for transplantation.⁴ This regimen remains an option for some patients that are older and with frailty due to its convenience as an oral regimen. More recently, the MAIA trial established the combination of daratumumab, lenalidomide, and dexamethasone as a new standard of care for older patients.⁵ However, the addition of daratumumab was shown to increase the risk of AEs, particularly infections and pneumonia; specifically, in the population of patients with frailty, more infections at grade 3 or 4 were observed with daratumumab, lenalidomide, and dexamethasone (41·7%) than with lenalidomide and dexamethasone alone (27·7%).⁶ Similarly, in the frailty subgroup of the ALCYONE study, more infections at

grade 3 or higher was seen in patients treated with
daratumumab plus bortezomib, melphalan, and
prednisone (30·0%) than in those treated with
bortezomib, melphalan, and prednisone (17·9%).<sup>7,8</sup>

Dexamethasone, a traditional component of multiple myeloma therapies, is associated with well-established toxicities, particularly in patients with frailty.⁹ However, prolonged dexamethasone use can increase the risk of AEs, such as infections, hypertension, or hyperglycaemia, potentially affecting patient outcomes. We hypothesised that reduced dexamethasone exposure would improve the safety and tolerability of multiple myeloma treatment regimens without compromising efficacy. The IFM2017-03 trial was designed to evaluate a dexamethasone-sparing regimen of reduced dose dexamethasone with lenalidomide plus daratumumab compared with the existing standard regimen of lenalidomide plus dexamethasone.

Methods

Study design and participants

In this multicentre, randomised, controlled, open-label, phase 3 trial, patients were enrolled from Oct 18, 2019 to July 20, 2021, at 61 active IFM sites in France (appendix pp 3, 4). The French National Agency for the Safety of Medicines and Health (ANSM) and an independent ethics committee approved the protocol (ID#19.02.28.43641; appendix). The IFM2017-03 trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference
on Harmonization Good Clinical Practice guidelines. All patients provided written informed consent. The trial was promoted by Lille University Hospital (CHU Lille) in collaboration with the IFM and with the support of Johnson & Johnson. This trial is registered with ClinicalTrials.gov, NCT03993912.

Eligible patients were 65 years or older with newly diagnosed multiple myeloma and measurable disease (any of serum M-spike ≥5 g/L, Bence Jones ≥200 mg per 24 h, or serum free light chain ≥100 mg/L, alone or in combination).¹⁰ Patients were required to have a simplified frailty score (ECOG proxy) of at least 2, corresponding to patients with frailty. ECOG performance status could be 0 to 4. Other inclusion criteria were a haemoglobin concentration of at least 7·5 g/dL, an absolute neutrophil count of 1000 per mm³ or higher, a platelet count of at least 70 000 per mm³ (>50 000 per mm³ if ≥50% of nucleated bone marrow cells were plasma cells), aspartate aminotransferase and alanine aminotransferase concentrations of no more than 2·5 times the upper limit of the normal range, a total bilirubin concentration of no more than 2·0 times the upper limit of the normal range, creatinine clearance of at least 30 mL/min (Cockcroft–Gault formula), and a corrected serum calcium concentration of 14 mg/dL or less (≤3·5 mmol/L). Full eligibility criteria are listed in the appendix p 31), exclusion criteria included monoclonal gammopathy other than multiple myeloma, previous systemic therapy, a history of malignancy within 5 years, clinical signs of meningeal involvement, and known chronic obstructive pulmonary disease.

## Randomisation and masking

Patients were randomly assigned in a 2:1 ratio to receive either reduced dose dexamethasone with lenalidomide plus daratumumab (dexamethasone-sparing group) or lenalidomide plus dexamethasone (control group) using a centralised, computer-generated allocation sequence implemented via the Ennov Clinical Interactive Web Response System (IWRS), managed by Euraxi Pharma. The randomisation sequence used a permuted block design with variable block sizes (3 and 6) and was stratified by International Staging System (ISS) stage (I/II vs III), age (<80 years vs ≥80 years), and centre. Allocation was concealed at the time of enrolment; investigators accessed the IWRS after confirming eligibility, and treatment assignments were revealed only after registration. The randomisation list was implemented by Euraxi Pharma, independent of the sponsor and investigators, and site investigators enrolled participants and assigned treatment via the IWRS. There was no masking to treatment assignment.

## Procedures

Treatments were given in 28-day cycles. In both groups, patients received oral lenalidomide (25 mg on days 1–21) until disease progression or unacceptable toxic effects.

For patients who had a creatinine clearance of 30–60 mL/min, a reduced dose of lenalidomide (10 mg) was recommended to principle investigators, for use at their discretion. Adjustment of the dose of lenalidomide (to 15 mg, 10 mg, or 5 mg, depending on the previous dose) was also recommended to principle investigators for use, at their discretion, in the case of neutropenia and thrombocytopenia.

In the dexamethasone-sparing group, patients received subcutaneous daratumumab at a dose of 1800 mg once weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter until disease progression or unacceptable toxic effects; pre-injection medications were administered approximately 1 h before each daratumumab dose. Dexamethasone was used as premedication for daratumumab during the first two cycles (20 mg on days 1, 8, 15, and 22 of each cycle); from cycle 3 onward, if clinically indicated, prednisone at a dose of 1 mg/kg could be used as an alternative premedication. Dexamethasone was therefore maintained during the first 8 weeks, corresponding to weekly daratumumab administration, and was discontinued once the daratumumab schedule shifted to every 2 weeks.

In the control group, in additional to lenalidomide, patients received oral dexamethasone at a dose of 20 mg on days 1, 8, 15, and 22 of each cycle until disease progression or unacceptable toxic effects (appendix p 55 [protocol p 36]). Dose reductions and treatment interruptions were permitted for lenalidomide and dexamethasone on the basis of tolerability and occurrence of AEs (particularly haematological toxicity), at the discretion of the principle investigator. For lenalidomide, dose adjustments were made, from a starting dose of 25 mg daily, depending on the severity and recurrence of toxicities; for patients with a baseline creatinine clearance of 30–60 mL/min, a starting dose of 10 mg was recommended. Dose reductions or omissions of any of the treatment drugs were allowed, at the discretion of the principle investigator, in cases of intolerance (eg, hyperglycaemia, psychiatric symptoms, or infections), based on investigator judgment. Patients who discontinued treatment (because of patient or investigator decision) were encouraged to continue study follow-up.

