Blood cancers

Use of CD38 antibodies in multiple myeloma and AL amyloidosis: Janssen H3 2021

Wednesday, 25 Aug 2021


The Janssen H3 medical education meeting on haematological malignancies was held on 8 May 2021, both virtually and live across six locations in Australia and New Zealand. Chaired by Dr Wojt Janowski of the Calvary Mater in Newcastle, NSW, the dinner session featured a presentation from international guest speaker Professor Wee Joo Chng, Director of National University Cancer Institute at the National University Health System in Singapore,  Group Director of Research Office at the National University Health System and Vice-Dean of Research at the Yong Loo Lin School of Medicine, as well as the Deputy Director and a Senior Principal Investigator at the Cancer Science Institute of Singapore and the National University of Singapore. Professor Chng spoke on the use of CD38 antibodies in multiple myeloma and amyloid light-chain (AL) amyloidosis.

CD38 antibodies in multiple myeloma

Professor Chng began his presentation with an overview of the CD38 antigen, pointing out its expression at a high level in a variety of malignancies before focussing on its role in multiple myeloma. Two monoclonal antibodies that target CD38 have been developed – daratumumab and isatuximab. Both have been shown to have immune mediated activity via antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP), as well as direct anti-tumour effects, an immunomodulatory effect on the tumour microenvironment and inhibition of ectoenzyme activity.1–6

Studies have shown the efficacy of these treatments as single-agents in multiple myeloma. Professor Chng highlighted the ability of daratumumab to produce a response rate of about 31% across a range of studies in very late stage disease, with a median overall survival of about 20.1 months.7 He noted “usually in these types of patients we’ll be lucky to get survival of about 12 months or so”. A similar response was seen with isatuximab in a phase 2 dose finding study, with around 30% overall response rate and a clinical benefit rate (minor response or higher) of 42%, when 10 mg/kg was given every 2 weeks.8

Professor Chng went on to describe data supporting the use of these agents in combination with established therapies, initially used in relapsed myeloma. Table 1 summarises the key data from these studies. He explained that “as with many other studies, it is clear that using novel targeted therapies in myeloma produces best results early, rather than later on.” When comparing the data for daratumumab and isatuximab, Professor Chng stated “it would appear that at least with these two monoclonal antibodies there is a class effect, and from my reading of these data there is little to tell the two apart, though infusion timing and dosing frequency may be a bit different.” He also touched on the fact that daratumumab may be used in a subcutaneous setting.

Table 1. Anti-CD38 combinations in relapsed multiple myeloma.

Study Primary endpoint Key secondary endpoints
CASTOR9

Multicentre, randomised, open-label, active-controlled, phase 3 study comparing daratumumab + bortezomib + dexamethasone (DVd) to bortezomib + dexamethasone (Vd)

PFS at 42 months in ITT population: 22% (D-Vd ) vs 1% (Vd); p<0.00019

 

Median PFS in ITT population: 16.7 months (D-Vd) vs 7.1 months (Vd)

 

PFS at 42 months in patients with 1 prior line of treatment: 30% (D-Vd) vs 2% (Vd); p<0.0001 10

 

Median PFS in patients with 1 prior line of treatment: 27 month (D-Vd) vs 7.9 months (Vd)

ORR at median 40 months of follow-up: 84% (D-Vd) vs 63% (Vd)9

 

MRD at median 40 months follow up: 13.3% (D-Vd) vs. 2.4% (Vd) in standard risk patients (p=0.0003) and 17.9% (D-Vd) vs. 9% (Vd) in high risk patients (p=0.0003)10

 

POLLUX11

Randomized, open-label, multicentre, phase 3 trial comparing daratumumab + lenalidomide + dexamethasone (D-Rd) to lenalidomide + dexamethasone (Rd)

PFS at 48 months in ITT population: 48% (D-Rd ) vs 21% (Rd); p<0.0001

 

Median PFS in ITT population: 16.7 months (D-Vd) vs 7.1 months (Vd)

 

