Role of CD38 Antibodies in Multiple Myeloma

CD38 is a multifunctional transmembrane glycoprotein with high expression on multiple myeloma (MM) cells and limited expression on normal cells, making it an attractive therapeutic target.¹ Acting as both a receptor and an ectoenzyme, CD38 is involved in regulation of calcium signaling and modulation of immune cell activation, proliferation, and migration; it also may contribute to creation of an immunosuppressive microenvironment.¹ The development of monoclonal antibodies (mAbs) targeting CD38 has transformed the treatment of MM, with 2 anti-CD38 mAbs (daratumumab and isatuximab-irfc) currently approved for use in the United States (Table 1).^2,3

Table 1. FDA-Approved Indications for Anti-CD38 mAbs in MM^2,3

ASCT, autologous stem cell transplant; MM, multiple myeloma; NDMM, newly diagnosed multiple myeloma; PI, proteasome inhibitor; RRMM, relapsed or refractory multiple myeloma.

^aSee full prescribing information for indication.

Mechanisms of Action

Daratumumab and isatuximab-irfc bind CD38 at distinct, nonoverlapping sites resulting in similarities and differences in their mechanisms of action.¹ Both mAbs appear to induce antibody-dependent, cell-mediated cytotoxicity that is mediated primarily by natural killer cells and by antibody-dependent cellular phagocytosis.^1-3 Modulation of the immunosuppressive microenvironment may also contribute to their efficacy. Complement-dependent cytotoxicity may play a greater role with daratumumab, whereas inhibition of cyclase activity and direct induction of apoptosis appear to be more significant with isatuximab-irfc.¹

Bone marrow aspirate cytology of multiple myeloma: ©David A Litman - stock.adobe.com

Clinical Evidence in Relapsed or Refractory Multiple Myeloma

Monotherapy

Daratumumab initially was studied as monotherapy in phase 1 (NCT00574288) and phase 2 (NCT01985126) trials in heavily pretreated relapsed or refractory MM (RRMM). Objective response rates (ORRs) of 36% and 29%, respectively, were reported, with 12-month overall survival (OS) of 77% and 65%.^4,5

Combinations With Immunomodulatory Drugs (IMiDs)

The phase 3 POLLUX trial (NCT02076009) compared lenalidomide and dexamethasone (Rd) versus daratumumab plus Rd (D-Rd) in 569 patients with RRMM (≥ 1 prior treatment).⁶ Twelve-month progression-free survival (PFS) was significantly higher with D-Rd than with Rd (83.2% vs 60.1%, respectively; HR, 0.37; P < .001), as was the ORR (92.9% vs 76.4%; P < .001) and minimum residual disease (MRD) negativity (22.4% vs 4.6%; P < .001). These benefits continue to be observed with longer follow-up (median, 44.3 months).⁷

In the phase 1b EQUULEUS trial (NCT01998971), investigators reported an ORR of 60% for daratumumab plus pomalidomide and dexamethasone (D-Pd) in 103 patients with RRMM, 89% of whom were refractory to lenalidomide.⁸ In the phase 3 APOLLO trial (NCT03180736), 304 patients with RRMM (≥ 1 prior treatment including lenalidomide and a proteasome inhibitor [PI]) were randomly assigned to receive D-Pd or Pd alone. Median PFS was significantly improved with D-Pd as compared with Pd (12.4 versus 6.9 months, respectively; HR, 0.63; P = .0018).⁹ Similarly, in the phase 3 ICARIA-MM trial (NCT02990338), 307 patients with RRMM (≥ 2 prior treatments, including lenalidomide and a PI) were randomly assigned to receive isatuximab-irfc plus Rd (I-Rd) versus Rd alone. Results again showed a significant improvement in PFS in the I-Rd group as compared with those given Rd (median, 11.5 vs 6.5 months; HR, 0.596; P = .001).¹⁰

Combinations With PIs

The combination of daratumumab plus bortezomib and dexamethasone (D-Vd) was compared with Vd alone in the phase 3 CASTOR trial (NCT02136134) in 498 patients with RRMM (≥ 1 prior treatment).^11,12 Results showed that D-Vd therapy, compared with Vd, significantly reduced the risk of progression (median PFS, 16.7 vs 7.1 months, respectively; HR, 0.31; P < .0001) and increased ORR (83.8% vs 63.2%; P =.0001) and MRD negativity (11.6% vs 2.4%; P = .000034).¹²

In the phase 3 CANDOR trial (NCT03158688), 466 patients with RRMM (1-3 prior therapies) were randomly assigned to receive daratumumab plus carfilzomib and dexamethasone (D-Kd) or Kd. PFS was significantly improved with D-Kd as compared with Kd (median, 28.6 vs 15.2 months; HR, 0.59; P < .0001).¹³ Similarly, in the phase 3 IKEMA trial (NCT03275285), 302 patients with RRMM (1-3 prior therapies) were randomly assigned receive to isatuximab-irfc with Kd versus Kd alone. At a median follow-up of 20.7 months, median PFS had not been reached in the I-Kd arm and was 19.15 months in the control arm (HR, 0.53; P = .0007); the associated MRD negativity noted in the arm given combination therapy was more than double the rate observed in the control arm (30% vs 13%).¹⁴

Newly Diagnosed Multiple Myeloma

Two phase 3 trials have reported results for combination therapies involving daratumumab in transplant-ineligible patients with newly diagnosed MM (NDMM). The phase 3 MAIA trial (NCT02252172) compared frontline treatment with D-Rd versus Rd in 737 patients, 43% of whom were older than 75 years.¹⁵ At a median follow-up of 56.2 months, median PFS was not been reached in the D-Rd arm and was 34.4 months in the control group (HR, 0.53; P < .0001). OS was significantly improved with D-Rd (medians not reached; HR, 0.68; P = .0013). The phase 3 ALCYONE trial (NCT02195479) evaluated the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) compared with VMP given alone in 706 patients with transplant-ineligible NDMM; addition of the anti-CD38 mAb resulted in benefits for both PFS (HR, 0.42; P < .0001) and OS (HR, 0.60; P = .0003).^16,17

Finally, the phase 3 CASSIOPEIA trial (NCT02541383) evaluated the addition of daratumumab to bortezomib, thalidomide, and dexamethasone (D-VTd) as induction and consolidation in 1085 patients with transplant-eligible NDMM, followed by a second randomization to daratumumab maintenance (n = 442) for 2 years versus observation (n = 444) for patients who achieved a partial response or better.^18,19 Following transplantation, 29% of patients in the D-VTd group had achieved a stringent complete response compared with 20% of patients in the VTd group (P = .0010).18 At a median follow-up of 18.8 months, median PFS from first randomization had not been reached in either group, although it favored those given D-VTd (HR, 0.47; P < .0001). Maintenance daratumumab was also associated with an improvement in PFS (HR, 0.53; P < .0001).¹⁹

Anti-CD38 mAbs represent an important advance in the treatment of MM, providing new effective options for patients with both NDMM and RRMM. Future studies will need to address sequencing considerations with other standard therapies, strategies for overcoming resistance, and compatibility with other emerging regimens for patients with MM.

REFERENCES:

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14. Moreau P, Dimopoulos MA, Mikhael J, et al; IKEMA Study Group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371. doi:10.1016/S0140-6736(21)00592-4

15. Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6

16. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518-528. doi:10.1056/NEJMoa1714678

17. Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395(10218):132-141. doi:10.1016/S0140-6736(19)32956-3

18. 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. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1

19. Moreau P, Hulin C, Perrot A, et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(10):1378-1390. doi:10.1016/S1470-2045(21)00428-9