## Outcomes

The primary endpoint was progression-free survival, which was defined as the time from randomisation to either disease progression or death. Secondary efficacy endpoints included overall response (including partial response, very good partial response, complete response, and stringent complete response); very good partial response (defined by a reduction of ≥90% in serum M protein plus a urinary M-protein concentration of <100 mg per 24 h) or better; complete response (defined by undetectable M-protein concentration on

Hospital of Poitiers, Poitiers, France (Prof X Leleu MD PhD)

Correspondence to: Prof Salomon Manier, Department of Hematology, University Hospital of Lille, Lille 59000, France

salomon.manier@chu-lille.fr

See Online for appendix
two consecutive serum and urine immunofixation tests and <5% plasma cells in bone marrow); the proportion of patients with negative status for minimal residual disease (defined as a threshold of 10⁻⁵ by clonoSEQ next generation sequencing [centralised in the Department of Myeloma Genomic at Toulouse University Hospital, France] at 12 months in patients with very good partial response or better); overall survival; time to next treatment; progression-free survival on next line of therapy (defined as the time from randomisation to progression on the next line of treatment or death, whichever comes first); and event-free survival (defined as the time from randomisation to progression or death or discontinuation of therapy or non-haematological grade ≥3 AE, whichever comes first). Progressive disease was defined according to IMWG criteria (appendix p 18).¹¹ Disease evaluations (serum M-protein quantitation by electrophoresis, and 24-h urine M-protein quantitation by electrophoresis urine and serum free light chain assay; appendix p 19) were performed every 28 days for the first 2 years and then every 8 weeks until disease progression. Response to trial treatment and disease progression were assessed locally by investigators according to the IMWG criteria, and a centralised review of all assessments was subsequently conducted by the IFM medical team to ensure consistency. Exploratory objectives included patient-reported quality of life

assessed by EORTC-C30 and EQ5-D questionnaires at screening, cycles 3, 6, 9, and 12, and every sixth cycle thereafter until end of treatment. Safety assessments included the evaluation of AEs (graded according to version 4 of the National Cancer Institute Common Terminology Criteria for Adverse Events), electrocardiography, clinical laboratory testing, physical examinations, and vital signs. During the study, all non-haematological AEs were collected and reported regardless of grade, whereas only haematological AEs of grade 3 or higher were systematically collected. AEs were assessed at each cycle and monitored continuously. Serious adverse events and any event leading to treatment discontinuation were recorded throughout the trial and up to 30 days following the last treatment dose. Complete definitions of these endpoints are provided in the appendix (p 70 [protocol p 51]). Ethnicity data were not collected in this study in accordance with French legislation.

## Statistical analysis

Our trial was designed to detect an improvement in median progression-free survival time from 20 months in the control group (based on the FIRST trial) to 32 months in the dexamethasone-sparing group, corresponding to a hazard ratio (HR) of 0.625. Assuming exponential distribution for progression-free survival time, with a two-sided type I error of 5%, and taking into account a 1:2 allocation ratio, 160 events were needed to ensure 80% power. Assuming an accrual period of 24 months and an additional follow-up time of 60 months, 294 patients were needed to be recruited.

The primary analysis was performed in the intention-to-treat population, which included all patients who were randomly assigned treatment. The safety population included all patients who received at least one dose of the trial treatment. Distribution of progression-free survival was estimated using Kaplan Meier method in each treatment group. The p value from the stratified log-rank test was calculated to compare both groups. The treatment effect (HR) and its two-sided 95% CI were estimated using a stratified Cox regression model with treatment as the sole explanatory variable. A forest plot was planned for progression-free survival to investigate homogeneity of treatment effect across subgroups. The prespecified subgroups were based on age, sex, ECOG status, ISS stage, CCI, IFM frailty score, cytogenetics profile, and renal function. Secondary endpoints of time-to-event efficacy endpoints, including progression-free survival on next line of therapy, overall survival, and time to subsequent anti-myeloma treatment, were analysed in the same way. Comparison of overall response, very good partial response, or complete response, and other binary endpoints between the two treatment groups were conducted using the stratified Cochran–Mantel–Haenszel test. The Mantel–Haenszel odds ratio, together with its two-sided 95% CI, were used as the measure of treatment

<figure><img src="image_5.png" /><figcaption>**Figure 1: Trial profile**</figcaption></figure>

Data cutoff date of Nov 6, 2024. *The safety and efficacy populations correspond to the intention-to-treat population. †11 investigator judgement, 3 treatment for another cancer, 1 treatment delay for toxicity, and 1 lost to follow up. ‡11 investigator judgment, 2 treatment for another cancer, and 1 treatment delay for toxicity.
effect. No adjustment for multiplicity was performed on secondary outcomes. Quality of life scores were summarised at each time point. In addition to number and proportion of AEs, relative risk for safety outcomes and its two-sided 95% CI were calculated in a post-hoc analysis. In another post-hoc analysis we also calculated infection rates per patient per year in each group by dividing the first infection of grade 3 or higher by the total exposure (defined as the cumulative follow-up of all patients between randomised assignment and the earlier event among end of study treatment [whatever the reason], first infection, and loss to follow-up). Incidence rate ratio and its two-sided 95% CI were estimated using a Poisson regression model, with treatment as the explanatory variable and exposure as an offset. The primary analysis, reported in this Article, assessed safety and efficacy after 160 events of disease progression or death had occurred. For statistical analyses, R (version 4.2.1) was used with the package survival, survRM2, and icenReg (for interval censored progression-free survival; appendix p 16).

## Role of the funding source

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

## Results

From Oct 18, 2019, to Jul 20, 2021, 335 patients were screened for eligibility, and 295 patients were enrolled and randomly assigned to treatment groups—200 to the dexamethasone-sparing group and 95 to the control group (figure 1, table 1, appendix p 8). The median age was 81 years (IQR 77–84, range 68–92); 151 (51%) were female, and 144 (49%) were male. 180 (61%) of the 295 patients randomly assigned were older than 80 years, and 125 (42%) had an ECOG performance status of 2 or more. 91 (31%) had stage III disease according to the ISS, and 45 (15%) presented with a high-risk cytogenetic profile (patients could have more than one high-risk feature). All patients were classified as frail with a simplified frailty score³ of 2 or higher. Specifically, 93 patients (32%) had a frailty score of 2, 107 (36%) had a score of 3, and 95 (32%) had a score of 4 or 5. The concordance between the simplified frailty score and the IMWG frailty score¹ was high, with 228 patients (77%) classified as frail by both scoring systems. Additionally, 60 patients (20%) were categorised by the IMWG frailty score as intermediate and 7 (2%) as fit (appendix p 9).

