Real-world experience with isatuximab in the treatment of relapsed-refractory multiple myeloma: a case series from the Grand Duchy of Luxembourg

ABSTRACT Background & objective Anti-CD38 targeting has become an important pillar of the treatment for patients with multiple myeloma (MM). This evolution was spearheaded by daratumumab, but more recently isatuximab became the second CD38-directed monoclonal antibody to receive EMA approval for the treatment of patients with relapsed/refractory (RR) MM. In recent years, real-world studies have become increasingly important to confirm and solidify the clinical potential of novel anti-myeloma therapies. Methods This article describes the real-world experience with isatuximab-based therapy in a selection of four RRMM patients treated with an isatuximab-based treatment regimen in the Grand Duchy of Luxembourg. Results Three of the four cases described in this article consist of heavily pretreated patients who were previously exposed to daratumumab-based therapy. Interestingly, the isatuximab-based therapy provided clinical benefit to all three of these patients illustrating that prior exposure to an anti-CD38 mAb does not preclude a response to isatuximab. As such, these findings further support the design of larger prospective studies looking into the impact of prior daratumumab use on the efficacy of isatuximab-based therapy. In addition, two of the cases included in this report displayed renal insufficiency and the experience with isatuximab in these patients further supports the use of this agent in this setting. Conclusion the clinical cases described illustrate the clinical potential of isatuximab-based treatment for RRMM patient in a real-world setting.


Introduction
Over the last decades, increased insights into the pathophysiology of multiple myeloma (MM) led to the development of a plethora of new treatment options and a continuous improvement in the survival prospects of MM patients [1].An important milestone in this evolution consists of the development of monoclonal antibodies (mAb) against CD38, a transmembrane glycoprotein with a high and uniform expression on MM cells and a relatively low expression level on normal lymphoid and myeloid cells [2].Daratumumab was the first of these mAbs to enter the clinic and the impressive results obtained with daratumumab-based regimens both in the first-line and relapsed/refractory setting rapidly established anti-CD38 targeting as a third essential pharmacological pillar in the treatment of MM patients, next to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) [3].Nevertheless, despite these therapeutic improvements, MM remains to be characterized by a succession of remissions and relapses and is still considered to be incurable.Furthermore, the remission periods for patients become increasingly shorter with an increasing number of treatment lines and, eventually, patients become refractory to all available therapies [3].
Isatuximab is a novel anti-CD38 mAb that recently entered the treatment paradigm for MM.Isatuximab is a chimeric humanized IgG1 monoclonal anti-CD38 antibody that binds to a distinct specific epitope on the human cell surface antigen CD38 [4].Pharmacological and preclinical studies with isatuximab have shown that this agent is able to induce direct apoptosis, a feature that is not seen with daratumumab [5].In addition, another key distinguishing feature of isatuximab is its higher capability to inhibit CD38 ecto-enzymatic activity [5].The clinical worth of isatuximab in the treatment of patients with relapsed/refractory (RR) MM was demonstrated in two randomized phase III trials: ICARIA-MM and IKEMA [6,7].In these studies, isatuximab was shown to significantly prolong the median progression-free survival (PFS) and increased the frequency and/or depth of response when added to pomalidomide and dexamethasone (isatuximab-Pd) in adults with RRMM who had received at least 2 previous lines of treatment (ICARIA-MM trial), and when added to carfilzomib and dexamethasone (isatuximab-Kd) in adults with RRMM who received ≥1 previous lines of treatment (IKEMA trial).Importantly, both isatuximab-based regimens came with a manageable safety profile, without any unexpected safety signals [6,7].Based on the results of these studies, the European Medicines Agency (EMA) approved isatuximab in these two settings.
As patient recruitment for clinical trials is highly selective, it is always important to see whether the results obtained in clinical trials can be translated to a real-world setting.In fact, the stringent inclusion criteria used by clinical trials often result in a lack of clinical data in specific subgroups of patients.As a result, real world studies have become increasingly important to confirm and solidify the clinical potential of novel anti-myeloma therapies.Specifically for isatuximab, an important unanswered question relates to the efficacy of isatuximab-based regimens in patients who were previously exposed to an anti-CD38 mAb.The latter is of increasing clinical relevance as daratumumab has become a component of most standard first-line treatment regimens for patients with MM [8].This article will describe the clinical experience with isatuximab-based therapy in a selected series of 4 RRMM patients of whom 3 were previously exposed to daratumumab.

