Patients with multiple myeloma (MM) are highly susceptible to developing relapsed and refractory (RR) disease towards lenalidomide and proteasome inhibitors (PIs) and require new active treatments at relapse.¹ As such, novel treatment options like isatuximab, a monoclonal antibody (mAb) that targets CD38, have been developed.^1,2 At the 2023 Annual Scientific Meeting of the Hong Kong Society of Myeloma, Professor Yong, Kwee from University College London shared the latest data on the encouraging response of isatuximab-based regimens among patients with lenalidomide-refractory disease and high-risk cytogenetics. She also talked about the sequencing of anti-CD38 mAb use based on a real-world study that investigated the efficacy of isatuximab after daratumumab treatment, highlighting the importance of a treatment-free interval between the two regimens.

Isatuximab as a potential candidate in RRMM treatment

MM can be a chronic threat to patients’ health due to relapse being an inevitable feature of the disease.¹ In the management of MM, lenalidomide forms the backbone of many current front-line regimens regardless of transplant eligibility.3,4 However, almost all MM patients eventually become refractory to lenalidomide.¹ As such, novel treatment options for MM with alternative mechanisms of action have emerged. Prof. Yong noted that there are many second-line options for lenalidomide-refractory patients, including proteasome inhibitor (PI)-based, pomalidomide-based, and anti-CD38 mAb-based treatments, and that regimens not used in earlier lines may be rechallenged.

Isatuximab is an anti-CD38 monoclonal antibody (mAb) that binds to a specific epitope of CD38 and exhibits anti-tumor properties through a number of unique biological mechanisms, including antibody-dependent cellular-mediated cytotoxicity, antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, and direct induction of apoptosis without cross-linking.^1,2 Furthermore, isatuximab possesses a dose-dependent inhibition property against CD38 ectoenzyme activity, which has key roles in cellular functions and contributes to immune system evasion of tumor cells.¹ Preclinical studies have demonstrated a favorable efficacy in tumor regression when isatuximab was combined with immunomodulatory agents or PIs.²

According to both the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines on MM, isatuximab-based regimens are one of the combination therapies indicated for lenalidomide-refractory, or lenalidomide-refractory and bortezomib-refractory patients.^3,4 Isatuximab plus carfilzomib/dexamethasone (Isa-Kd) is recommended at first relapse while isatuximab plus pomalidomide/dexamethasone (Isa-Pd) is recommended in a similar group of patients at the second or subsequent relapses.^3,4

Clinically meaningful and sustained response of Isa-Pd in lenalidomide-refractory MM patients reported in the ICARIA-MM study

Prof. Yong presented findings of the ICARIA-MM study, which was the first phase 3 study that investigated the clinical efficacy of Isa-Pd among patients with RRMM.¹ In this study, 307 patients with RRMM who received ≥2 lines of treatment and exhibited refractory towards lenalidomide and PIs were randomized 1:1 to receive Isa-Pd (n=154) or Pd only (n=153) until disease progression, unacceptable toxicities, or patient withdrawal.¹

At a median follow-up of 11.6 months, the median progression-free survival (PFS) of the Isa-Pd arm was significantly longer than that of the Pd-only arm, indicating an approximately 40% reduced risk of progression and death (11.5 vs. 6.5 months; HR=0.596; 95% CI: 0.44-0.81; p=0.001).¹ In addition, the overall response rate (ORR) of the Isa-Pd arm was also significantly higher than that of the Pd-only arm (60% vs. 35%; OR=2.795; 95% CI: 1.75-4.56; p<0.0001).¹ A subsequent subgroup analysis revealed that compared to the Pd-only arm, a higher ORR was observed in Isa-Pd arm among patients who were lenalidomide-refractory (59.0% vs. 31.4%) and those who were lenalidomide-refractory at last line (55.9% vs. 29.5%), with the proportion of patients who exhibited very good partial response (VGPR) maintained at 30.6% and 32.3% respectively (figure 1).⁵

The desirable clinical responses of Isa-Pd were retained even 3 years after treatment.6 At a median follow-up of 35.3 months, the ORR was reported at 63.0% vs. 33.3% with Isa-Pd and Pd-only respectively, with the proportion of patients in the Isa-Pd arm who exhibited VGPR being tripled that of the Pd-only arm (38.3% vs. 10.5%).⁶

Consistent clinical benefits of Isa-Pd in MM patients with high-risk cytogenetics

In another subgroup analysis of ICARIA-MM, which explored the clinical efficacy of Isa-Pd among MM patients with high-risk cytogenetics, the Isa-Pd regimen demonstrated comparable clinical benefits between the standard-risk and high-risk patient subgroups.⁷ Amongst the MM patients with high-risk chromosomal abnormalities including del(17p), t(4;14), or t(14;16) mutations (n=60), patients who received Isa-Pd treatment (n=24) exhibited a significantly higher ORR compared to those who received Pd only (n=36) (50.0% vs. 16.7%; p=0.0031) (figure 2).⁷ The survival outcomes associated with Isa-Pd were also consistent regardless of chromosomal abnormalities.⁷ When stratified by cytogenetic risk, the PFS benefit induced by Isa-Pd among high-risk patients (HR=0.66; 95% CI: 0.33-1.28) was comparable with standard-risk patients (HR=0.62; 95% CI: 0.42-0.93).⁷

