The Lynx Group

Studying the Use of Novel Therapies in Various Multiple Myeloma Disease Settings

Faculty Perspectives: The Evolving Clinical and Pharmacoeconomic Impact of Isatuximab in Multiple Myeloma Management
Monique Hartley-Brown, MD, MMSc
Medical Oncologist, Department of Medicine
Member of Faculty, Harvard Medical School
Attending Physician, Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute
Boston, MA
Paul G. Richardson, MD
Clinical Program Leader and Director of Clinical Research
Jerome Lipper Multiple Myeloma Center
Institute Physician
RJ Corman Professor of Medicine
Harvard Medical School
Boston, MA

Isatuximab is 1 of the 2 FDA-approved anti-CD38 monoclonal antibodies used to treat patients with multiple myeloma.1 The other, daratumumab, was the first to be FDA-approved in this drug category.2 The addition of isatuximab is important in expanding the landscape of therapies available to treat multiple myeloma, which remains an incurable disease. The uniqueness of isatuximab in comparison with daratumumab has to do with the specific epitope by which isatuximab binds the CD38 antigen on myeloma cells.3 This difference is important in that it impacts the antimyeloma, immunogenic, and bone marrow microenvironmental effects of each agent. Isatuximab mechanistically has an advantage. It causes apoptosis of myeloma cells directly, without need for crosslinking agents or use of effector cells.4 Isatuximab is comparatively more potent in its inhibition of the CD38 enzymatic intracellular effects. This results in reducing adenosine levels within the bone marrow microenvironment, which potentially enhances the immunogenicity locally in the myeloma niche.5 More so, isatuximab eradicates regulatory CD38+ T-cells, which are immunosuppressive, thereby indirectly enhancing the circulatory immune system.6

These differences in the mechanism of isatuximab potentially explain the results of the phase 2 trial evaluating use of isatuximab after daratumumab exposure.7 In the study, the depth of response was moderate yet sustained for many patients. The study results highlight the fact that indeed isatuximab can be used effectively after daratumumab exposure, with the caveat that the timing of isatuximab use in this setting should be carefully considered, with a delay of at least 6 months between the last anti-CD38 therapy to starting isatuximab being more ideal. Patients with a clinical history of prior daratumumab use and good response, with biochemical relapse or slowly progressive disease relapse beyond 6 months of last anti-CD38 therapy, may benefit from isatuximab use in the relapsed/refractory multiple myeloma (RRMM) setting.

It is important to be aware of the off-target effects of both isatuximab and daratumumab. By nature of being monoclonal antibodies, they will result in false-positive testing of an M-spike in the blood. For isatuximab, the M-spike can also be identified using mass spectrometry to separate drug effect from measurable disease.8

Isatuximab is gaining in FDA approval for its use earlier in the course of disease. The phase 3 ICARIA and IKEMA studies were the first to highlight the use of isatuximab in triplet combination in the relapsed/refractory disease setting.3,9-11 ICARIA was pivotal in illustrating superior progression-free survival (PFS) of the isatuximab plus pomalidomide plus dexamethasone (Isa-Pd) triplet over the Pd doublet (11.5 months vs 6.5 months), a near doubling of PFS.10 This translated to FDA approval in the RRMM disease setting for patients who had been treated with ≥2 prior lines of therapy. The safety and tolerability were favorable in elderly (age >70 years) patients. The secondary end points evaluating quality of life and improvement in bone pain were also favorable and addressed real-life concerns that affect patients. The depth of response, a clinical end point linked to improved PFS, was also better in the Isa-Pd group.3,9 The IKEMA trial moved the use of isatuximab plus carfilzomib plus dexamethasone (Isa-Kd) forward earlier in RRMM disease to use after only 1 prior line of therapy. Using Isa-Kd, including patients with disease refractory to lenalidomide, correlates with improved PFS (not reached vs 19.2 months) over Kd, with a remarkable hazard ratio of 0.53.11 In other words, there is a 47% relative risk reduction of disease progression or death. The Isa-Kd combination also addressed the high-risk RRMM disease population, identifying a new triplet combination that would be effective for this specific patient population.10-12 These led to category 1 approvals in the National Comprehensive Cancer Network guidelines for use of isatuximab in patients with RRMM. These studies have paved the way for isatuximab use in the second-, third-, and fourth-line disease settings.

An exciting next step is the use of isatuximab in the frontline newly diagnosed MM disease setting. The phase 3 GMMG HD7 trial is the first phase 3 study to evaluate isatuximab in quadruplet combination in the frontline setting and reach its primary end point. The favorable minimal residual disease (MRD) negativity rates (50.1% vs 35.6%) post-induction for the isatuximab-containing arm are very encouraging. Such high MRD-negative rates being observed after a mere 18 weeks of induction speaks to the high efficacy of this regimen. In addition, the very good partial response (VGPR; 77.3% vs 60.5%) rate and the rate of disease progression (1.5% vs 4.0%) were more favorable in the isatuximab group.13 This, combined with the comparable safety and tolerability to the bortezomib plus lenalidomide plus dexamethasone (VRd) triplet, means this trial will likely result in FDA approval for the use of isatuximab plus VRd (Isa-VRd) as a quadruplet in the frontline setting for transplant-eligible patients. The PFS data are eagerly awaited, which is an end point of the second part of the GMMG HD7 study, where patients will undergo a second randomization to receive isatuximab with lenalidomide compared with lenalidomide alone as maintenance. The PFS outcome of this study will be practice-informing regarding use of an anti-CD38 monoclonal antibody in combination with lenalidomide in the maintenance setting.

