# Retreatment with Anti-CD38-Based Combinations in Multiple Myeloma in Real-Life: Results from the Emmy Cohort Study

Alexis Talbot, Cyrille Hulin, Aurore Perrot, Margaret Macro, Karim Belhadj-Merzoug, Mohamed Mohty, Arthur Bobin, Lionel Karlin, Salomon Manier, Laure Vincent, et al.

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Alexis Talbot, Cyrille Hulin, Aurore Perrot, Margaret Macro, Karim Belhadj-Merzoug, et al. Retreatment with Anti-CD38-Based Combinations in Multiple Myeloma in Real-Life: Results from the Emmy Cohort Study. Clinical Lymphoma Myeloma and Leukemia, 2025, 10.1016/j.clml.2025.05.015. hal-05163087

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Original Study

# Retreatment With Anti-CD38-Based Combinations in Multiple Myeloma in Real-Life: Results From the Emmy Cohort Study

Alexis Talbot,<fnref n="1" /> Cyrille Hulin,<fnref n="2" /> Aurore Perrot,<fnref n="3" /> Margaret Macro,<fnref n="4" /> Karim Belhadj Merzoug,<fnref n="5" /> Mohamed Mohty,<fnref n="6" /> Arthur Bobin,<fnref n="7" /> Lionel Karlin,<fnref n="8" /> Salomon Manier,<fnref n="9" /> Laure Vincent,<fnref n="10" /> Abderrazak El Yamani,<fnref n="11" /> Wajed Abarah,<fnref n="12" /> Regis Kaphan,<fnref n="13" /> Thomas Chalopin,<fnref n="14" /> Daniel Ré,<fnref n="15" /> Adrienne de Labarthe,<fnref n="16" /> Olivier Fitoussi,<fnref n="17" /> Chanaz Lounis,<fnref n="18" /> Ronan Garlantezec,<fnref n="19" /> Olivier Decaux<fnref n="19" />,<fnref n="20" />, on behalf of Emmy and the IFM group

## Abstract

**Introduction:** Anti-CD38 monoclonal antibodies (aCD38) are increasingly used in early lines of therapies in multiple myeloma (MM). Retreatment with aCD38-based regimen is a widely used practice in later lines. However, data coming from clinical trials are currently limited. Emmy is a noninterventional, prospective dynamic cohort study conducted in 73 centers in France to assess the real-life management of MM in France and which can explore the efficacy of aCD38-based retreatment. **Methods:** Patients who initiated a second line of treatment with aCD38-based combinations after a first exposure to aCD38 were identified and described and the outcomes of progression-free survival (PFS) and overall survival (OS) were estimated. **Results:** In the Emmy cohort, 286 patients received 2 lines of treatment including aCD38. For all aCD38-retreated patients, median PFS was estimated at 5.1 months. Median PFS was 23.6 m in patients sensitive to aCD38 and 4.6 in nonsensitive patients, *P* = .0003. Median OS was estimated at 17.3 months for all patients, 14.8 months in patients nonsensitive to aCD38, and not reached (NR) in sensitive patients, *P* = .0004. No significant differences in PFS or OS were observed between the refractory and nonrefractory to aCD38 groups. **Conclusion:** These results of aCD38 retreatment in a large sample of real-life patients (n = 286) in extensively pretreated patients show that retreatment may be a meaningful strategy for aCD38 sensitive patients. These findings need to be investigated further while the use of aCD38 is emerging as a first-line treatment for newly diagnosed patients.

*Clinical Lymphoma, Myeloma and Leukemia*, Vol. 000, No. xxx, 1–10 © 2025 The Author(s). Published by Elsevier Inc.

