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Melflufen plus dexamethasone for relapsed/refractory multiple myeloma — results from a phase I/II study

Apr 22, 2020

Melphalan flufenamide (melflufen) is a first-in-class, peptide–drug conjugate that induces irreversible DNA damage in multiple myeloma (MM) cells. 1,2The alkylating activity of melflufen is initiated by aminopeptidases, which are often overexpressed by MM cells. Melflufen demonstrates favorable selectivity and is highly penetrative of MM cells as a result of its high lipophilicity. 3

Promising early efficacy has been reported in a number of ongoing clinical trials investigating melflufen for the treatment of relapsed and/or refractory MM (RRMM). 3The MM Hub previously covered the results from the phase II HORIZON (OP-106) trial( NCT02963493), which explored the safety and efficacy of melflufen in combination with dexamethasone (dex) in patients with RRMM. The results from the primary analysis of an open-label, multicentre, international, phase I–II study (O-12-M1; NCT01897714), investigating melflufen both with or without dex for the treatment of patients with RRMM, have since been published by Paul Richardsonand colleagues — below is a summary. 3

Study design

Patient eligibility

  • Adult patients with RRMM (N = 75) following treatment with2 lines of prior therapy, including an immunomodulatory drug (lenalidomide) and a proteasome inhibitor (bortezomib), were enrolled
  • Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2,adequate organ function, progression to most recent anti-myeloma therapy, and measurable disease defined as ≥ 1 of
    • serum monoclonal protein ≥ 0.5 g/dL
    • urine monoclonal protein200 mg/24 hours
    • serum immunoglobulin free light chain (FLC)10 mg/dL and abnormal kappa/lambda FLC ratio
  • Eligible patients were assigned to the phase I (n = 23) and/or phase II (n = 58) portion of the study and received treatment with melflufen± dex in 21-day cycles* as per the dosing schedules illustrated in Table 1
    • Melflufen was administered as an intravenous infusion for 30 minutes on Day 1 of each cycle
      • Dose reductions were permitted after Cycle 1 in phase I and in any cycle of phase II, to a minimum of 15 mg
    • Dex (40 mg) was given orally, weekly
      • Patients unable to tolerate dex discontinued dex and could remain on single-agent melflufen at the discretion of the investigator
    • Patients were treated at three sites in the United States of America and one site in each of Italy, Denmark, Sweden, and the Netherlands

*On May 28, 2015, the cycle length in phase II was increased to 28 days

Phase I

  • Primary objective: establish the maximum tolerated dose (MTD) of melflufen when combined with dex
  • Secondary objective: define any dose-limiting toxicities (DLT)

  Phase II

  • Primary objective: evaluate the overall response rate (ORR) and clinical benefit rate (CBR) to melflufen ± dex at the MTD determined in phase I
  • Secondary objectives:
    • determine complete response (CR), stringent CR (sCR), partial response (PR), very good PR (VGPR), time to progression, duration of response, progression-free survival (PFS) and overall survival (OS)
    • assess the safety and tolerability of melflufen± dex at the MTD
  • This primary analysis was conducted in
    • all-treated patients
    • efficacy evaluable population (patients who received2 doses of melflufen with a response assessment at baseline)

Results

Patient characteristics

  • Data collection cutoff: November 9, 2017
  • Baseline patient characteristics according to melflufen dosing schedules across the phase I and phase II studies are presented in Table 1

Table 1. Patient characteristics by treatment regimen 3

dex, dexamethasone; IMiD, immunomodulatory drug; IQR, interquartile range, PI, proteasome inhibitor

*Melflufen IV infusion on Day 1 of 21–day cycles + 40 mg oral dex weekly.

40mg melflufen IV on Day 1 in 21–day cycles± 40 mg oral dex weekly. Cycle length was increased to 28 days on May 28, 2015.

Patients harbored ≥ of the following mutations: del (17p); loss of signals for TP53; loss of 17p13; t (4;14); t (14;16); t (14;20); gain (1q); +1Q; +1Q22; 3 1p and 1q signals; 3 1q signals; 3 signals for 1p/1q; extra signals for CCND1; a non-hyperdiploid karyotype; karyotype del (13); –13 or 13 Q MINUS.  

 

Phase I*

Phase II

Melflufen dose

15 mg

(n = 4)

25 mg

(n = 7)

40 mg

(n = 6)

55 mg

 (n = 6)

Melflufen + dex

(n = 45)*

Melflufen

(n = 13)

Median age, years (IQR)

68.0 (63.25–69.75)

69.0 (58.50–75.0)

62.0 (55.25–65.75)

67.5 (62.50–68.75)

66.0 (59.0–70.0)

61.0 (58.0–70.0)

Sex, male %

50

43

67

50

67

62

Median number of previous therapies (IQR)

4.0 (3.0–5.5)

4.0 (4.0–7.5)

4.0 (4.0–6.25)

6.5 (4.5–7.75)

4.0 (3.0–5.0)

5.0 (4.0–6.0)

Double refractory to a PI and an IMID®, %

50

57

67

100

67

92

High-risk cytogenetics , %

75

43

17

50

44

46

Phase I

  • MTD: 40 mg melflufen on Day 1 plus 40 mg oral dex weekly
  • DLTs
  • No DLTs were recorded in the 15 mg, 25 mg, or 40 mg melflufen cohorts
  • Four patients in the 55 mg cohort experienced DLTs in their first treatment cycle; Grade 4 neutropenia occurred in in all four patients, with Grade 4 thrombocytopenia also reported in three of these patients
  • Due to the DLTs reported at 55 mg, the planned dose of 70 mg was not tested
  • Twenty-one patients discontinued, predominantly due to disease progression (52%) and adverse events (35%)
  • All patients experienced AEs and50% of patients in each cohort developed Grade3 AEs ( Table 2)
  • A proportion of patients discontinued treatment due to treatment-emergent AEs (TEAEs), and serious TEAEs were observed in both treatment cohorts ( Table 2)
  • One death, due to fatal bacteremia (Cycle 2, Day 28), that occurred in a patient in the 25 mg cohort was considered to be related to study treatment