The phase 3 IMROZ study is evaluating the same Isa-VRd quadruplet compared with VRd for newly diagnosed transplant-ineligible patients. This trial addresses the question of efficacy of the Isa-VRd quadruplet in a prolonged dosing schema where the regimen is de-intensified post-induction with removal of the proteasome inhibitor (bortezomib) after cycle 4 for both arms, and further de-escalation of therapy at cycle 18 and beyond with the use of isatuximab dosed monthly in the relevant arm. Crossover is allowed from the Rd arm to the Isa-Rd arm in this section of the trial for patients who progress on Rd alone. The primary end point of this study is PFS, with important secondary end points inclusive of complete response, ≥VGPR, and MRD-negativity rates.14 Currently, this trial is enrolling and has not yet achieved its primary end point, but given the positive outcome of the GMMG HD7 study to date, it is likely this trial will be practice-changing as well.

It is also important to note that in the advent of increasing numbers of novel therapies for the treatment of multiple myeloma, there is an associated rising cost to patients. Many of these therapies, including isatuximab, may negatively impact not only out-of-pocket patient costs but also indirect costs. These indirect costs include, but are not limited to, loss of revenue secondary to loss of work hours/income, especially in the case of injectable medications such as isatuximab.15 However, isatuximab may have an advantage in its calculated cost estimate over a 12-month period.16 That being said, considering that this encapsulates only a small section of the entire treatment cost in the lifetime of a patient with multiple myeloma, concerns regarding cost and resource constraints remain an area for better translation to real-world practice and optimizing overall value to further improve patient outcomes.17,18

References

  1. Sanofi-Aventis. SARCLISA® (isatuximab-irfc) injection, for intravenous use [package insert]. Sanofi-Aventis U.S. LLC. Revised March 2021. Published March 2021. https://products.sanofi.us/Sarclisa/sarclisa.pdf. Accessed February 4, 2022.
  2. Janssen. DARZALEX (daratumumab) injection for intravenous use [package insert]. Hosham, PA: Janssen Pharmaceutical Companies. Revised August 2020. Published August 2020. www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf. Accessed December 17, 2020.
  3. Richardson PG, Attal M, Campana F, et al. Isatuximab plus pomalidomide/dexamethasone versus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma: ICARIA phase III study design. Future Oncol. 2018;14:1035-1047.
  4. Moreno L, Zabaleta A, Alignani D, et al. Critical analysis on the mechanism of action (MoA) of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma (MM). Blood. 2016;128:2105.
  5. Martin TG, Corzo K, Chiron M, et al. Therapeutic opportunities with pharmacological inhibition of CD38 with isatuximab. Cells. 2019;8:1522.
  6. Feng X, Zhang L, Acharya C, et al. Targeting CD38 suppresses induction and function of T regulatory cells to mitigate immunosuppression in multiple myeloma. Clin Cancer Res. 2017;23:4290-4300.
  7. Mikhael J, Belhadj-Merzoug K, Hulin C, et al. A phase 2 study of isatuximab monotherapy in patients with multiple myeloma who are refractory to daratumumab. Blood Cancer J. 2021;11:89.
  8. Frampton JE. Isatuximab: a review of its use in multiple myeloma. Target Oncol. 2021;16:675-686.
  9. Moreau P, Dimopoulos MA, Yong K, et al. Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA phase III study design. Future Oncol. 2020;16:4347-4358.
  10. Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394:2096-2107.
  11. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397:2361-2371.
  12. Spicka I, Moreau P, Martin TG, et al. Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis. J Clin Oncol. 2021;39(15_suppl):8042-8042.
  13. Goldschmidt H. Addition of isatuximab to lenalidomide, bortezomib and dexamethasone as induction therapy for newly-diagnosed, transplant-eligible multiple myeloma patients: the phase III GMMG-HD7 Trial. In: ASH; 2021. https://ash.confex.com/ash/2021/webprogram/Paper145097.html. Accessed January 28, 2022.
  14. Orlowski RZ, Goldschmidt H, Cavo M, et al. Phase III (IMROZ) study design: isatuximab plus bortezomib (V), lenalidomide (R), and dexamethasone (d) vs VRd in transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). J Clin Oncol. 2018;36(15_suppl):TPS8055-TPS8055.
  15. Merola D, Yong C, Noga SJ, Shermock KM. Costs associated with productivity loss among U.S. patients newly diagnosed with multiple myeloma receiving oral versus injectable chemotherapy. J Manag Care Spec Pharm. 2018;24:1019-1026.
  16. AlRawashdh N, Choi B, Obeng-Kusi M, et al. Economic evaluation of six and 12 month (m) treatment with isatuximab and carfilzomib and dexamethasone (IKd) versus daratumumab and carfilzomib and dexamethasone (DKd) in patients with relapsed or refractory multiple myeloma (RRMM). J Clin Oncol. 2021;39(15_suppl):e20010-e20010.
  17. Richardson PG, San Miguel JF, Moreau P, et al. Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting. Blood Cancer J. 2018;8:109.
  18. Fonseca R, Abouzaid S, Bonafede M, et al. Trends in overall survival and costs of multiple myeloma, 2000-2014. Leukemia. 2017;31:1915-1921.

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