This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/))

**Keywords:** Immunotherapy, Monoclonal antibody, Real-life data, Relapsed or refractory multiple myeloma, Rechallenge

## Introduction

Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells in the bone marrow. The course of the disease consists of multiple relapses, as MM is still not curable. Effective and safe novel therapy strategies are needed for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). The treatment of RRMM is particularly challenging after the use of the main MM drug classes:

<footnote n="1">¹Hôpital Saint Louis, AP-HP, Paris, France</footnote>

<footnote n="2">²CHU Pessac, Pessac, France</footnote>

<footnote n="3">³IUCT Oncopole, UMR 1037 Institut Universitaire du Cancer de Toulouse, France</footnote>

<footnote n="4">⁴CHU Caen, Caen, France</footnote>

<footnote n="5">⁵AP-HP, Hôpital Henri Mondor, Créteil, France</footnote>

<footnote n="6">⁶AP-HP, Hôpital Saint Antoine, Paris, France</footnote>

<footnote n="7">⁷CHU de Poitiers, Poitiers, France</footnote>

<footnote n="8">⁸CHU de Lyon, Lyon, France</footnote>

<footnote n="9">⁹CHRU Lille, Lille, France</footnote>

<footnote n="10">¹⁰CHU Montpellier, Montpellier, France</footnote>

<footnote n="11">¹¹Centre Hospitalier Simone Veil de Blois, Blois, France</footnote>

<footnote n="12">¹²Grand Hôpital de l'Est Francilien, Meaux, France</footnote>

<footnote n="13">¹³Centre Hospitalier de Cannes, Cannes, France</footnote>

<footnote n="14">¹⁴CHU Tours, Hôpital Bretonneau, Tours, France</footnote>

<footnote n="15">¹⁵Centre Hospitalier Antibes, Antibes, France</footnote>

<footnote n="16">¹⁶CH Chartres Louis Pasteur, Le Coudray, France</footnote>

<footnote n="17">¹⁷Oncologie de la Polyclinique Bordeaux Nord Aquitaine, Bordeaux, France</footnote>

<footnote n="18">¹⁸IFM, Paris, France</footnote>

<footnote n="19">¹⁹CHU Rennes, Rennes, France</footnote>

<footnote n="20">²⁰MOBIDIC - Microenvironment and B-cells: Immunopathology, Cell Differentiation, and Cancer, Rennes, France</footnote>

<footnote>Submitted: Mar 11, 2025; Revised: May 15, 2025; Accepted: May 16, 2025; Epub: xxx</footnote>

<footnote>Address for correspondence: Alexis Talbot, Hôpital Saint Louis, AP-HP, 1 avenue Claude Vellefaux, 75010 Paris, France</footnote>

<footnote>E-mail contact: alexis.talbot@aphp.fr</footnote>
Rechallenge with anti-CD38 monoclonal antibody in RRMM

immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (aCD38).¹

Despite the growing number of new treatment modalities such as antibody-drug conjugates, bispecific antibodies² and chimeric antigen receptor (CAR)-T cell therapies,³⁻⁵ the management of RRMM remains a significant clinical challenge. In recent years, the use of aCD38, such as daratumumab (DARA) and isatuximab (ISA), has revolutionized the treatment landscape of MM by demonstrating remarkable efficacy and improving patient outcomes.⁶⁻⁸ However, a subset of patients may experience disease progression or relapse following treatment with aCD38, raising the question of the optimal management strategy in this setting. The development of resistance to treatment remains the main obstacle to curing MM, and most patients develop a disease refractory to treatment, including PIs, IMiDs and aCD38. aCD38-based treatment has become a mainstay therapy⁹ but more patients will be refractory to these drugs used in the first line. In clinical practice, management of these patients depends either on the use of drugs with new mechanisms of action or on retreating with previously used agents.¹⁰ Previous studies have described a poor prognosis of these patients.¹,¹¹ In addition, the results of the study on outcome of MM patient's refractory to aCD38 may differ with the use of triplet-containing aCD38 in earlier lineages rather than the later monotherapy.

Rechallenge with aCD38 represents a compelling therapeutic approach that warrants further investigation. By re-administering these agents to patients who have previously responded to them, there is a potential to regain treatment efficacy, overcome resistance mechanisms, and prolong disease control. Moreover, the safety profile of aCD38 supports their use in rechallenge strategies, as they are generally well-tolerated and associated with manageable side effects. This study included patients with RRMM who were exposed to aCD38 with a DARA- or ISA-based regimen and who received other therapy with aCD38, after relapse or progression to first exposition. There have been few real-world studies describing this population so far. To address this, we used the real-world French study EMMY (Epidemiology of Multiple Myeloma) to determine the characteristics and outcomes of patients with MM receiving a retreatment with aCD38-based combinations.