Robust data for alternative isatuximab-based triplet regimen in the IKEMA trial

Aside from Isa-Pd, Isa-Kd, the sister regimen of Isa-Pd has also shown remarkable clinical benefits among high-risk patients with RRMM.² To demonstrate its efficacy, Prof. Yong presented the recent findings of the IKEMA trial, a phase 3 open-label study that evaluated the clinical efficacy of Isa-Kd among early-relapse MM patients.² In this study, 302 patients with relapsed or refractory MM with 1 to 3 prior lines of therapy were randomized 3:2 to receive Isa-Kd (n=179) and Kd (n=123) until disease progression, unacceptable toxicities, or patient withdrawal.²

Significant improvements in PFS were reported in the Isa-Kd arm at a median follow-up of 20.7 months, resulting in a 47% risk reduction in progression or death (HR=0.53; 99% CI: 0.32-0.89; p=0.0007).² This survival benefit was maintained at a follow-up of 44 months, where there was a 42% reduced risk of progression or death (HR=0.58; 95% CI: 0.42-0.79).⁹ Despite the similar ORR between the Isa-Kd and Kd-only arms (86.6% vs. 83.7%), the benefits of Isa-Kd over Kd monotherapy were more apparent as patients who received Isa-Kd had a higher achievement rate of VGPR (72.6% vs. 56.1%) and stringent complete or complete responses (sCR/CR) (44.1% vs. 28.5%).^2,9

Echoing the exploratory data of the ICARIA-MM study, the ORR data among patients in IKEMA also indicated consistent clinical efficacy of Isa-Kd regardless of patients’ lenalidomide-refractory status (figure 3).⁸

Additionally, at the median follow-up of 44 months, the safety profile was similar to previous analyses where the treatment discontinuation rate of Isa-Kd was even lower than that of Kd alone (12.4% vs. 18.0%). Prof. Yong also highlighted the similar incidence of cardiac failure (8.5% vs. 7.4%) and grade ≥3 cardiac failure (4.5% vs. 4.1%) between the Isa-Kd arm and Kd-only arm, suggesting that the addition of isatuximab did not incur any additional cardiotoxicity, and that a triplet therapy enables more opportunities for dose adjustment if so required.⁹

Isatuximab in real-life post-daratumumab populations

Prof. Yong reflected that while isatuximab-based regimens have been proven to be an efficacious second-line option for treating RRMM, the management of patients in real life may be more complex as they are often heavily pretreated prior to the use of isatuximab-based regimens, with other anti-CD38 mAbs such as daratumumab. She also raised the question of how prior daratumumab treatment may affect patients’ response to isatuximab-based regimens and noted the need for a washout period between the 2 treatments.

In a retrospective study, patients with RRMM from 4 US academic institutions (Medical College of Wisconsin, University of Arkansas for Medical Sciences, Memorial Sloan Kettering Cancer Center, and MD Anderson Cancer Center) who had ≥1 cycle of daratumumab therapy and subsequently had isatuximab-based regimen were analyzed.10 The study reported that these patients were heavily pretreated with a median of 6 prior lines of therapy (range: 1-18) and that 64.4% of patients had an interval of >6 months between daratumumab and isatuximab therapy. A clinical benefit rate (CBR) (defined as the percentage of patients who achieved a sCR, CR, VGPR, PR, or MR) of 44% was attained among the study population, with a significantly higher CBR being observed in patients with a >6 months washout period (n=38) compared to those who received isatuximabbased regimens ≤6 months (n=21) from the last daratumumab dose (58% vs.19%; p=0.004).10 Results from the multivariate analysis also showed that a washout period of >6 months is independently associated with better CBR response (OR=0.23; 95% CI: 0.06-0.88; p=0.032).¹⁰

Based on the findings of this study, it was speculated that the benefit of the washout period stemmed from possible antigen downregulation or impaired effector cell function from prior anti-CD38 mAb therapy, but Prof. Yong asserted that the precise mechanisms behind these interactions warrant further investigation.

Conclusion

With the increasing prevalence of lenalidomide-refractory patients, the role of anti-CD38 mAbs has become increasingly important.¹ High rates of ORR sustained in lenalidomide-refractory patients of the Isa-Pd and Isa-Kd regimens from the ICARIA-MM and IKEMA trials respectively have demonstrated its value in later-line treatment in RRMM patients as well as patients with high-risk cytogenetics.^1,2,6,9 When used in real-life practice, where patients may be heavily pre-treated with other anti-CD38 mAb regimens, Prof. Yong reminded us that a washout period of >6 months between daratumumab-based and isatuximab-based regimens may improve the response to isatuximab-based regimens.