Case 1
The first patient consists of a man from African origin, born in 1968.In 2010 he presented with anemia after which he was diagnosed with MM type IgG.At diagnosis, no cytogenetic analysis was performed, and the patient had a normal renal function.The patient was treated with an induction regimen consisting of bortezomib (V), liposomal doxorubicin and dexamethasone (d) followed by an autologous stem cell transplantation (ASCT) and maintenance lenalidomide (R) until June 2012.In 2015 the patient suffered a first biological progression after which he was treated with a combination of pomalidomide (P) and dexamethasone (d), followed by a second ASCT.Of note, at that time the patient's myeloma had light chain characteristics and was accompanied by proteinuria and a mild anemia.In 2017, the patient again suffered disease progression.At that time, a cytogenetic analysis revealed a complex karyotype.A further cytogenetic characterization of the patient using fluorescence in situ hybridization (FISH) failed to show any high-risk cytogenetic aberrations, but did reveal a genomic rearrangement involving cMYC, which has been found to be associated with a shorter PFS and OS in this setting.[9,10] The patient subsequently received radiotherapy for a lytic bone lesion in a sacral vertebra and was treated with daratumumab-Vd.Unfortunately, the initial light chain response to this regimen proved to be shortlived, with a slow increase in light chains from month 6 onwards.The disease progression was treated with carfilzomib (K) Rd followed by an allogenic stem cell transplantation in April 2019.In December of that year, the patient again relapsed and in February 2020 he received radiotherapy for a disabling maxillary lesion in the mouth.Treatment was subsequently initiated with a combination of elotuzumab (E) and Rd, but the patient did not have a response to this regimen.In April 2020, treatment was initiated with daratumumab-Rd resulting in a light chain response until August 2020 after which he was treated with bendamustine until October 2020.In October 2020, the patient again suffered progression and treatment was initiated with isatuximab-Kd (bi-weekly schedule) again resulting in a partial light chain response until March 2021.During the treatment with isatuximab-Kd, the patient had an acceptable quality of life allowing the patient to manage his daily family life and visit the gym on a regular basis.During this treatment, the patient was hospitalized for retinitis of the right eye, with CMV-related necrotic lesions.This adverse event was successfully treated with foscavir.Following disease progression in March 2021, the patientinitiated yet another line of treatment consisting of 4 cycles of belantamab vedotin.The patient did not experience a biological response to this treatment and developed a cranial mass (which was irradiated) and masses in the lung and abdomen.From July 2021 until 2022 the patient received additional treatment with DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin), melflufen and K-cyclophosphamide-d.However, none of these treatments induced a durable response and the patient died in January 2022 with a suspicion of meningeal involvement.
This case describes a very heavily pretreated and double daratumumab-exposed MM patient in whom the combination of isatuximab-Kd induced a (reasonably) durable treatment response of 6 months during which the patient had a good quality of life.

Case 2
The second case describes a female patient born in 1945 with a history of papillary thyroid carcinoma (2008) and breast cancer (2012).In May 2014 the woman was diagnosed with MM IgG lambda.At diagnosis, the patient had a normal kidney function and a hemoglobin level of 11.4 g/dl.A myelogram revealed 24% of plasmocytes.The patient was treated with 6 cycles of Vd and refused to undergo an ASCT.In June 2016 the patient suffered a biological progression after which she was treated with Rd.In August 2019 the treatment had to be discontinued due to the development of neuropathy.In October 2019, disease progression led to the initiation of a new treatment line consisting of 9 cycles of daratumumab and ixazomib (I).Unfortunately, the patient suffered several hypertensive crises during treatment (always shortly after the administration of daratumumab) and by May 2020, she had developed serious arterial hypertension and the treatment was discontinued.In September 2020 the patient had a new biological progression and a treatment with P was initiated.In February 2021 imaging in the context of a lung cancer that was diagnosed in October 2020 revealed a plasmocytic lesion in the pelvis after which treatment was started with a combination of Kd (once weekly schedule) and isatuximab.The choice for K in a patient with a history of hypertension may be surprising, but it was deemed safe as her hypertension was well controlled at the time.
By September 2022 the patient is still under treatment with isatuximab-Kd (Kd is now given in a biweekly schedule) and continues to be in a partial remission.The patient continues to have a good quality of life allowing her to travel on a regular basis.Interestingly, in contrast to what we observed with the daratumumab-based treatment in this patient, the patient did not develop any hypertensive crises under Isatuximab.By March 2022 the patient did indicate a slight increase in her neuropathy, but her hypertension remained to be under control.
This case describes a women treated with Isa-K in fifth line resulting in a very durable treatment response (almost 2 years) despite prior daratumumab exposure.The patient maintains a good quality of life under treatment.