Methods

Real-world evidence complements data obtained from clinical trials, particularly providing data on a targeted population. It can also be used to assess the actual therapeutic and clinical management of patients in everyday practice. We have reported results from patients aged ≥ 80 years or older with MM and enrolled in the EMMY study.¹² EMMY is a noninterventional, prospective dynamic cohort study conducted in 73 centers in France since 2017 and sponsored by the IFM (Intergroupe Francophone du Myélome).¹³ Each year, any patient initiating treatment for MM over a 3-month observation period, from October to December, is included (800-1000 additional patients each year; 5200 patients included at the end of 2022) and data are updated annually from hospital records up to 2022. This approach allowed us to sample a representative population from each year.

Patients who initiated a second line of treatment with aCD38-based combinations after a first exposure to DARA or ISA were identified and described. Progression-free survival (PFS) and overall survival (OS) were described for the overall population, by line of treatment, by combination with aCD38 (IMiD, PI, others), consecutive or nonconsecutive aCD38 lines, for aCD38 refractory status. There is no consensus for the definition of sensitivity to immunotherapy in MM, only a definition of the characteristics of a refractory disease (progression either during therapy or within 60 days of last treatment). Given the half-life of aCD38 antibodies, this period of 60 days seems inappropriate. Based on clinical experience we propose a definition of sensitivity for nonrefractoriness to aCD38. Patients were classified as sensitive if the time between the end date of first exposure with aCD38 and the start date of the next line was at least 12 months (± 1 month) without discontinuation for progressive disease. Patients were classified as nonsensitive and refractory to aCD38 if the time between the end date of the first line of aCD38 and the start date of the next line was less than 90 days, including disease progression. Patients were considered nonsensitive and nonrefractory to aCD38 if the delay between the end date of the first line with aCD38 and the start date of the next line was between 90 days and 11 months. PFS for post aCD38 treatment line failure was calculated from the start date of this therapy until progression, death or date of last follow-up. OS for aCD38 failure was defined as the time since the start of the next line of treatment until the date of death or last follow-up. All patients were treated in France and started aCD38 treatment from January 1, 2018, to December 31, 2022. Disease response and progression were assessed according to institutional standards and international protocols, using the International Myeloma Working Group (IMWG) criteria for assessing response and progression.

The EMMY study is classified as research not involving human subjects as defined in article L. 1121-1 of the French Public Health Code. This retrospective and prospective personal data study is being conducted in accordance with the Declaration of Helsinki and has been submitted to the French Health Data Hub (N°F20220518161845) Epidemiology of the therapeutic management of MM in France—EmmY Project | Health Data Hub (health-data-hub.fr) No ethical approval for this study was required. All patients were informed about the processing of their data prior to enrolment in the study.

Statistical Analysis

Quantitative variables are described with minimum and maximum values, quartiles, and median for data with a normal distribution, with a 95% confidence interval (95% CI). Qualitative variables will be described in terms of frequencies and percentages (with a 95% confidence interval, binomial law). Survival data (progression-free and overall) were estimated using the Kaplan-Meier method. Median survival time with a 95% CI and median follow-up was estimated using the reverse Kaplan-Meier method. The duration of response in responding subjects is expressed using descriptive statistics (median, range). The database will be reported in compliance with the General Data Protection Regulation (GDPR) of the European Union.
<figure><img src="image_2.png" /><figcaption>**Figure 1** Flow-chart.</figcaption></figure>