ORR at median 54.8 months of follow-up: 93% (D-Rd) vs 76% (Rd)11

 

MRD-negative rates were >3 times higher with DRd compared with Rd alone at all 3 sensitivity thresholds: 31.8% vs 8.8% at 10–4; 24.8% vs 5.7% at 10–5; and 11.9% vs 2.5%, at 10–6; (p<0.0001 for all)11

CANDOR12

Randomised, multicentre, open-label, phase 3 study comparing carfilzomib + dexamethasone + daratumumab (KdD) to carfilzomib + dexamethasone (Kd)

Median PFS not reached in KdD group vs 15.8 months in Kd group; p=0.0014

 

PFS hazard ratio in patients with previous exposure to lenalidomide: 0.52 (95% CI: 0.34, 0.80)

 

PFS hazard ratio in patients refractory to lenalidomide:  0.45 (95% CI: 0.28, 0.74)

APOLLO13

Open-label, multicentre, phase 3 study comparing daratumumab + pomalidomide + dexamethasone (D-Pd) to pomalidomide + dexamethasone (Pd)

PFS at 12 months: 52% (D-Pd ) vs 35% (Pd); p<0.0018

 

Median PFS: 12.4 months (D-Pd) vs 6.9 months (Pd)

 

ORR at median 16.9 months of follow-up: 69% (D-Pd) vs 46% (Pd)

 

D-Pd produced significantly more MRD-negative rates vs Pd (p=0.0102)

 

ICARIA-MM14

Randomised, multicentre, open-label, phase 3 study comparing isatuximab + pomalidomide + dexamethasone (IsaPD) to pomalidomide + dexamethasone (Pd)

Median PFS: 11.53 months (IsaPd) vs 6.47 months (Pd); p=0.0001

 

IKEMA15

Phase 3 study comparing isatuximab + carfilzomib + dexamethasone (Isa-Kd) to carfilzomib + dexamethasone (Kd)

Median PFS: Not reached (Isa-Kd) vs 19.15 months (Kd); p=0.000716

 

ORR was 86.6% (Isa-Kd) vs 82.9% (Kd), p=0.1930

 

MRD negativity in the ITT population was 29.6% (Isa-Kd) vs. 13.9% (Kd), p<0.000416

CI: confidence interval ; ITT: intent-to-treat; MRD: minimal residual disease; ORR:overall response rate; PFS: progression-free survival.

Frontline targeting of CD38 in newly diagnosed patients

Explained Professor Chng, “Once we have tested novel agents in the relapsed setting, we move them upfront to newly diagnosed patients.” Combinations that have been studied in randomised clinical trials of transplant eligible patients, including those with daratumumab, are listed in Table 2. 17–20 Regardless of the combinations given, you can achieve very similar outcomes – the important difference is that the daratumumab produces a deep response like stringent complete response or MRD-negativity in more patients”, noted Professor Chng.17–20 Briefly touching on daratumumab in transplant ineligible patients in this setting, he pointed out that the data is “potentially even more impressive”21,22 though perhaps “not so relevant to practice in Australia right now, as it may not be available under reimbursement for some time yet.”

Table 2. Combinations of CD38 antibodies and existing treatments for newly diagnosed, transplant eligible multiple myeloma.17–20

  • Daratumumab + bortezomib + thalidomide + dexamethasone (D-VTd)
  • Daratumumab + Lenalidomide + bortezomib + dexamethasone (D-RVd)
  • Isatuximab + carfilzomib + lenalidomide + dexamethasone (Isa-KRd)

 

Subcutaneous daratumumab – an exciting prospect for the future

Professor Chng provided a brief overview of the data around subcutaneous daratumumab. “In Singapore there is a lot of interest and excitement about this option, as we are always looking for opportunities to get treatment outside of the hospital setting, or reduce infusion time to maximise the number of chairs for patients”. Significant time savings were achieved with subcutaneous versus intravenous administration. Response rates were similar, including those in subgroup analyses.23 Safety outcomes were also attractive, with fewer infusion reactions with subcutaneous versus intravenous administration.23 Professor Chng opined “this is a strong differentiator in my mind to isatuximab, though in time we will have similar studies for isatuximab.”