At the time of data cutoff for the primary analysis (Nov 6, 2024), 119 (60%) of 200 patients in the dexamethasone-sparing group and 84 (88%) of 95 patients in the control group had discontinued treatment, most commonly because of progressive disease (44 [22%] in the dexamethasone-sparing group and 39 [41%] in the control group) or due to AEs (36 [18%])

<table><thead><tr><th></th><th>Lenalidomide plus daratumumab group (n=200)</th><th>Lenalidomide plus dexamethasone group (n=95)</th></tr></thead><tbody><tr><td>Age, years</td><td></td><td></td></tr><tr><td>Median (IQR)</td><td>81 (77-84)</td><td>81 (77-84)</td></tr><tr><td>65 to &lt;75</td><td>32 (16%)</td><td>15 (16%)</td></tr><tr><td>75 to &lt;80</td><td>49 (25%)</td><td>19 (20%)</td></tr><tr><td>≥80</td><td>119 (60%)</td><td>61 (64%)</td></tr><tr><td>Sex</td><td></td><td></td></tr><tr><td>Female</td><td>102 (51%)</td><td>49 (52%)</td></tr><tr><td>Male</td><td>98 (49%)</td><td>46 (48%)</td></tr><tr><td>ECOG performance status</td><td></td><td></td></tr><tr><td>0</td><td>21 (11%)</td><td>9 (9%)</td></tr><tr><td>1</td><td>92 (46%)</td><td>48 (51%)</td></tr><tr><td>2</td><td>76 (38%)</td><td>35 (37%)</td></tr><tr><td>≥3</td><td>11 (6%)</td><td>3 (3%)</td></tr><tr><td>Charlson Comorbidity Index</td><td></td><td></td></tr><tr><td>≤1</td><td>117 (59%)</td><td>57 (60%)</td></tr><tr><td>&gt;1</td><td>83 (42%)</td><td>38 (40%)</td></tr><tr><td>IFM frailty score</td><td></td><td></td></tr><tr><td>2</td><td>58 (29%)</td><td>35 (37%)</td></tr><tr><td>3</td><td>80 (40%)</td><td>27 (28%)</td></tr><tr><td>4</td><td>46 (23%)</td><td>24 (25%)</td></tr><tr><td>5</td><td>16 (8%)</td><td>9 (9%)</td></tr><tr><td>ISS disease stage</td><td></td><td></td></tr><tr><td>I</td><td>33 (17%)</td><td>19 (20%)</td></tr><tr><td>II</td><td>103 (52%)</td><td>49 (52%)</td></tr><tr><td>III</td><td>64 (32%)</td><td>27 (28%)</td></tr><tr><td>Type of measurable disease</td><td></td><td></td></tr><tr><td>IgG</td><td>126 (63%)</td><td>56 (59%)</td></tr><tr><td>IgA</td><td>40 (20%)</td><td>22 (23%)</td></tr><tr><td>BJP</td><td>6 (3%)</td><td>7 (7%)</td></tr><tr><td>SFLC</td><td>26 (13%)</td><td>10 (11%)</td></tr><tr><td>Other*</td><td>2 (1%)</td><td>0</td></tr><tr><td>Cytogenetics profile</td><td></td><td></td></tr><tr><td>Standard risk</td><td>146 (73%)</td><td>56 (59%)</td></tr><tr><td>High risk†</td><td>28 (14%)</td><td>17 (18%)</td></tr><tr><td>del17p</td><td>16 (8%)</td><td>11 (12%)</td></tr><tr><td>t(4;14)</td><td>9 (5%)</td><td>5 (5%)</td></tr><tr><td>t(14;16)</td><td>5 (3%)</td><td>2 (2%)</td></tr><tr><td>Missing sample or technical failure</td><td>26 (13%)</td><td>22 (23%)</td></tr><tr><td>Creatinine clearance</td><td></td><td></td></tr><tr><td>&lt;30 mL/min</td><td>0</td><td>3 (3%)</td></tr><tr><td>30 to &lt;60 mL/min</td><td>121 (61%)</td><td>50 (53%)</td></tr><tr><td>≥60 mL/min</td><td>79 (40%)</td><td>42 (44%)</td></tr><tr><td>Quality of life, baseline assessments</td><td></td><td></td></tr><tr><td>EORTC-C30, mean sum score (IQR)</td><td>71 (54-82)</td><td>71 (54-82)</td></tr><tr><td>EQ-5D-3L, mean health score (IQR)</td><td>50 (40-70)</td><td>50 (50-70)</td></tr></tbody></table>

Data are n (%) unless otherwise stated. BJP=Bence Jones protein. ECOG=Eastern Cooperative Oncology Group. EORTC=European Organisation for Research and Treatment of Cancer. EQ-5D-3L=EuroQol 5-Dimensions 3-Levels questionnaire. IFM=Intergroup Francophone Myeloma. ISS=International Staging System. SFLC=serum free light chain. *IgD or IgM multiple myeloma. †Patients could have more than one high-risk feature.

<caption>**Table 1:** Baseline characteristics (intention-to-treat population)</caption>
<figure><img src="image_6.png" /><figcaption>**Figure 2: Survival outcomes**</figcaption></figure>

(A) Progression-free survival. Kaplan-Meier estimates of progression-free survival among patients in the intention-to-treat population. The analysis of progression-free survival was performed after 162 events of disease progression or death had occurred. (B) Overall survival. Kaplan-Meier estimates of overall survival among patients in the intention-to-treat population. HR=hazard ratio. NR=not reached.

and 23 [24]). Patients who discontinued treatment for reasons other than disease progression and remained in the trial were followed for the primary end point. The median duration of treatment was 31.6 months (IQR 12.0–45.3) in the dexamethasone-sparing group and 14.3 months (5.2–30.3) in the control group, and the median number of treatment cycles was 33.5 (13.8–49.0) in the dexamethasone-sparing group and 16 (6.0–30.5) in the control group (appendix p 5). The median relative dose intensity for daratumumab was 95.2% (84.6–98.4). The median relative dose

intensity for lenalidomide was 34.8% (22.3–57.1) in the dexamethasone-sparing group and 47.1% (29.0–75.8) in the control group. This difference reflects a higher rate of dose modification in the dexamethasone-sparing group occurring after the start of treatment. 27 (14%) of 200 patients in the dexamethasone-sparing group discontinued lenalidomide completely but continued to receive daratumumab monotherapy. Among these patients, the median duration of single-agent daratumumab treatment was 4 months (0.6–10.3). The median relative dose intensity for dexamethasone in the lenalidomide group was 53.1% (23.2–90.2).