# Results

## Population

In the Emmy cohort, 286 patients received 2 lines of treatment with aCD38-based combinations for MM and RRM. The flow chart of the study is shown in Figure 1. Median age was 69.9 years (quartile [Q1-Q361.8-75.9]) with an ECOG score of 0-1 for 75.8% patients, a high cytogenetic risk for 36.3%, an ISS of I, II, or III for 19.4%, 31.3% and 48.8%, respectively (Table 1). Retreatment with aCD38 consisted of DARA after DARA (DARA-DARA) for 145 patients (51%), DARA-ISA for 120 patients (42%) and ISA-DARA for 19 patients (7%). Lines of aCD38 were consecutive for 133 patients (46.5%) and nonconsecutive for the others (1 middle line in 81 [28.3%] and ≥ 2 in 72 [25.2%]). Median duration between consecutives lines was 0.8 months (Q1-Q3, 0.1-6.4) and 15.7 months (Q1-Q3, 9.1-24.9) in patients with nonconsecutive lines. Patients had previously received 2 lines of treatment (n = 28: 9.8%), 3 (n = 43: 15%), 4 (n = 53: 18.5%), 5 (n = 56: 19.6%), ≥ 6 (n = 106: 37%), respectively (results not shown). Most had previously received the PIs bortezomib (n = 276: 96.5%) or carfilzomib (n = 151: 52.8%); the IMiDs lenalidomide (n = 253: 88.5%), pomalidomide (167: 58.4%), or thalidomide (n = 120: 42%), and 134 (46.9%) had received cyclophosphamide. One hundred and sixty-four patients (57.3%) had had a prior autologous stem cell transplantation (Table 2).

When re-used, aCD38 were combined with an IMiD in 178 patients (62.2%), with an IP in 62 patients (21.7%), with both in 21 (7.3%) or with other drugs in 25 patients (8.7%).

## PFS

For all aCD38-retreated patients, median PFS was estimated at 5.1 months (95% CI, 4.2-6.6) (Figure 2A), median PFS was 9.5 months (95% CI, 4.9-23.6) in aCD38 nonrefractory patients and 4.6 months (95% CI, 3.8-6.0) in patients refractory to aCD38. Also, median PFS was 23.6 months (95% CI, 11.6-NR) in patients sensitive to aCD38 (n = 29) and 4.6 months (95% CI, 3.8-6) in nonsensitive (n = 248) patients, P = .0003 (Figure 2B).

## OS

Median OS was 17.3 months (95% CI, 14-22.5) for all patients (Figure 3A), median OS was 22.3 months in patients with aCD38 in a consecutive line, 16.2 months and 9.1 months in patients with 1 nonconsecutive and ≥ 2 middle lines, respectively. The median OS was 14.8 months (95% CI, 12.6-19.5) in patients not-sensitive to aCD38 and was NR in sensitive patients (P = .0004) (Figure 3B).

No significant differences in PFS or OS were observed between the refractory and nonrefractory to aCD38 groups (Figure 4). No difference was observed in terms of PFS or OS with respect to the choice of aCD38 in the retreatment regimen, and there was also no
# Rechallenge with anti-CD38 monoclonal antibody in RRMM

<table><caption>**Table 1** Characteristics of Patients</caption><thead><tr><th></th><th>N = 286 (%)</th><th></th></tr></thead><tbody><tr><td rowspan="7">Age at retreatment with aCD38, yrs</td><td>Median</td><td>69.9</td></tr><tr><td>Q1-Q3</td><td>61.8-75.9</td></tr><tr><td>Min-Max</td><td>33.6-93.6</td></tr><tr><td>&lt; 65</td><td>99 (34.6)</td></tr><tr><td>[65-69]</td><td>44 (15.4)</td></tr><tr><td>[70-74]</td><td>57 (19.9)</td></tr><tr><td>[75-79]</td><td>61 (21.3)</td></tr><tr><td rowspan="2">Sex</td><td>[80-84]</td><td>18 (6.3)</td></tr><tr><td>≥ 85</td><td>7 (2.4)</td></tr><tr><td rowspan="2">ECOG score</td><td>Male</td><td>154 (53.8)</td></tr><tr><td>0-1</td><td>175 (75.8)</td></tr><tr><td rowspan="4">ISS at diagnosis</td><td>2-3</td><td>56 (24.2)</td></tr><tr><td>I</td><td>31 (19.4)</td></tr><tr><td>II</td><td>50 (31.3)</td></tr><tr><td>III</td><td>78 (48.8)</td></tr><tr><td rowspan="2">High-risk cytogenetics</td><td>Yes</td><td>49 (36.3)</td></tr><tr><td>No</td><td>86 (63.7)</td></tr></tbody></table>

Abbreviations: Q = quartile; Min = minimum; Max = maximum; ECOG = Eastern Cooperative Oncology Group; ISS = international staging system.

difference in the treatment sequencing between them (Figure 4A, Figure 4B).