Anti-CD38 in AL amyloidosis
Professor Chng covered data supporting the use of daratumumab in AL amyloidosis, highlighting the updated outcome data showing a significant improvement in haematological response and good organ response with subcutaneous daratumumab in addition to bortezomib, cyclophosphamide and dexamethasone (VCd).24–29 He noted that his clinic is using daratumumab more in the frontline setting along with VCd in AL amyloidosis patients, particularly those with cardiac involvement or significant renal involvement that are considered high risk.” Deciding which patients are most suitable is based on “who may benefit the most – based on the organ improvements shown, we are targeting those with significant organs affected by AL amyloidosis.”

Ending with consideration of isatuximab, Professor Chng noted that studies are underway but pointed out that “it’s really too early, though we can see that isatuximab appears active in AL amyloidosis as well.”

Take home messages

Professor Chng concluded with his take-home messages on anti CD38 therapies:

  • Anti-CD38 antibodies are now fully established as a critical component of myeloma treatment in both relapsed and newly diagnosed patients
  • This approach could soon become standard for upfront therapy in many jurisdictions
  • The therapies are generally well tolerated, and infusion reactions do not appear to be a significant issue
  • Subcutaneous daratumumab will be advantageous for delivery, particularly for longer-term treatment to prevent the need for patients to return to hospital for infusions
  • Daratumumab data in AL amyloidosis appears impressive, although we only have early data so far

 

References:

  1. Lin P, et al. Am J Clin Pathol 2004;121(4):482-488.
  2. Santonocito AM, et al. Leuk Res 2004;28(5):469-477.
  3. de Weers M, et al. J Immunol 2011;186(3):1840-1848.
  4. Overdijk MB, et al. MAbs 2015;7(2):311-321.
  5. Krejcik J, et al. ASH 2015; Abstract 3037.
  6. Jiang H, et al. Leukemia 2016;30:399-408.
  7. Usmani SZ, et al. Blood. 2016;128(1):37-44.
  8. Mikhael J, et al. Leukemia 2020;34:3298–3309.
  9. Weisel K, et al. Presented at EHA 2017; Abstract S459, oral presentation.
  10. Weisel K, et al. J Clin Onc 2019; 37(15 suppl): 8040-8040 ASCO 2019.
  11. Dimopoulos et al. Presented at EHA 2017; Abstract P334, poster presentation.
  12. Dimopoulos M, et al. Lancet 2020;396(10245):186-197.
  13. Dimopoulos M, et al. ASH 2020; Abstract 412, oral presentation.
  14. Attal M, et al. Lancet 2019;394(10214):2096-2107.
  15. Moreau P, et al. Future Oncol 2020;16(2):4347-4358.
  16. Moreau P, et al. EHA25 Annual Congress; Jun 14, 2020. Oral abstract 303392.
  17. Moreau P, et al. Lancet 2019;394:29-38.
  18. Avet-Loiseau et al. IMW 2019; Abstract AB767.
  19. Kaufman JL, et al. ASH 2020; Abstract 549.
  20. Weisel K, et al. ASCO 2020; oral presentation.
  21. Mateos MV, et al. Lancet 2020; 395(10218):132-141.
  22. Dimopoulos et al. Presented at ASH 2020; Abstract 412, oral presentation. ASH 2020.
  23. Mateos MV, et al. Lancet Haematol 2020; 7(5):e370-e380.
  24. Kastritis E, et al. Presented at EHA 2020; Abstract LB2604, oral presentation.
  25. Comenzo, et al. ASH 2020; Abstract 552.
  26. Minnema, et al. ASH 2020; Abstract 1392.
  27. Suzuki, et al. ASH 2020; Abstract 1409.
  28. Sanchorawala, et al. ASH 2020; Abstract 1640.
  29. Wechalekar, et al. ASH 2020; Abstract 2305.

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