At the primary analysis, after a median follow-up of 46.3 months (IQR 46.0–52.7), disease progression or death had occurred in 162 patients (93 [47%] of 200 patients in the dexamethasone-sparing group and 69 [73%] of 95 patients in the control group). Median progression-free survival was 53.4 months (95% CI 35.3–not reached) in the dexamethasone-sparing group and 22.5 months (16.5–39.0) in the control group (HR for disease progression or death 0.51 [95% CI 0.37–0.70, p<0.0001; figure 2, table 2].

Prespecified subgroup analyses showed superiority of lenalidomide plus daratumumab over lenalidomide plus dexamethasone across most subgroups, including clinically relevant subgroups defined by age, ECOG performance status, ISS disease stage, and cytogenetic risk group (figure 3). The between-group difference in progression-free survival was not affected by age (≤80 years or >80 years) or CCI (<1 or ≥1), but was impacted by the degree of frailty (appendix p 10). The time to next treatment was longer in the dexamethasone-sparing group, with a median of not reached (95% CI not reached–not reached), compared with 47.8 months (22.7–not reached) in the control group (HR 0.45; 95% CI 0.30–0.67; p<0.0001; appendix p 12), reflecting prolonged disease control.

Overall response rate was higher in the dexamethasone-sparing group (92%) than in the control group (85%). In the intention-to-treat population, the percentage of patients with very good partial response or better was higher in the dexamethasone-sparing group compared with the control group (69% [95% CI 62–75] vs 51% [40–61], p=0.0050; (table 2; appendix p 11). Notably, higher rates of very good partial response or better were observed as early as cycle 4 in the dexamethasone-sparing group compared with the control group (32% [26–39] vs 20% [12–29], p=0.044), indicating that the stringent dexamethasone-sparing strategy did not compromise rapid responses (appendix p 11). The percentage of patients who were negative for minimal residual disease was higher in the dexamethasone-sparing group than in the control group, although this did not reach statistical significance (10% [7–16] vs 4% [1–10], p=0.11; table 2, appendix p 11). Of note, data on minimal residual disease status was not assessable (for technical reasons) or was missing for 47 patients (24%) in dexamethasone-sparing group and 15 (15%) in the control group.
<table><thead><tr><th></th><th>Lenalidomide plus<br>daratumumab group (n=200)</th><th>Lenalidomide plus<br>dexamethasone group (n=95)</th><th>HR (95%CI)</th><th>p value</th></tr></thead><tbody><tr><td colspan="5"><strong>Time-to-event endpoints, median (95% CI)</strong></td></tr><tr><td>Progression-free survival</td><td>53.4 (35.3 to NR)</td><td>22.5 (16.5-39.0)</td><td>0.51 (0.37-0.70)</td><td>&lt;0.0001</td></tr><tr><td>Overall survival</td><td>NR (NR to NR)</td><td>47.3 (36.0 to NR)</td><td>0.52 (0.35-0.77)</td><td>0.0010</td></tr><tr><td>Time to next treatment</td><td>NR (NR to NR)</td><td>47.8 (22.7 to NR)</td><td>0.45 (0.30-0.67)</td><td>&lt;0.0001</td></tr><tr><td>Progression-free survival on next line of therapy</td><td>NR (53.4 to NR)</td><td>39.0 (33.5-49.0)</td><td>0.54 (0.38-0.77)</td><td>0.0007</td></tr><tr><td>Event-free survival</td><td>6.8 (3.7-10.2)</td><td>4.0 (2.5-8.4)</td><td>0.70 (0.54-0.91)</td><td>0.0070</td></tr><tr><td colspan="5"><strong>Response rates, n (% [95% CI])</strong></td></tr><tr><td>Overall response</td><td>183 (92% [87-95])</td><td>81 (85% [77-92])</td><td>--</td><td>0.1800</td></tr><tr><td>Very good partial response or better</td><td>138 (69% [62-75])</td><td>48 (51% [40-61])</td><td>--</td><td>0.0050</td></tr><tr><td>Complete response</td><td>68 (34% [27-41])</td><td>11 (12% [6-20])</td><td>--</td><td>0.0001</td></tr><tr><td>Negative for minimal residual disease &lt;10<sup>-5</sup>*</td><td>21 (10% [7-16])</td><td>4 (4% [1-10])</td><td>--</td><td>0.1100</td></tr></tbody></table>

HR=hazard ratio. NR=not reached. *Data on minimal residual disease was missing or not assessable for 47 patients (24%) in the dexamethasone-sparing group and 15 (15%) in the control group; for the purposes of intention-to-treat analysis, missing or not assessable values were considered positive.

<figure><img src="image_7.png" /><figcaption>Figure 3: Prespecified subgroup analysis of progression free survival</figcaption></figure>

A high-risk cytogenetic profile was defined by the detection of a del17p, t(14;16), or t(4;14) on fluorescence in-situ hybridisation or next generation sequencing. ECOG=Eastern Cooperative Oncology Group. HR=hazard ratio. IFM=Intergroup Francophone Myeloma. ISS=International Staging System. PFS=progression-free survival.
103 patients (35%) received a subsequent line of therapy; 58 (29%) of 200 patients in the dexamethasone-sparing group and 45 (47%) of 95 patients in the control group (HR 0.45, 95% CI 0.30–0.67, p<0.0001; appendix p 12, table 2). In the control group, 31 (33%) of 95 patients received a daratumumab-based regimen as a subsequent line of treatment (appendix p 12). Among patients receiving a subsequent line of therapy, disease progression or death had occurred in 72 (36%) of 200 patients in the dexamethasone-sparing group and 53 (56%) of 95 patients in the control group. In the dexamethasone-sparing group, 27 (14%) of 200 patients progressed on the next line of therapy and 45 patients (23%) died without progression on the next line of therapy. In the control group, 15 (16%) of 95 patients progressed on the next line of therapy and 38 patients (40%) died without progression on the next line of therapy (appendix p 13). Event-free survival was higher in the dexamethasone-sparing group, with 175 (88%) of patients having an event compared with 94 (99%) in the control group (HR 0.70, 95% CI 0.54–0.91, p=0.0070; table 2, appendix p 14).

