Outcomes of anti-CD38 isatuximab plus pomalidomide and dexamethasone in five relapsed myeloma patients with prior exposure to anti-C38 daratumumab: case series

ABSTRACT Objectives: Daratumumab is the first anti-CD38 monoclonal antibody (Mab) used to treat myeloma in the newly diagnosed setting and in the relapsed setting. Isatuximab, another Mab targeting a specific epitope on the CD38 receptor, was recently approved in the UK in combination with pomalidomide and dexamethasone (IsaPomDex) to treat myeloma patients who received three prior lines of therapy. However, there is a lack of understanding of whether using a prior anti-CD38 Mab (e.g. daratumumab) can affect the efficacy of another Mab (e.g. isatuximab), when the latter is used to treat a subsequent relapse. Methods: We performed a UK-wide outcomes study of IsaPomDex in the real-world. In this case series, we report a detailed descriptive analysis of the characteristics and clinical outcomes of five IsaPomDex patients in UK routine practice (Patients I to V), with a prior exposure to daratumumab. Results: Age range was 51–77 years with two patients >70 and three patients <70 years. The cytogenetic risk was standard in two patients, high in two patients and not known in one patient. Prior daratumumab regimen were monotherapy (dara-mono) in one patient (II), and daratumumab with bortezomib and dexamethasone (DVd) in four patients. Responses to prior daratumumab were: very good partial response (VGPR) in two patients (I and III), minor response-stable disease (MR-SD) in one patient (II), and progressive disease (PD) in two patients (IV and V). Median (range) number of IsaPomDex cycles received was 2 (1–4). Outcomes of IsaPomDex were PD in three patients (II, IV and V) and a response in two patients. Response categories were: MR-SD in patient I and PR in patient III. Discussion: Despite the limitations of our case series, we described the first UK real-world report of IsaPomDex outcomes in myeloma patients with a prior exposure to daratumumab. Conclusion: Large prospective studies are required to further evaluate myeloma outcomes in this setting.


Introduction
The management of multiple myeloma (MM) has witnessed significant advances over the last two decades, which led to landmark improvements in progressionfree survival (PFS) and overall survival (OS). The ongoing evolution of the treatment paradigm is attributed to a better understanding of the disease, as well as the advent of a number of novel treatment combinations from distinct pharmacological classes such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (Mab) such as daratumumab. Despite this progress, myeloma remains incurable, where most patients become relapsed/refractory (R/R) to novel therapies.
Isatuximab is an alternative anti-CD38 Mab which works by binding to a specific epitope on the CD38 receptor [1,2]. It differs from datatumumab by displaying a comparatively more effective inhibition of enzymatic activity, and by inducing direct rather than indirect MM cell apoptosis [1,3]. Efficacy of isatuximab in combination with pomalidomide and dexamethasone (IsaPomDex) was demonstrated in the phase 3 ICARIA-MM trial, which showed its PFS superiority over PomDex [4]. Subsequently, it was approved in the UK to treat MM patients who received three prior lines of therapy [5].
However, it is unclear whether exposure to a prior anti-CD38 Mab (e.g. daratumumab) could affect the efficacy of another Mab (e.g. isatuximab), especially when the latter is used to treat a subsequent relapse.
In the isatuximab arm of ICARIA-MM, only one patient received prior daratumumab [5].
A descriptive analysis of nine IsaPomDex patients with prior daratumumab exposure, reported a partial response or better (≥PR) in five patients [6]. A phase 2 single-arm study of isatuximab monotherapy (20 mg/kg weekly for 4 weeks, then fortnightly thereafter) in 32 daratumumab-refractory patients with a median number of 7 prior therapies (range 2-14), demonstrated no objective response (OR) in the study population [7].
We performed a UK-wide study to evaluate outcomes of IsaPomDex in routine care. In this manuscript, we report a detailed descriptive analysis of the characteristics and clinical outcomes of a subgroup of five relapsed myeloma patients with a prior exposure to daratumumab, who were later treated with IsaPomDex.

Methods
Baseline patient characteristics collected included age, performance status (PS), co-morbidities using Charlson co-morbidity index (CCI), and renal impairment (e-GFR). Baseline disease characteristics included known cytogenetics since diagnosis, and MM International Staging System (ISS). Prior daratumumab data included regimen name, number of cycles received, best response, refractoriness, reason for discontinuation, and period (in months) from end of daratumumab to start of isatuximab. IsaPomDex outcomes included: number of cycles received, dose attenuation, best response, time to best response, reason for discontinuation, PFS, OS and adverse events (AEs). Response was assessed according to the International Myeloma Working Group (IMWG) response assessment criteria. AEs were documented according to the Common Terminology Criteria for Adverse Events (CTCAE v5) [8].