## Discussion

These results highlight the assessment of aCD38 retreatment in a large sample of 286 real-life patients. Patients had been extensively treated when they received a second line of aCD38, most of them (73.1%) were refractory to aCD38 and had received previous lines for MM. The most meaningful results are found in patients not refractory to aCD38 and particularly in those sensitive to aCD38. aCD38 play a crucial role in the treatment of both newly diagnosed and RRMM. DARA and ISA have received approval from the US Food and Drug Administration for use in various combinations. While these aCD38 demonstrate significant efficacy, the development of drug resistance is inescapable for patients over time. The effectiveness of retreatment with these antibodies in subsequent lines of therapy remains a topic of uncertainty, particularly with limited data from clinical trials and a few retrospective clinical studies.¹⁴

Here, we have investigated which patient patients could benefit the most from aCD38 retreatment. Patients who were retreated with aCD38-based combinations experienced a median of 5.1 months PFS. Our findings revealed that nonrefractory patients and those who had been off aCD38 for more than 12 months, benefited the most from this approach. One study noted a gradual resurgence in CD38 expression on MM cells post-treatment cessation, albeit not reaching the levels seen in patients who hadn't previously received anti-CD38 antibodies.¹⁵ Conversely, retreatment in MM patients nonsensitive to aCD38 has not demonstrated benefit and should not be offered as a therapeutic option.

This is not the first study to explore outcomes after aCD38 therapy. In the MAMMOTH study, investigating the outcomes of

MM patients refractory to aCD38, the overall response rate to the first regimen post relapse was 31% with a median PFS and OS of 3.4 and 9.3 months, respectively (10). However, patients now have fewer prior lines, indicating an earlier use of aCD38 therapy, closer to the current real-world paradigm in which combinations of DARA and ISA have been approved for first-line use. More recently, in the real-life setting, the LocoMMotion study showed a median PFS of 4.6 months, and median OS of 12.4 months.¹ The median PFS in the standard of care arm of the KarMMa-3 study was 4.4 months, with 38% of patients treated with combinations based on DARA.⁵ In the context of retreatment with aCD38, a study found that a first prolonged response to aCD38 is a predictive factor for obtaining the best results in the event of re-exposure. In this previously published cohort, PFS after aCD38 failure for patients who had a duration of response of >12 months was 11.3 months (95% CI, 6.7-17.9) versus 5.2 months (95% CI, 4.3-6.2) months (95% CI, 0.27-0.70, P = .001). PFS ≥ 12 months during first aCD38 therapy was the most important prognostic factor for PFS post-aCD38 failure (median duration of response of 26.7 [95% CI, 11.4-42] versus 9.4 months [95% CI, 5.5-13]). Similarly, the duration of response prior to IMiD therapy when switching from lenalidomide to pomalidomide or the addition of IMiD in DARA-refractory MM patients to overcome refractoriness to both agents, has also been reported.¹⁶,¹⁷ Nevertheless, all of these data indicate that the refractoriness to previous therapies, in different combinations, is a transition strategy that has offered prolonged remissions only in selected patients.¹⁶,¹⁸ Refractoriness to aCD38-based therapy is given at a critical point in the natural history of the disease¹⁴,¹⁹ and new approaches and treatment strategies are a priority for these patients. We propose a new definition of sensitivity to immunotherapy in MM to better study which patients could benefit the most from this treatment. These findings support the
<figure><img src="image_3.png" /><figcaption>**Figure 2** A) Progression-free survival. B) Progression-free survival: sensitive versus nonsensitive CI = confidence interval; NR = not reached.</figcaption></figure>
Rechallenge with anti-CD38 monoclonal antibody in RRMM

<figure><img src="image_4.png" /><figcaption>Figure 3 A) Overall survival. B) Overall survival sensitive versus nonsensitive to aCD38.</figcaption></figure>

