Relapsed/refractory patients

Daratumumab plus carfilzomib and dexamethasone for patients with RRMM

Nearly all patients with multiple myeloma (MM) relapse, despite the introduction of novel compounds improving clinical outcomes. Lenalidomide use as first-line or early maintenance therapy after autologous stem cell transplantation (ASCT), has highlighted the need for effective treatments in lenalidomide-refractory RRMM.

Ajai Chari, from the Tisch Cancer Institute, Mount Sinai School of Medicine, New York, US, and colleagues, conducted a phase Ib study (NCT 01998971) evaluating the use of daratumumab plus carfilzomib with dexamethasone (D-Kd) in patients with RRMM after 1−3 lines of therapy.

The primary endpoints of the study were safety and tolerability of D-Kd. Secondary endpoints included overall survival (OS) and overall response rate (ORR), and exploratory endpoints investigated were progression-free survival (PFS), minimal residual disease (MRD), and pharmacokinetics.

Patient characteristics

Of all patients treated, 62 (73%) had prior ASCT, with 33 (65%) of patients in the lenalidomide refractory arm previously undergoing ASCT. From all enrolled patients, 26 (31%) were refractory to bortezomib, and 21 (41%) of patients in the lenalidomide arm were also refractory to botezomib. 29% of patients were refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), with 43% of lenalidomide-refractory patients were also refractory to PI and IMiD.

Methods
  • Patients treated in 28-day cycles (cycle 1 was 29 days)
  • IV daratumumab, 16mg/kg:
    • Weekly during cycles 1 and 2 (days 1, 8, 15, and 22)
    • Fortnightly during cycles 3−6 (days 1 and 15)
    • Every four weeks thereafter
    • Ten patients received a single first dose on cycle 1, day 1. The remaining patients received split doses: 8mg/kg on days 1 and 2, to collect safety and pharmacokinetic data
  • Carfilzomib, 30-minute infusion weekly, on days 1, 8, and 15 of each cycle (prior to daratumumab on days when both were administered
    • Initial dose of 20mg/m2, escalated to 70mg/m2 if deemed tolerable
  • Dexamethasone, 40mg (20mg if aged >75 years) per week as a single dose
    • On days of infusion, 20mg was administered before and after
Key findings
  • Median follow-up was 16.6 months (range, 0.5−4) overall and 16.4 months (range 0.5−27.2) for the lenalidomide-refractory cohort
  • ORR at median follow-up:
    • 84%, with 33% response of CR or better
    • Lenalidomide-refractory cohort: 79%, with 29% response of CR or better
    • Bortezomib-refractory cohort: 84%, with 20% response of CR or better
  • VGPR, at median follow-up:
    • 71% VGPR or better
    • Lenalidomide-refractory cohort: 69% VGPR
  • OS at 12 months:
    • 82% for all treated patients
    • Refractory subgroups (Lenalidomide, immunomodulatory drug (IMiD)/proteasome inhibitor (PI), bortezomib): 75%
  • Median PFS not reached:
    • 12- and 18-month PFS 74% and 66% respectively
    • Lenalidomide-refractory 12- and 18-month PFS were 65% and 56% respectively

Table 2: A total of 45% of patients discontinued treatment

Discontinued treatment

%

Progressive disease

31

Withdrawal of consent

6

AEs

5

Physician’s decision

2

Death

1

 

Table 3: Grade III/IV AEs experienced by >20% of patients

AE

%

Thrombocytopenia

31

Lymphopenia

24

Anemia

21

Neutropenia

21

 

Table 4: Other treatment-emergent adverse events (TEAEs) experienced by >20% of patients at any grade

TEAE

%

Thrombocytopenia

67

Anemia

51

Nausea

41

Upper respiratory tract infection

41

Asthenia

40

Vomiting

40

Pyrexia

35

Diarrhea

34

Dyspnea

34

Insomnia

32

Neutropenia

31

Hypertension

28

Lymphopenia

27

Cough

2

Headache

25

Back pain

24

 

Conclusion

The study found that the combination of daratumumab and weekly Kd showed efficacy in patients with RRMM, inducing a deep and durable response, regardless of prior lenalidomide exposure. The combination was also well-tolerated. No new safety signals were shown for D-Kd, with low neutropenia rates being observed. As the need for novel or combination therapies continues to rise, daratumumab-based regimens will continue to be clinically investigated.

Reference

Chari A, et al. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2019 Jan 1. DOI: blood-2019000722.

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