At the median follow-up of 46.3 months, 104 patients had died, 59 (30%) of 200 in the dexamethasone-sparing group and 45 (47%) of 95 in the control group. The median overall survival was not reached in the dexamethasone-sparing group, and was 47.3 months (95% CI 36–not reached) in the control group (HR 0.52 [95% CI 0.35–0.77], p=0.0001; figure 2B). The EORTC QLQ-C30 summary score and the EQ-5D-3L health score improved and remained stable over time in the two groups, with no significant differences observed (appendix p 15). For all time to event endpoints, the proportional hazards assumption was tested, with significant deviation seen only for event-free survival (p=0.0047); as such, the HR for event-free survival should be interpreted as an averaged estimation.

In the safety population, 196 (98%) of 200 patients in the dexamethasone-sparing group and 93 (98%) of 95 patients in the control group had at least one AE (relative risk [RR] 1.01, 95% CI 0.97–1.04; table 3, appendix p 17). 126 (63%) patients in the dexamethasone-sparing group and 66 (69%) patients in the control group had at least one serious adverse event (RR 0.91; 95% CI 0.76–1.08), and 178 (89%) patients in the dexamethasone-sparing group and 75 (79%) patients in the control group had at least one grade 3–5 AE (RR 1.13, 95% CI 1.01–1.26). 60 (30%) patients in the dexamethasone-sparing group and 32 (34%) patients in the control group had an AE that led to discontinuation of at least one of the drugs, with 36 (18%) and 23 (24%) discontinuing treatment entirely due to AEs (RR 0.74, 95% CI 0.47–1.18; appendix p 6).

The most common grade 3–5 AEs were neutropenia (110 [55%] of 200 patients in the dexamethasone-sparing group vs 23 [24%] of 95 patients in the control group) and infection (38 [19%] vs 20 [21%]). Haematological AEs of

grade 3–5 occurred in 123 (62%) of 200 patients in the dexamethasone-sparing group and 32 (34%) of 95 in the control group (RR 1.83, 95% CI 1.35–2.47), with neutropenia (RR 2.27, 95% CI 1.56–3.31), anaemia (RR 3.38, 95% CI 1.17–12.31), and thrombocytopenia (RR 1.81, 95% CI 0.78–1.08) being the most common. Non-haematological AEs of grade 3–5 occurred in 132 (66%) of 200 patients in the dexamethasone-sparing group and 68 (72%) of 95 patients in the control group (RR 0.92, 95% CI 0.78–1.08). The proportion of patients who had infections, including pneumonia, was similar between groups, although among patients with an IFM frailty score of 4 or 5, pneumonia was more common in the control group than in the dexamethasone-sparing group (appendix p 7). 35 patients died due to AEs (23 [12%] of 200 patients in the dexamethasone-sparing group and 12 [13%] of 95 patients in the control group; RR 0.91, 95% CI 0.47–1.75).

Discussion

To our knowledge, the IFM2017-03 trial is the first phase 3 study specifically designed for older patients with frailty and newly diagnosed multiple myeloma. The median age of our cohort was 81 years, with more than 60% of patients being older than 80 years, and nearly half had an ECOG performance status of 2 or more. As such, this trial represents a population of patients that is often under-represented in clinical studies. In comparison, the median age in the FIRST and MAIA trials was 73 years.⁴,⁵ Cross-trial comparisons are limited by differences in patient populations and trial designs but are important to contextualise our findings.

The results of the IFM2017-03 trial show a substantial reduction in risk of disease progression or death with lenalidomide plus daratumumab compared with lenalidomide plus dexamethasone, with a consistent benefit across subgroups, including those defined by age, disease stage, and cytogenetic risk. The median progression-free survival of 53.4 months observed in the dexamethasone-sparing group is remarkable for a population of patients with frailty. By comparison, the HOVON 143 trial reported a median progression-free survival of 21.6 months with daratumumab, ixazomib, and dexamethasone in older patients with frailty.¹² In addition, a retrospective frailty subgroup analysis from the MAIA study (MAIA-frail)—which used the same simplified frailty score as used in our study—reported a comparable median progression-free survival of 52.2 months for patients treated with lenalidomide plus daratumumab plus dexamethasone.⁶,¹³ Progression-free survival in the lenalidomide plus dexamethasone control group of the MAIA-frail sub-study was higher than in our trial (30.4 months in MAIA-frail vs 22.5 months in IFM2017-03), which might reflect differences in patient characteristics; for example, the median age in the MAIA frailty subgroup was 77 years, compared with 81 years in IFM2017-03.
The effect size that we observed for progression-free survival (HR of 0.51 (95% CI 0.37-0.70)) indicates a stronger treatment effect than the estimated HR (0.625) used for the sample size calculation. Although the upper bound of the confidence interval exceeds the target HR, we believe that even the least favourable estimate (HR 0.70) represents a clinically meaningful benefit in this patient population with frailty, particularly in view of the safety profile of the regimen.

The incidence of haematological AEs in the dexamethasone-sparing group was expected based on the results of the MAIA trial,⁵ but the rate of grade 3 or 4

infections and pneumonia were comparatively lower than those observed in the MAIA-frail sub-study, which reported infection rates of 41.7% and 27.7% and pneumonia rates of 19.6% and 10.2% in patients with frailty treated with lenalidomide plus dexamethasone plus daratumumab vs lenalidomide plus dexamethasone, respectively.⁶ The lower infection rates in IFM2017-03 compared to the MAIA trial suggests that a dexamethasone-sparing strategy lowers the risk of infection when combining an anti-CD38 antibody with lenalidomide. Rates of treatment discontinuation due to AEs were also similar between groups in our trial, despite