<table><tr><td></td><td>aCD38 N = 282</td></tr><tr><td>Median [95% CI]</td><td>17.3 [14; 22.5]</td></tr><tr><td>IQR</td><td>6.5; 50.2</td></tr></table>

A

<figure><img src="image_5.png" /></figure>

B
<figure><img src="image_6.png" /><figcaption>Figure 4: A) Progression Free Survival—refractoriness to aCD38. B) Overall survival—refractoriness to aCD38.</figcaption></figure>
# Rechallenge with anti-CD38 monoclonal antibody in RRMM

<table><caption>**Table 2** Previous Line of Treatment</caption><thead><tr><th></th><th>N = 286 (%)</th><th></th></tr></thead><tbody><tr><td>ASCT</td><td>Yes</td><td>164 (57.3)</td></tr><tr><td></td><td>No</td><td>122 (42.7)</td></tr><tr><td rowspan="3">Refractory statues</td><td>Tri- refractory</td><td>151 (52.7)</td></tr><tr><td>Quadri- refractory</td><td>119 (41.6)</td></tr><tr><td>Penta-refractory</td><td>51 (17.8)</td></tr><tr><td rowspan="2">Exposure to PI,</td><td>Yes</td><td>279 (97.6)</td></tr><tr><td>No</td><td>7 (2.4)</td></tr><tr><td rowspan="3">PI</td><td>Bortezomib</td><td>276 (96.5)</td></tr><tr><td>Carfilzomib</td><td>151 (52.8)</td></tr><tr><td>Ixazomib</td><td>43 (15.0)</td></tr><tr><td rowspan="2">Refractory PI</td><td>Yes</td><td>210 (73.4)</td></tr><tr><td>No</td><td>76 (26.6)</td></tr><tr><td rowspan="3">PI refractory</td><td>1</td><td>105 (50.0)</td></tr><tr><td>2</td><td>90 (42.9)</td></tr><tr><td>3</td><td>13 (6.2)</td></tr><tr><td rowspan="2">Exposure to IMiD</td><td>Yes</td><td>275 (96.2)</td></tr><tr><td>No</td><td>11 (3.8)</td></tr><tr><td rowspan="3">IMiD</td><td>Thalidomide</td><td>120 (42.0)</td></tr><tr><td>Lenalidomide</td><td>253 (88.5)</td></tr><tr><td>Pomalidomide</td><td>167 (58.4)</td></tr><tr><td rowspan="2">Refractory to IMiD</td><td>Yes</td><td>222 (77.6)</td></tr><tr><td>No</td><td>62 (21.7)</td></tr><tr><td rowspan="3">IMiD refractory</td><td>1</td><td>115 (51.8)</td></tr><tr><td>2</td><td>96 (43.2)</td></tr><tr><td>3</td><td>11 (5.0)</td></tr><tr><td>Exposure to aCD38</td><td>Yes</td><td>286 (100.0)</td></tr><tr><td rowspan="2">aCD38</td><td>Daratumumab</td><td>267 (93.4)</td></tr><tr><td>Isatuximab</td><td>19 (6.6)</td></tr><tr><td rowspan="2">Refractory to aCD38</td><td>Yes</td><td>209 (73.1)</td></tr><tr><td>No</td><td>76 (26.6)</td></tr><tr><td rowspan="2">Exposure to alkylating agent</td><td>Yes</td><td>249 (87.1)</td></tr><tr><td>No</td><td>37 (12.9)</td></tr><tr><td rowspan="3">Alkylating agent</td><td>Melphalan</td><td>207 (72.4)</td></tr><tr><td>Cyclophosphamide</td><td>134 (46.9)</td></tr><tr><td>Bendamustine</td><td>44 (15.4)</td></tr></tbody></table>

Abbreviations: ASCT = autologous stem cell transplant; PI = proteasome inhibitor; IMiD = immunomodulatory drug.

concept that sensitivity to anti-CD38 therapy, rather than simple refractoriness, may be a more meaningful predictor of treatment response.