Case 3
Patient 3 is a man born in 1966.In October 2018 he presented with a severe anemia, a low reticulocyte count and a vitamin B12 and B9 deficiency.Serological and cytogenetic analyses revealed a prominent monoclonal IgA peak with 58% plasmocytes and a complex karyotype, including a trisomy of 1q, monosomy 1p and rearrangements of the MYC gene (no 1q21 gain/ amplification).At presentation, the patient had a slight renal impairment with a creatinine clearance of 1.46 mg/dl and a glomerular filtration rate (GFR) of 50 ml/min.Treatment was initiated with Vd for one cycle, followed by three cycles of VRd, an ASCT, 2 cycles of VRd consolidation and maintenance therapy with R until June 2019.In July 2021 an instable lytic bone lesion was observed in the C6 spinal vertebra.A subsequent myelogram revealed a plasmocyte level of 20% and recurrence of the IgA peak.A molecular-cytogenetic analysis of the MM cells again revealed a complex karyotype, including a translocation between long arms of chromosomes 2 and 4, deletion of 1p32, gains of 9q22 and 15q22 and a MYC rearrangement.Treatment was initiated with isatuximab monotherapy followed by cervical vertebrae surgery in September 2021 and postoperative isatuximab-Kd (once weekly schedule).Overall, the isatuximab-based treatment was well tolerated, except for an episode of pneumonia in January 2022.The patient remains to be in complete remission under the isatuximab-Kd treatment (response assessed on blood, not bone marrow) and continues to have a good quality of life, with a stable renal function (last update September 2022).
This case describes a MM patient with mild renal impairment having a durable complete remission on isatuximab-Kd in first relapse, without compromising the quality of life.

Case 4
The fourth patient consists of a man born in November 1948.In April 2012 the patient developed an acute renal insufficiency rendering him dialysis dependent.The patient was diagnosed with a light chain kappa MM with diffuse bone involvement, complicated by a recent vertebral compression of vertebrae D7-D9, D11 and L1.The patient had a hemoglobin level of 10.8 g/dl and displayed hypercalcemia (15 g/dl).A myelogram revealed a plasmocyte level of 45% and a cytogenetic analysis showed a normal karyotype.The patient started therapy with Vd for 4 cycles, but the hypercalcemia worsened, and the level of light chain kappa further increased.Subsequently, a treatment with R was started, but the patient immediately developed a serious cutaneous allergic reaction.In July 2012 the patient was treated with five cycles of bendamustine resulting in a complete remission on the myelogram.The patient never proceeded to an ASCT as it proved to be impossible to harvest stem cells.In September 2014, the patient suffered a biological progression after which he was treated with a combination of P and cyclophosphamide from August 2015 until March 2016.In September 2016 the patient suffered a second biological progression countered by a Kd treatment.However, after only two cycles, the Kd treatment was stopped on request of the patient as the side effects of this treatment hampered him from riding his bicycle.From March 2017 until January 2022, the patient suffered several biological progressions which were respectively treated with daratumumab-I (March 2017), elotuzumab-R (January 2018) and K-endoxan (July 2020).Following the final progression in January 2022, the patient-initiated treatment with isatuximab-Pd resulting in a partial remission.The treatment was well tolerated by the patient, and he is able to ride his bicycle on a regular basis.Until now, the patient has never been hospitalized for infectious problems.The patient is currently not on dialysis and has a GFR of 10-15 ml/min.This case describes a heavily pretreated and daratumumab-exposed MM patient with severe renal impairment in whom isa-Pd induced a durable partial response with a good tolerability.