<table><thead><tr><th rowspan="2"></th><th colspan="4">Lenalidomide plus daratumumab group (n=200)</th><th colspan="4">Lenalidomide plus dexamethasone group (n=95)</th></tr><tr><th>Grade 1-2</th><th>Grade 3</th><th>Grade 4</th><th>Grade 5 (deaths)</th><th>Grade 1-2</th><th>Grade 3</th><th>Grade 4</th><th>Grade 5 (deaths)</th></tr></thead><tbody><tr><td>All AEs</td><td>18 (9%)</td><td>98 (49%)</td><td>57 (29%)</td><td>23 (12%)</td><td>18 (19%)</td><td>56 (59%)</td><td>7 (7%)</td><td>12 (13%)</td></tr><tr><td>Haematological AEs</td><td>14 (7%)</td><td>71 (36%)</td><td>52 (26%)</td><td>0</td><td>14 (15%)</td><td>29 (31%)</td><td>3 (3%)</td><td>0</td></tr><tr><td>Neutropenia</td><td>8 (4%)</td><td>66 (33%)</td><td>44 (22%)</td><td>0</td><td>3 (3%)</td><td>21 (22%)</td><td>2 (2%)</td><td>0</td></tr><tr><td>Anaemia</td><td>37 (19%)</td><td>21 (11%)</td><td>3 (2%)</td><td>0</td><td>21 (22%)</td><td>3 (3%)</td><td>0</td><td>0</td></tr><tr><td>Thrombocytopenia</td><td>19 (10%)</td><td>13 (7%)</td><td>6 (3%)</td><td>0</td><td>6 (6%)</td><td>4 (4%)</td><td>1 (1%)</td><td>0</td></tr><tr><td>Non-haematological AEs</td><td>60 (30%)</td><td>95 (48%)</td><td>14 (7%)</td><td>23 (12%)</td><td>24 (25%)</td><td>52 (55%)</td><td>4 (4%)</td><td>12 (13%)</td></tr><tr><td>Gastrointestinal disorders</td><td>107 (54%)</td><td>14 (7%)</td><td>1 (1%)</td><td>2 (1%)</td><td>48 (51%)</td><td>5 (5%)</td><td>0</td><td>0</td></tr><tr><td>Diarrhoea</td><td>69 (35%)</td><td>7 (4%)</td><td>1 (1%)</td><td>0</td><td>28 (29%)</td><td>1 (1%)</td><td>0</td><td>0</td></tr><tr><td>Constipation</td><td>51 (26%)</td><td>2 (1%)</td><td>0</td><td>0</td><td>27 (28%)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Nausea</td><td>27 (14%)</td><td>0</td><td>0</td><td>0</td><td>13 (14%)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Dysphagia</td><td>0</td><td>2 (1%)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Melena</td><td>0</td><td>2 (1%)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Hepatobiliary dysfunction</td><td>0</td><td>2 (1%)</td><td>0</td><td>1 (1%)</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Gastrointestinal obstruction</td><td>0</td><td>0</td><td>0</td><td>1 (1%)</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Infections</td><td>86 (43%)</td><td>25 (13%)</td><td>4 (2%)</td><td>9 (5%)</td><td>27 (28%)</td><td>18 (19%)</td><td>1 (1%)</td><td>1 (1%)</td></tr><tr><td>COVID-19</td><td>49 (25%)</td><td>4 (2%)</td><td>2 (1%)</td><td>5 (3%)</td><td>9 (9%)</td><td>3 (3%)</td><td>0</td><td>1 (1%)</td></tr><tr><td>Pneumonia</td><td>6 (3%)</td><td>11 (6%)</td><td>1 (1%)</td><td>0</td><td>3 (3%)</td><td>9 (9%)</td><td>0</td><td>0</td></tr><tr><td>Bronchitis</td><td>36 (18%)</td><td>2 (1%)</td><td>0</td><td>0</td><td>9 (9%)</td><td>1 (1%)</td><td>0</td><td>0</td></tr><tr><td>Urinary tract infection</td><td>17 (9%)</td><td>3 (2%)</td><td>0</td><td>0</td><td>6 (6%)</td><td>2 (2%)</td><td>0</td><td>0</td></tr><tr><td>Unspecified sepsis</td><td>6 (3%)</td><td>5 (3%)</td><td>1 (1%)</td><td>4 (2%)</td><td>3 (3%)</td><td>2 (2%)</td><td>0</td><td>0</td></tr><tr><td>Nervous system disorder</td><td>59 (30%)</td><td>16 (8%)</td><td>3 (2%)</td><td>1 (1%)</td><td>28 (29%)</td><td>6 (6%)</td><td>0</td><td>0</td></tr><tr><td>Peripheral neuropathy</td><td>28 (14%)</td><td>3 (2%)</td><td>0</td><td>0</td><td>6 (6%)</td><td>1 (1%)</td><td>0</td><td>0</td></tr><tr><td>Stroke</td><td>0</td><td>2 (1%)</td><td>1 (1%)</td><td>1 (1%)</td><td>0</td><td>1 (1%)</td><td>0</td><td>0</td></tr><tr><td>Cognitive disorder</td><td>1 (1%)</td><td>2 (1%)</td><td>0</td><td>0</td><td>3 (3%)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Confusion</td><td>3 (2%)</td><td>2 (1%)</td><td>0</td><td>0</td><td>1 (1%)</td><td>1 (1%)</td><td>0</td><td>0</td></tr><tr><td>Psychiatric disorders</td><td>34 (17%)</td><td>1 (1%)</td><td>0</td><td>0</td><td>17 (18%)</td><td>5 (5%)</td><td>0</td><td>0</td></tr><tr><td>Anxiety</td><td>15 (8%)</td><td>1 (1%)</td><td>0</td><td>0</td><td>3 (3%)</td><td>2 (2%)</td><td>0</td><td>0</td></tr><tr><td>Depression</td><td>7 (4%)</td><td>0</td><td>0</td><td>0</td><td>2 (2%)</td><td>2 (2%)</td><td>0</td><td>0</td></tr><tr><td>Skin rash</td><td>38 (19%)</td><td>6 (3%)</td><td>0</td><td>0</td><td>15 (16%)</td><td>5 (5%)</td><td>0</td><td>0</td></tr><tr><td>Creatinine increase</td><td>17 (9%)</td><td>14 (7%)</td><td>0</td><td>0</td><td>6 (6%)</td><td>4 (4%)</td><td>0</td><td>0</td></tr><tr><td>Venous thromboembolism</td><td>5 (3%)</td><td>11 (6%)</td><td>1 (1%)</td><td>0</td><td>0</td><td>3 (3%)</td><td>0</td><td>0</td></tr><tr><td>Pulmonary embolism</td><td>1 (1%)</td><td>8 (4%)</td><td>1 (1%)</td><td>0</td><td>0</td><td>3 (3%)</td><td>0</td><td>0</td></tr><tr><td>Venous thrombosis</td><td>4 (2%)</td><td>4 (2%)</td><td>0</td><td>0</td><td>0</td><td>1 (1%)</td><td>0</td><td>0</td></tr><tr><td>Cardiac disorders</td><td>40 (20%)</td><td>20 (10%)</td><td>2 (1%)</td><td>5 (3%)</td><td>23 (24%)</td><td>12 (13%)</td><td>0</td><td>2 (2%)</td></tr><tr><td>Cardiac failure</td><td>6 (3%)</td><td>3 (2%)</td><td>1 (1%)</td><td>4 (2%)</td><td>2 (2%)</td><td>4 (4%)</td><td>0</td><td>2 (2%)</td></tr><tr><td>Arrhythmia</td><td>6 (3%)</td><td>5 (3%)</td><td>0</td><td>0</td><td>2 (2%)</td><td>2 (2%)</td><td>0</td><td>0</td></tr><tr><td>Acute coronary syndrome</td><td>0</td><td>2 (1%)</td><td>0</td><td>1 (1%)</td><td>0</td><td>1 (1%)</td><td>0</td><td>0</td></tr><tr><td>Hypertension</td><td>8 (4%)</td><td>5 (3%)</td><td>0</td><td>0</td><td>3 (3%)</td><td>2 (2%)</td><td>0</td><td>0</td></tr></tbody><tfoot><tr><td colspan="9">(Table 3 continues on next page)</td></tr></tfoot></table>
<table><thead><tr><th rowspan="2"></th><th colspan="4">Lenalidomide plus daratumumab group (n=200)</th><th colspan="4">Lenalidomide plus dexamethasone group (n=95)</th></tr><tr><th>Grade 1-2</th><th>Grade 3</th><th>Grade 4</th><th>Deaths (Grade 5)</th><th>Grade 1-2</th><th>Grade 3</th><th>Grade 4</th><th>Deaths (Grade 5)</th></tr></thead><tbody><tr><td>(Continued from previous page)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>General disorders</td><td>112 (56%)</td><td>38 (19%)</td><td>0</td><td>3 (2%)</td><td>41 (43%)</td><td>22 (23%)</td><td>0</td><td>6 (6%)</td></tr><tr><td>Asthenia or fatigue</td><td>80 (40%)</td><td>8 (4%)</td><td>0</td><td>0</td><td>29 (31%)</td><td>8 (8%)</td><td>0</td><td>0</td></tr><tr><td>General deterioration</td><td>16 (8%)</td><td>8 (4%)</td><td>0</td><td>3 (2%)</td><td>5 (5%)</td><td>2 (2%)</td><td>0</td><td>6 (6%)</td></tr><tr><td>Bone pain</td><td>46 (23%)</td><td>7 (4%)</td><td>0</td><td>0</td><td>18 (19%)</td><td>7 (7%)</td><td>0</td><td>0</td></tr><tr><td>Bone fracture</td><td>2 (1%)</td><td>8 (4%)</td><td>0</td><td>0</td><td>4 (4%)</td><td>5 (5%)</td><td>0</td><td>0</td></tr><tr><td>Cramps</td><td>24 (12%)</td><td>0</td><td>0</td><td>0</td><td>11 (12%)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Arthralgia</td><td>28 (14%)</td><td>2 (1%)</td><td>0</td><td>0</td><td>8 (8%)</td><td>2 (2%)</td><td>0</td><td>0</td></tr><tr><td>Decreased appetite</td><td>15 (8%)</td><td>5 (3%)</td><td>0</td><td>0</td><td>6 (6%)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Deceased weight</td><td>7 (4%)</td><td>1 (1%)</td><td>0</td><td>0</td><td>4 (4%)</td><td>1 (1%)</td><td>0</td><td>0</td></tr><tr><td>Dyspnoea</td><td>18 (9%)</td><td>3 (2%)</td><td>0</td><td>0</td><td>4 (4%)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Respiratory distress</td><td>0</td><td>0</td><td>0</td><td>2 (1%)</td><td>0</td><td>0</td><td>1 (1%)</td><td>2 (2%)</td></tr><tr><td>Fever</td><td>24 (12%)</td><td>1 (1%)</td><td>0</td><td>0</td><td>9 (9%)</td><td>1 (1%)</td><td>0</td><td>0</td></tr><tr><td>Peripheral oedema</td><td>37 (19%)</td><td>0</td><td>0</td><td>0</td><td>16 (17%)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Diabetes</td><td>2 (1%)</td><td>1 (1%)</td><td>0</td><td>0</td><td>0</td><td>1 (1%)</td><td>0</td><td>0</td></tr><tr><td>Metabolism disorders</td><td>37 (19%)</td><td>11 (6%)</td><td>1 (&lt;1%)</td><td>0</td><td>18 (19%)</td><td>6 (6%)</td><td>0</td><td>0</td></tr><tr><td>Hypokalaemia</td><td>16 (8%)</td><td>3 (2%)</td><td>0</td><td>0</td><td>4 (4%)</td><td>1 (1%)</td><td>0</td><td>0</td></tr><tr><td>Hypocalcaemia</td><td>2 (1%)</td><td>2 (1%)</td><td>0</td><td>0</td><td>3 (3%)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Hypercalcaemia</td><td>1 (1%)</td><td>0</td><td>1 (&lt;1%)</td><td>0</td><td>1 (1%)</td><td>3 (3%)</td><td>0</td><td>0</td></tr><tr><td>Gout</td><td>5 (3%)</td><td>2 (1%)</td><td>0</td><td>0</td><td>1 (1%)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Second primary malignancies</td><td>11 (6%)</td><td>9 (5%)</td><td>2 (1%)</td><td>3 (2%)</td><td>5 (5%)</td><td>5 (5%)</td><td>3 (3%)</td><td>2 (2%)</td></tr><tr><td>Non-cutaneous</td><td>4 (2%)</td><td>7 (4%)</td><td>2 (1%)</td><td>3 (2%)</td><td>4 (4%)</td><td>2 (2%)</td><td>3 (3%)</td><td>2 (2%)</td></tr><tr><td>Cutaneous</td><td>7 (4%)</td><td>2 (1%)</td><td>0</td><td>0</td><td>2 (2%)</td><td>4 (4%)</td><td>0</td><td>0</td></tr></tbody></table>