The recycling of previous therapies, in different combinations, is an available strategy. The above results confirm that patients with aCD38 therapeutic failure have a poor prognosis. However, the median PFS was 23.6 months in aCD38 sensitive patients. Exploring the role of rechallenge with aCD38 has the potential to optimize treatment strategies, improve patient outcomes, and advance the management of RRMM.

## Clinical Practice Points

* Efficacy of Anti-CD38 Retreatment in Sensitive Patients

* Patients classified as "sensitive" to anti-CD38 monoclonal antibodies (mAbs), defined as those with a treatment-free interval of ≥ 12 months before re-exposure, demonstrated a significantly prolonged median progression-free survival (PFS) of 23.6 months.

* Limited Benefit in Anti-CD38 Refractory Patients

* Patients who were refractory to anti-CD38 therapy (defined as relapse within 90 days of prior exposure) exhibited poor clinical
outcomes upon retreatment, with a median PFS of only 4.6 months.

* Overall Survival Outcomes and Clinical Implications

* The median overall survival (OS) for the entire cohort was 17.3 months. However, in patients deemed sensitive to anti-CD38 therapy, OS was not reached (NR), while nonsensitive patients had a median OS of 14.8 months. These data support the clinical utility of retreatment in select patient populations but highlight the need for alternative strategies in nonresponders.

* Need for a Refined Definition of Sensitivity to Anti-CD38 Therapy

* The study underscores the necessity of establishing a standardized definition of immunotherapy sensitivity in multiple myeloma to optimize patient selection for retreatment.

## Data sharing statement

The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

## Disclosure

Alexis Talbot: Board Pfizer, Sanofi. Cyrille Hulin: Amgen, BMS, GSK, Janssen, Sanofi, Takeda. Aurore Perrot: received honoraria from Abbvie, Amgen, BMS, GSK, Janssen, Pfizer, Sanofi and Takeda. Margaret Macro: Honoraria: Amgen, BMS, GSK, Janssen, Sanofi, Takeda. Karim Belhadj Merzoug: Honoraria: Amgen, BMS, Janssen, Pfizer, Sanofi. Mohamed Mohty: received honoraria from Janssen, Sanofi, BMS, Amgen, Takeda, GSK, Pfizer, Novartis, Jazz pharmaceuticals, Stemline and Astellas. Arthur Bobin: Johnson & Johnson, Sanofi, Amgen, Pfizer, Stemline Menarini. Lionel Karlin: Amgen, Abbvie, Celgene-BMS, Pfizer, Takeda, Sanofi, Janssen: honoraires, advisory boards, travel support (congress). Salomon Manier: AbbVie, Adaptive Biotechnology, Amgen, BMS, GSK, Janssen, Regeneron, Roche, Sanofi, Takeda. Laure Vincent: being a board member for Bristol Myers Squib and Takeda. And receiving honoraria from Janssen and Pfizer. Abderazzak El Yamani: None. Wajed Abarah: None. Régis Kaphan: None. Thomas Chalopin: Consulting / advisory boards: Amgen, Stemline, Janssen, Sanofi, Pfizer, BMS. Daniel Re: None. Adrienne de Labarthe: None. Olivier Fitoussi: None. Chanaz Lounis: None. Ronan Garlantezec: None. Olivier Decaux: Honoraria: BMS, GSK, Janssen, Sanofi, Takeda, Roche, Gilead.

## CRediT authorship contribution statement

**Alexis Talbot:** Writing – review & editing, Writing – original draft, Visualization, Validation, Formal analysis. **Cyrille Hulin:** Writing – review & editing, Visualization, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **Aurore Perrot:** Writing – review & editing, Validation, Methodology, Investigation. **Margaret Macro:** Writing – review & editing, Validation. **Karim Belhadj Merzoug:** Writing – review & editing, Validation. **Arthur Bobin:** Writing – review & editing. **Salomon Manier:** Writing – review & editing.