Discussion
The basis for the EMA approval of isatuximab in the treatment of RRMM relates to the clinical data from the pivotal randomized phase III ICARIA-MM and IKEMA studies, in which the addition of isatuximab to Pd or Kd resulted in a significant prolongation of the median PFS in patients with RRMM [6,7].In both ICARIA-MM and IKEMA, the PFS benefit obtained with isatuximab was observed irrespective of age, renal function, the presence of high-risk cytogenetics, the number of prior treatment lines and IMID or PI refractoriness [6,7,[11][12][13][14][15][16][17][18][19].Based on these findings, the most recent International Myeloma Working Group (IMWG) recommendations for the treatment of patients with RRMM include isatuximab-Kd as one of the preferred options for lenalidomide-refractory patients in first relapse.In addition, both isatuximab-Kd and isatuximab-Pd are recommended options for RRMM patients who received 2 or more previous lines of therapy [20].
The four cases described above further illustrate the clinical potential of isatuximab-based therapy in patients with RRMM.Three of the cases described here consist of heavily pretreated patients who were all previously exposed to daratumumab.In all three patients, the isatuximab-based treatment, given in the fourth line or beyond, resulted in a durable partial remission (response duration ranging from 6 months to beyond 2 years).As such, these cases underscore that pretreatment with another CD-38 directed monoclonal antibody does not preclude a response to isatuximab in patients with RRMM.The fourth case describes a patient who received his isatuximabbased therapy in first relapse.In this patient, the treatment resulted in an ongoing durable complete remission (exceeding 1 year).
Over the last decade, advances in the understanding of MM led to the development of a plethora of novel therapeutic agents, ultimately culminating in a better survival for patients.However, MM remains to be an incurable disease and patients typically move from treatment line to treatment line throughout their disease course.In this chronic disease context, avoiding long-term toxicity and safeguarding quality of life are becoming increasingly important [21].In fact, apart from prolonging the remission and survival of patients, novel therapies should ideally also reduce the MM symptom burden and avoid a further deterioration of a patients' performance status, which may render him/her ineligible for further treatment lines.Across the four patients described in this article, the isatuximab-based treatment was well tolerated, without a detrimental impact on their quality of life.The latter is in line with the available quality of life data coming from the pivotal clinical trials with this agent.In fact, in the phase III ICARIA-MM study, the addition of isatuximab to Pd did not have a negative impact on the health-related quality of life (HRQoL) of patients [22].Similarly, also in the IKEMA study, the HRQoL was maintained with the addition of isatuximab to Kd [7].
While ICARIA-MM and IKEMA demonstrated the clinical benefit of isatuximab across all investigated patient subgroup, they don't answer all challenges that are encountered in clinical practice.One of the key unanswered questions in this respect consists of the efficacy of isatuximab in patients who were previously treated with daratumumab.Of note, while the pivotal trials ICARIA-MM and IKEMA allowed inclusion of patients with prior anti-CD38 albeit not being refractory to anti-CD38, neither trial included patients with prior anti-CD38 based therapy.Three of the four patients discussed here were previously exposed to a daratumumab-based treatment regimen illustrating that a prior daratumumab use does not preclude a treatment response to a later isatuximab-based treatment.Albeit being scarce, the available data on this matter seem to point in the same direction.In fact, in a descriptive analysis of nine daratumumab-pretreated RRMM patients, isatuximab-Pd induced a partial response or better in five patients [23].Also in a case series from the UK, reported by Djebbari et al. isatuximab-Pd was found to induce a response in two out of five RRMM patients with prior daratumumab exposure [24].Similarly, in Part B of a phase 1b study including 7 daratumumab-refractory patients, three (50%) of the six patients who were evaluable for response experienced a minimal response or better [25].More recently, Mohan et al. presented the results of an analysis looking into the efficacy of isatuximab-based therapy in 59 RRMM who received at least one cycle of daratumumab-based therapy [26].The median number of prior treatment lines before the isatuximab-based therapy in these patients was 6 and most patients had previously been treated with at least two IMIDs and two PIs.Furthermore, one-fifth of patients (20.3%) received more than one line of daratumumab-based therapy and the median time to the start of the isatuximab-based therapy