Data are n (%). The table shows all grade 1 and 2 AEs occurring in at least 10% of patients in either group, and all grade 3, 4, and 5 events. AE=adverse event.

<caption>**Table 3:** Most common adverse events (including second primary cancers) reported during treatment in the safety population</caption>

a significantly longer treatment duration in the dexamethasone-sparing group (31.6 months vs 14.3 months), which reflects the good safety profile of the lenalidomide plus daratumumab regimen and aligns with the observed improvement in patient-reported health-related quality of life during treatment (appendix p 15). Notably, some patients in the dexamethasone-sparing group continued treatment with daratumumab after discontinuing lenalidomide (27 [14%] of 200), which contributed to the extended treatment duration. Of note, the median relative dose intensity of lenalidomide in the dexamethasone-sparing group was low (34.8%), reflecting frequent dose reductions over time. Although initiating treatment at 25 mg was feasible in most patients, in practice, many patients transitioned to a maintenance phase at 10 mg, which could be considered as a predefined strategy in future protocols. Alternatively, initiating treatment with a lower dose upfront—particularly in patients with frailty—could be appropriate, as explored in the UKMRA Myeloma XIV FiTNEss trial.¹⁴

A notable observation in our trial is the low rate of minimal residual disease negativity, partly due to a high proportion of unassessable or missing data, highlighting the limitations of bone marrow-based minimal residual disease evaluation in older patients with frailty. Future trials should explore minimal residual disease activity

assessment using peripheral blood, particularly with mass spectrometry, which could be better suited for this population. We also note that the early discontinuation of dexamethasone in the dexamethasone-sparing group did not compromise the achievement of rapid and deep responses, as shown by the significantly higher rate of very good partial response or better as early as 4 months after the treatment initiation.

Although lenalidomide plus dexamethasone represents a previous standard of care, it remains commonly used globally for patients with frailty as an all-oral regimen. Although using a regimen of the combination of daratumumab, lenalidomide, and dexamethasone as the control group would have provided a direct comparison to lenalidomide plus daratumumab, it was not the standard of care at the time the protocol for this trial was developed. Despite this, the trial clearly showed the superiority of lenalidomide plus daratumumab over lenalidomide plus dexamethasone in older patients with frailty, along with the absence of higher toxicity when adding the anti-CD38 antibody (daratumumab) to lenalidomide.

In conclusion, the IFM2017-03 trial, in which lenalidomide plus daratumumab was combined with early dexamethasone discontinuation, showed evidence of efficacy with no additional safety concerns for patients with frailty and newly diagnosed multiple myeloma.
### Contributors

SM and TF designed the trial. SM, CH, MMa, KL, CA, GMP, CT, PG, BS, LK, FOP, MD, LS, PiM, AEY, MT, RT, VR, LG, BR, BB, CM, EF, DR, CC, SR, HD, LF, OD, MMo, BA, AP, PhM, XL, and TF enrolled and treated patients. JC, and HA-L performed minimal residual disease analyses. JL, NB, and J-YM participated in the study design and performed statistical analyses. All authors contributed to the writing of the manuscript and approved its final version. All authors had access to all the data, SM, JL, and TF verified the data.

### Declaration of interests

SM reports consultancy (honorarium to CHU Lille) and travel fees from AbbVie, Adaptive Biotechnology, Amgen, Celgene/BMS, GSK, Janssen, Kite, Novartis, Pfizer, Regeneron, Roche, Sanofi, and Takeda. CH reports consultancy and honoraria from Janssen-Cilag; and received consultancy, honoraria, and travel fees from Sanofi, Janssen-Cilag, Kite/Gilead, Amgen, Novartis, Takeda, Pfizer, Oncopeptide, AbbVie, GSK, and Bristol Myers Squibb. LK received consultancy, honoraria, and travel fees from Sanofi, Janssen-Cilag, Kite/Gilead, Amgen, Novartis, Takeda, Pfizer, Oncopeptide, AbbVie, GSK, and Bristol Myers Squibb. MMo received consultancy, honoraria, and travel fees from Sanofi, Janssen-Cilag, Kite/Gilead, Amgen, Novartis, Takeda, Pfizer, Oncopeptide, AbbVie, GSK, and Bristol Myers Squibb. AP received consultancy, honoraria, and travel fees from AbbVie, Amgen, Bristol Myers Squibb, Janssen, GSK, Menarini Stemline, Pfizer, Sanofi, and Takeda. JC received consultancy, honoraria, and travel fees from Janssen, Sanofi, Bristol Myers Squibb, Pfizer, and Adaptive; and research support from Sanofi, and Bristol Myers Squibb. HA-L received consultancy, honoraria, and travel fees from Janssen, Sanofi, Bristol Myers Squibb, Pfizer, and Adaptive; and research support from Sanofi and Bristol Myers Squibb. PhM reports consultancy fees and honoraria from Janssen-Cilag, Amgen, Novartis, Takeda, Pfizer, AbbVie, GSK, Bristol Myers Squibb, and Sanofi. XL received consultancy, honoraria, and travel fees from Sanofi, Janssen-Cilag, Kite/Gilead, Amgen, Novartis, Takeda, Pfizer, Oncopeptides, AbbVie, GSK, and Bristol Myers Squibb. All other authors declare no competing interests.

### Data sharing

Access to clinical trial data, such as anonymised, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, analysis plans, and data dictionaries), can be requested via email to the corresponding author by any qualified researchers who engage in rigorous, independent, scientific research. These data will be provided following review and approval of a research proposal, statistical analysis plan, and execution of a Data Sharing Agreement. The trial protocol and informed consent form are available in the appendix.

### Acknowledgments

This study was sponsored by CHU Lille, France. The study was funded by Johnson & Johnson. Johnson & Johnson provided the supply of daratumumab. We thank the patients who volunteered to participate in the trial, their families, and the staff at the trial sites who participated in the trial. A complete list of investigators in the IFM2017-03 trial is provided in the appendix. We are thankful to the IFM team, including C Louni, G Belot, M O Petillon, and S Rollet. We also give special thanks to the IFM2017-03 trial project managers of the protocol: B Courtois, A Kemkem, and A Courquin; and the pharmacovigilance team at the sponsor, CHU Lille: C Potey, T Ouk, E Gers, and C Leclercq. Data

management was performed by Euraxi Pharma (Joué Les Tours). We would also like to thank the members of the independent Data and Safety Monitoring Committee: P Casassus, J-P Fermand, and J-L Harousseau. During the preparation of this manuscript the authors used ChatGPT 40 in order to improve language and readability for certain sentences. After using this tool, all authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

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