**Vincent:** Writing – review & editing. **Abderrazak El Yamani:** Writing – review & editing, Validation. **Wajed Abarah:** Writing – review & editing, Validation. **Regis Kaphan:** Writing – review & editing, Validation. **Thomas Chalopin:** Writing – review & editing, Validation. **Daniel Ré:** Writing – review & editing, Validation. **Adrienne de Labarthe:** Writing – review & editing, Validation. **Olivier Fitoussi:** Writing – review & editing, Validation. **Chanaz Lounis:** Writing – review & editing, Validation, Project administration, Methodology. **Ronan Garlantezec:** Writing – review & editing, Validation. **Olivier Decaux:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

## Acknowledgment

The authors wish to thank the patients and families, the centers that participated in the study, the IFM and Emmy teams, and the statistical team (Kappa Santé). This study was funded by the Inter-groupe Francophone du Myelome (IFM) (https://www.myelome.fr/), with the support of a consortium of pharmaceutical companies. The writing of this Emmy publication was defined and conducted by the Emmy Scientific Committee members, independently of contributors external to the IFM.

## References

1. Mateos M-V, Weisel K, De Stefano V, et al. LocoMMotion: a prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma. *Leukemia*. 2022; 36(5):1371–1376.

2. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. *N Engl J Med*. 2022;387(6):495–505.

3. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. *Lancet Lond Engl*. 2021;398(10297):314–324.

4. Martin T, Usmani SZ, Berdeja JG, et al. Ciltacabtagene Autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: cARTITUDE-12-year follow-up. *J Clin Oncol Off J Am Soc Clin Oncol*. 2023;41(6):1265–1274.

5. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. *N Engl J Med*. 2023;388(11):1002–1014.

6. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. *Lancet Lond Engl*. 2019;394(10192):29–38.

7. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, Lenalidomide, and dexamethasone for multiple myeloma. *N Engl J Med*. 2024;370(4):301–313.

8. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. *N Engl J Med*. 2019;380(22):2104–2115.

9. Dimopoulos MA, Moreau P, Terpos E, et al. Multiple myeloma: EHA-ESMO clinical practice guidelines for diagnosis, treatment and follow-up†. *Ann Oncol*. 2021;32(3):309–322.

10. Bahlis NJ, Zonder JA, Wroblewski S, et al. Subcutaneous daratumumab in patients with multiple myeloma who have been previously treated with intravenous daratumumab: a multicenter, randomized, phase II study (LYNX). *J Clin Oncol*. 2020;38(15_suppl):TPS8553.

11. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. *Leukemia*. 2019;33(9):2266–2275.

12. Chalopin T, Macro M, Decaux O, et al. Real-life management of patients aged 80 years old and over with multiple myeloma: results of the Emmy cohort. *Clin Lymphoma Myeloma Leuk*. 2024;S2152-2650(24):02350–02354.

13. Decaux O, Garlantézec R, Belhadj-Merzoug K, et al. The Emmy longitudinal, cohort study: real-world data to describe multiple myeloma management and outcomes as more therapeutic options emerge. *Clin Hematol Int*. 2024;6(3):22–27.

14. Kastritis E, Theodorakakou F, Ntanasis-Stathopoulos I, et al. Management and outcomes of anti-CD38 refractory patients: the impact of retreatment and of subsequent therapies. *HemaSphere*. 2023;7(11):e975.
Rechallenge with anti-CD38 monoclonal antibody in RRMM

15. Malavasi F, Faini AC, Morandi F, et al. Molecular dynamics of targeting CD38 in multiple myeloma. *Br J Haematol*, 2021;193(3):581-591.

16. Gavriatopoulou M, Kastritis E, Ntanasis-Stathopoulos I, et al. The addition of IMIDs for patients with daratumumab-refractory multiple myeloma can overcome refractoriness to both agents. *Blood*, 2018;131(4):464-467.

17. Siegel DS, Schiller GJ, Samaras C, et al. Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment. *Leukemia*, 2020;34(12):3286-3297.

18. Nooka AK, Joseph NS, Kaufman JL, et al. Clinical efficacy of daratumumab, pomalidomide, and dexamethasone in patients with relapsed or refractory myeloma: utility of re-treatment with daratumumab among refractory patients. *Cancer*. 2019;125(17):2991-3000.

19. Perez de Acha O, Reiman L, Jayabalan DS, et al. CD38 antibody re-treatment in daratumumab-refractory multiple myeloma after time on other therapies. *Blood Adv*. 2023;7(21):6430-6440.