Results
Baseline patient, disease, and prior daratumumab characteristics are fully presented in Table 1, where the five patients are referred to as patients I to V. Age range was 51-77 years with two patients >70 and three patients <70, median CCI score (range) was 4 (1-4), four patients presented with renal impairment (e-GFR < 60 ml/min). The cytogenetic risk was standard in two patients (I and II), high in two patients (III and IV) and not known (NK) in one patient (V). The number of prior therapies was 3 in all patients and this included a transplant in two patients (IV and V). All patients received a prior IMiD and a prior PI.  Prior daratumumab regimen were monotherapy (dara-mono) in one patient (II), and daratumumab with bortezomib and dexamethasone (DVd) in four patients. Median number (range) of cycles received was 2 (1-13). Responses achieved were: very good partial response (VGPR) in two patients (I and III), minor response-stable disease (MR-SD) in one patient (II), and progressive disease (PD) in two patients (IV and V). Reasons for daratumumab discontinuation were PD in three patients (III, IV and V), switch to an alternative oral lenalidomide-based regimen in one patient (I) at the start of the pandemic to minimize hospital visits. One patient (II) stopped dara-mono due to grade 4 (G4) sepsis and later relapsed. Median (range) time from end of daratumumab to start of isatuximab was 5.3 months (2-10).
Outcomes of IsaPomDex treatment are fully presented in Table 2. Median (range) number of cycles received was 2 (1-4) at a median (range) follow of 1.6 months (0.9-3.4). Pomalidomide and dexamethasone doses were attenuated in one and two patients, respectively. Responses achieved at the last follow-up were PD in three patients (II, IV and V) and a response in two patients. Response categories were: MR-SD in patient I and PR in patient III. Therefore, OR rate (≥PR) was 20% Median (range) number of any grade adverse events (AEs) on IsaPomDex per patient was 1 (0-3). Median (range) number of ≥ G3 AEs per patient was 1 (0-2). Haem AEs and non-Haem AEs were experienced by two and three patients, respectively. One patient acquired SARS-CoV-2 infection during treatment. Four patients discontinued therapy due to death, whilst one patient (I) continues to receive treatment. Causes of death were PD in three patients and COVID-19 in one patient.

Discussion
Our case series adds to the limited data available on isatuximab use in previously daratumumab-treated patients. A descriptive analysis of nine patients reported that eight patients achieved PR response to prior datatumumab and one patient achieved a MR-SD (Bencnel 2020). When later treated with IsaPomDex, a PR response was achieved in five out of the nine patients [6]. These results are superior to ours (PR in 1/5, MR-SD in 1/5, PD in 3/5). However, two of our patients with PD as the best response to IsaPomDex, were primary refractory to daratumumab. Patient III achieved a VGPR to prior daratumumab, and later achieved PR with IsaPomDex, despite high-risk cytogenetic features. It is likely that this response is not solely mediated by C38 inhibition, but also by pomalidomide and high-dose dexamethasone.
Patient I in our report, who achieved VGPR to prior daratumumab and experienced peripheral neuropathy then switched to oral lenalidomide to reduce hospital visits during the pandemic, achieved MR-SD when subsequently treated with IsaPomDex. Patient II, who achieved a MR-SD to daratumumab monotherapy which was stopped due to G4 sepsis, was subsequently primary refractory to isatuximab, A phase 2 single-arm study investigated isatuximab monotherapy in 32 daratumumab-refractory patients, around 60% of whom received the last daratumumab dose within 6 months of starting isatuximab, and as the last line of therapy, and where the best response to prior daratumumab was PD in four patients [7]. This trial reported no OR in any patient; 1 patient achieved an MR and 17 patients achieved an SD [7]. It is difficult to compare trial data to our data, because we did not use isatuximab monotherapy. In addition, there is a difference in the median  number of prior therapies (3 in our case series vs. 7 in the trial). Our series is limited by its small size, its retrospective nature and the possibility of patient selection bias. Although it is not possible to draw any firm conclusions or provide any generalizable recommendations from this small case series, we described in detail our experience of five IsaPomDex patients with prior exposure or primary refractoriness to daratumumab. Large prospective studies are required to further evaluate the influence of prior daratumumab exposure/refractoriness on isatuximab outcomes.

Conclusion
This is the first UK real-world report of IsaPomDex outcomes in a subgroup of five relapsed myeloma patients who received a prior anti-CD38 Mab daratumumab. IsaPomDex outcomes showed a clinical benefit with at least disease stabilization in two patients, of whom one achieved an objective response (PR). Large prospective studies are required to further evaluate the impact of prior daratumumab exposure/ refractoriness on isatuximab outcomes.

Disclosure statement
FD (Sanofi: honoraria for education evening for haematologists). SB (Sanofi: honoraria and advisory board). KR (Sanofi: honoraria and advisory board; BMS: research support, honoraria, advisory board, travel support). All other authors have no conflicts of interest to declare.

Ethical approval
The study received NHS service evaluation approval at each participating site.

Funding
The author(s) reported there is no funding associated with the work featured in this article.

Data availability statement
All available data relating to this report are presented in the manuscript and the accompanying tables (Tables 1 and 2).