after discontinuation of daratumumab was 13.2 months.All but one patient in this series (98.3%) received isatuximab as part of a combination regimen (93.1% in combination with an IMiD) In this dataset, 25% of patients experienced disease stabilization with the isatuximab-based therapy, while a PR was the best response in another quarter of the patients.In total, five patients had a ≥VGPR to the isatuximab-based therapy.Interestingly, a higher clinical benefit rate with Isatuximab-based therapy was observed in patients who received isatuximab more than 6 months after the discontinuation of daratumumab compared to those who were treated within 6 months (57.9% vs. 19%; p = 0.004).Finally, a prior response of ≥VGPR to daratumumab did not prove to be predictive for a response to isatuximab in this dataset [26].In contrast to these findings, a phase I/II study reported by Mikhael et al. failed to show an objective response to isatuximab-based therapy in 32 daratumumab-refractory RRMM patients.In this study, a disease control rate (i.e.minimal response or disease stabilization for at least 8 weeks) of 37.5% was reported, but similar to the study from Mohan et al., this rate proved to be higher among patients with a longer interval between the last daratumumab dose and the start of the isatuximab treatment (58.3% for patients with a daratumumab washout ≥6 months vs. 28.6% with a washout <3 months).As such, the fact that two-thirds of patients in this study started isatuximab within 6 months after daratumumab discontinuation may in part be responsible for the lack of objective responses [26,27].
Renal impairment (RI) is a common complication of MM, affecting up to 50% of patients [28].This MMrelated RI is caused by an accumulation and precipitation of immunoglobulin-free light chains in the distal tubules of the kidney, leading to tubule obstruction and a decreased renal function [29].In MM, it is therefore important that novel treatment regimens can safely be used in renally impaired patients.Furthermore, the presence of RI in MM patients was found to be an independent predictive factor for a worse OS, spurring the interest for anti-myeloma treatments that are able to improve the renal function of patients [20].Two of the four patients described in this article presented with RI.While case 3 only had a mild RI, with a GFR of 50 ml/min, case 4 had a history of dialysis dependency and had a far worse renal function with a GFR of only 10-15 ml/min.In both patients, the isatuximabbased treatment was well tolerated and induced a durable treatment response.The feasibility of using isatuximab-based therapy in renally impaired patients is further supported by subgroup analyses of ICARIA-MM and IKEMA [11,16].In fact, in both these studies the clinical benefit obtained when adding isatuximab to Pd or Kd in patients with RI was similar to what was observed in patients without RI or in the overall study populations [11,16].Interestingly, data from ICARIA-MM further show that, compared to Pd alone, isatuximab-Pd was associated with a higher proportion of patients experiencing an improvement in their renal function [11].On a critical note, however, it is important to underscore that the proportion of patients with severe RI in these two clinical trials was very small, and that the results obtained in these subgroup analyses are therefore mainly applicable to patients with a moderate decrease in their renal function.However, the durable partial remission that was obtained with isatuximab-Pd in case 4 of this article, a patient with an eGFR of only 10-15 ml/min, illustrates that isatuximab can also be safe, tolerable, and effective in patients with a severely impaired renal function.

Conclusions
This article describes the real-world experience with isatuximab-based therapy in a selection of four RRMM patients.Although it is impossible to draw firm conclusions on the basis of these cases, they do illustrate the clinical potential of isatuximabbased treatment in a real-world setting.Three of the four cases described here consist of heavily pretreated patients who were previously exposed to daratumumab-based therapy.The isatuximab-based therapy provided clinical benefit to all three of these patients illustrating that prior exposure to an anti-CD38 mAb does not preclude a response to isatuximab.In this respect, the available data do suggest that a wash-out period of ≥6 months between the last daratumumab dose and the start of the isatuximab treatment increases the likelihood for a response.As such, these findings further support the design of larger prospective studies looking into the impact of prior daratumumab use on the efficacy of isatuximab-based therapy.Finally, two of the cases included in this report displayed RI and the experience with isatuximab in these patients further supports the use of this agent in this setting.

Disclosure statement
No potential conflict of interest was reported by the author(s).