Table 2.Grade ≥ 3 AEs and TEAEs by treatment regimen 3

AE, adverse event; TEAE, treatment emergent adverse event

 

Melflufen dose

15 mg (n = 4)

25 mg (n = 7)

40 mg (n = 6)

55 mg (n = 6)

Grade ≥ 3 AEs, %

50

71

83

100

Serious TEAEs, %

50

14

17

50

Most common serious TEAEs, n

Neutropenia

Pneumonia

 

0

1

 

0

0

 

0

0

 

3

2

Discontinuation due to TEAEs, n

TEAE leading to discontinuation, n

Thrombocytopenia Neutropenia

0

0

0

1

1

1

3

3

1

3

2

1

Phase II

  • Patient responses to melflufen± dex are presented in Table 3
    • Six of the 45 patients receiving melflufen +dex were from the phase I portion
    • In the combination arm, 62% started the treatment with 21-day cycles
  • The majority of patients in the combination (n = 34; 76%) and single (n = 11; 85%) cohorts received ≥ 2 doses of melflufen, constituting the efficacy evaluable population
    • ORR: 41% (14/34)
    • CBR: 65% (22/34)
  • Patient responses in the efficacy evaluable combination cohort were superior to those in the all-treated population ( Table 3)
  • The most common reasons for treatment discontinuation in single vscombination cohorts wereAEs (40% vs23%) and disease progression (29% vs31%)
  • Enrollment in the single agent cohort was stopped early, with patients in this cohort allowed to receive 40 mg of dex at the discretion of the investigator

  Table 3. Patient responses to melflufen± dex and treatment cohort characteristics 3

CBR, clinical benefit rate; CR, complete response; dex, dexamethasone; IQR, interquartile range; MR, minimal response; NR, not reached; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; VGPR, very good partial response

 

Melflufen + dex (n = 45)

Melflufen (n = 13)

Patient response

ORR, %

95% CI

31

18.2–46.6

8

0.2–36.0

CBR, %

95% CI

   CR

   VGPR

   PR

   MR

   SD

   PD

   Missing

49

33.7–64.2

0

11

20

18

27

16

9

23

5.0–53.8

0

0

8

15

69

8

0

Median follow-up, months

27.9

17.3

 

Median PFS, months

95% CI

5.7

3.7–9.2

4.4

2.8–7.6

OS, months (range)

20.7 (11.8 – NR)

15.5 (4.9 – NR)

Study characteristics

Median number of cycles (IQR)

5 (2–7)

3 (2–7)

Median duration of cycles, months (IQR)

4.1 (1.4–7.4)

Patients receiving ≥ 8 cycles, %

22

23

  Adverse events

  • Twenty-four serious TEAEs were reported in 38% of patients in the combination cohort ( Table 4)
  • Out of four deaths occurring in the combination cohort, two were considered to be melflufen-related and occurred after the first dose:
    • one due to neutropenic sepsis and one due to Escherichia colisepsis
    • both occurred in the setting of disease progression
  • Treatment cycle length influenced the establishment of Grade 4 thrombocytopenia
    • 1 event occurred in 32% of patients on a 21-day schedule vsnone in the patients on a 28-day schedule

  Table 4. Grade≥ 3 AEs and TEAEs by treatment regimen 3

AE, adverse event; dex, dexamethasone; WBC, white blood cell

 

Melflufen + dex (n = 45)

Melflufen (n = 13)

Most common TEAEs, n (%)

Thrombocytopenia

Neutropenia

 

26 (58)

26 (58)

 

Serious TEAEs related to melflufen, n (%)

Thrombocytopenia

Pneumonia

Neutropenia

Febrile neutropenia

Diarrhea

Pyrexia

Sepsis

Pneumonitis

Decreased WBC count

12 (27)

0

4

2

2

2

2

1

1

0

4 (31)

2

1

1

0

0

0

1

0

1

Discontinuation due to TEAEs, n (%)

17 (38)

3 (23)

  Conclusion

  • The study identified a melflufen treatment regimen that was well tolerated in patients with RRMM: 40 mg melflufen on Day 1 of a 28-day cycle plus 40 mg oral dex weekly
  • The study suggests that clinical improvement and long-term benefit is achievable with melflufen plus weekly dex for patients with RRMM
  • The safety profile of melflufen was consistent with previous studies and no additional toxicities were reported
    • The most commonly observed toxicities were reversible and clinically manageable thrombocytopenia and neutropenia
  • Melflufen plus dex may be a viable approach for patients with RRMM who do not have alternative treatment options
  1. About melflufen. https://oncopeptides.se/en/about-melflufen/ . Accessed April 8, 2020.

  2. Wickström M, Nygren P, Larsson R, et al. Melflufen - a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017;8(39):66641–66655. DOI: 18632/oncotarget.18420

  3. Richardson PG, Bringhen S, Voorhees P, et al. Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12 -M1): a multicentre, international, open-label, phase 1-2 study. Lancet Haematol. 2020. DOI: 1016/S2352-3026(20)30044-2