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Accelerated approval granted by FDA for daratumumab sc + VCd for AL amyloidosis in light of the phase III ANDROMEDA trial updated results

Jan 22, 2021
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The subcutaneous (sc) formulation of daratumumab + hyaluronidase with bortezomib, cyclophosphamide, and dexamethasone has been granted accelerated approval by the U.S. Food and Drug Administration (FDA) for adult patients with newly diagnosed light-chain (AL) amyloidosis.1 This is the only FDA approved therapy for this condition. The European Medicines Agency (EMA) is also evaluating this expanded use of daratumumab since November 2020.2

The combination of daratumumab with bortezomib, cyclophosphamide, and dexamethasone (D-VCd) has been tested in the ANDROMEDA trial (NCT03201965). The approval was granted based on the hematologic response rate identified in this phase III study.

Find below a summary of the latest update of the ANDROMEDA study provided by Raymond L Comenzo at the 62nd American Society of hematology (ASH) Annual Meeting & Exposition.3 This update provided further information regarding the primary endpoint of hematologic complete response (hemCR) rates and reported the key secondary endpoint: major organ deterioration progression-free survival (MOD-PFS). The study design and patient characteristics have been reported previously by the Multiple Myeloma Hub and can be found here.

Primary endpoint

HemCR was defined as normalization of free light chain (FLC) and FLC ratio (FLCr) along with negative urine and serum immunofixation. As hemCR has come under increased scrutiny recently, the ANDROMEDA study analyzed multiple criteria for deep hemCR, including:

  • Involved FLC (iFLC) ≤ 20 mg/L
  • Difference between iFLC and uninvolved FLC (dFLC) < 10 mg/L
  • International Society of Amyloidosis (ISA) criteria: normal FLCr and negative urine and serum immunofixation3

The results are shown in Table 1 and demonstrate that all measurements of hemCR agree that D-VCd significantly improved response rate compared with VCd alone. The median follow-up was 15.7 months (range 0−24.1).

Table 1. Hematologic response rates in different treatment arms according to different criteria3

D-VCd, daratumumab-bortezomib, cyclophosphamide, and dexamethasone; dFLC, difference between involved free light chain and uninvolved free light chain; hemCR, hematologic complete response; iFLC, involved free light chain.

*HemCR defined as normalization of FLC and FLC ratio (FLCr) along with negative urine and serum immunofixation.

ISA criteria for hemCR: normal FLCr and negative urine and serum immunofixation.

HemCR criteria

Treatment arms

Hematologic response rate, n (%)

OR (95% CI)

p value

ANDROMEDA primary endpoint*

D-VCd

111 (56.9)

5.68 (3.58−9.00)

< 0.0001

VCd

36 (18.7)

iFLC ≤ 20 mg/L

D-VCd

139 (71.3)

9.8 (6.1−15.7)

< 0.0001

VCd

39 (20.2)

dFLC < 10 mg/L

D-VCd

128 (65.6)

4.3 (2.8−6.6)

< 0.0001

VCd

59 (30.6)

ISA criteria

D-VCd

96 (49.2)

3.25 (2.09−5.06)

< 0.0001

VCd

45 (23.3)

 

Secondary endpoint MOD-PFS

Defined as the time until whichever event comes first, out of:

  • Death
  • Cardiac deterioration requiring interventions such as transplant, left ventricular assist device or intra-aortic balloon pump
  • End-stage kidney disease requiring renal transplant or hemodialysis
  • Hematologic disease progression per consensus guidelines2

In the D-VCd group, MOD-PFS events were recorded in 17.4% of patients compared with 27.5% in the VCd group.  

  • Out of the patients treated with D-VCd that experienced a MOD-PFS event, the most common events were death (73.5%), hematologic disease progression (23.5%), followed by end-stage heart or kidney failure in only 2.9%.
  • In the VCd group hematologic disease progression was the most frequent (47.2%), followed by death (39.6), and cardiac or renal end-stage failure (13.2%).
  • Overall, there were 27 deaths in the D-VCd cohort and 29 in the VCd group.

The deep hemCR responses were associated with increased MOD-PFS in the D-VCd cohort compared with VCd alone. Patients treated with D-VCd experienced a significant delay in organ deterioration, hematologic disease progression, or death (HR 0.58, 95% CI [0.36-0.93]; p = 0.0211).

Conclusion

D-VCd is the first therapeutic combination approved for patients with newly diagnosed AL amyloidosis. Adding daratumumab to the standard of care VCd consistently improved hemCR and MOD-PFS compared with VCd alone. The accelerated approval should aid efficient development and allow patients to receive treatment as soon as possible.

To read more about AL amyloidosis, please see this month’s Editorial Theme covering its incidence, diagnosis, and treatment. Click here to find the first in our series of articles.

  1. U.S. Food and Drug Administration. FDA grants accelerated approval to Darzalex Faspro for newly diagnosed light chain amyloidosis. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-darzalex-faspro-newly-diagnosed-light-chain-amyloidosis. Published Jan 15, 2021. Accessed Jan 18, 2021.
  2. Janssen: Pharmaceutical Companies of Johnson & Johnson. Janssen seeks expanded use of DARZALEX®▼ (daratumumab) subcutaneous formulation for the treatment of patients with light chain (AL) amyloidosis. https://www.janssen.com/emea/sites/www_janssen_com_emea/files/janssen_seeks_expanded_use_of_darzalexrv_daratumumab_subcutaneous_formulation_for_the_treatment_of_patients_with_light_chain_al_amyloidosis.pdf. Published Nov 5, 2021. Accessed Jan 20, 2021.
  3. Comenzo RL, Kastritis, Palladini G, et al. Reduction in absolute involved free light chain and difference between involved and uninvolved free light chain is associated with prolonged major organ deterioration progression-free survival in patients with newly diagnosed AL amyloidosis receiving bortezomib, cyclophosphamide, and dexamethasone with or without daratumumab: Results from Andromeda. Oral Abstract #552. 62nd ASH Annual Meeting & Exposition; Dec 7, 2020; Virtual.

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