Patients eligible for transplant

Monoclonal antibody-based quadruplet regimen with daratumumab, carfilzomib, lenalidomide, and dexamethasone with MRD–based response-adapted therapy in patients with newly diagnosed MM

The MM Hub was delighted to be present at the 61st American Society of Hematology (ASH) Annual Meeting held in Orlando, FL, US, from 7–10 December 2019. On Monday 9th December, an oral abstract was presented by Luciano J. Costa  from the O’ Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Vestavia, AL, entitled (Abstract #860): Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, autologous transplantation and post-transplant, response-adapted, measurable residual disease (MRD)-based Dara-Krd consolidation in patients with newly diagnosed multiple myeloma (NDMM).1 This article is based on data presented at ASH and may supersede the data in the published abstract.

Trial design
  • Key eligibility criterial for the MASTER trial (NCT03224507) included:
    • NDMM with measurable disease
    • Untreated patients (up to 1 cycle of bortezomib, cyclophosphamide, and dexamethasone [VCD] allowed)
    • Creatinine clearance ≥ 40mL/min,
    • No significant cardiopulmonary disease, concomitant or recent malignancy
    • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2
    • Age >18 years
  • Treatment regimen:
    • Cycles consisted of daratumumab 16mg/kg intravenously (IV) Days 1, 8, 15, 22 (Days 1, 15 Cycle 3–6; Day 1 Cycles > 6), carfilzomib 56mg/m2 IV Days 1, 8, 15, lenalidomide 25mg orally (PO) days 1–21, and dexamethasone 40mg PO/IV Days 1, 8, 15, 22 repeated every 28 days
    • Patients received 4 cycles of Dara-KRd as induction, ASCT, and received 0, 4 or 8 cycles of Dara-KRd consolidation, according to MRD status at each phase of therapy.
    • MRD was evaluated at the end of induction, post-transplant, and during each 4-cycle block of Dara-KRd consolidation
    • Patients received therapy until achievement of two consecutive MRD reads < 10-5 (confirmed MRD-negative remission; e.g., post-induction and post-transplant or post-transplant and during consolidation)
    • Confirmed MRD-negative patients received no further therapy and were surveilled for MRD resurgence 6 and 18 months after treatment discontinuation
    • Patients who didn’t meet the criteria for confirmed MRD-negative remission received lenalidomide maintenance
  • Hypothesis: therapy with Dara-KRd, autologous stem cell transplant (ASCT), and MRD-based, response-adapted Dara-KRd consolidation would reach ≥ 75% MRD-negative complete response (CR)
  • Trial endpoints:
    • Primary: rate of MRD-negative responses (< 10-5) using next generation sequencing (NGS; clonoSEQ®)
    • Secondary: toxicity of Dara-KRd, frequency of imaging plus MRD-negative CR, impact of ASCT on MRD, traditional International Myeloma Working Group (IMWG) response and outcomes of observation without maintenance upon confirmed MRD-negativity
    • Exploratory: MRD-negativity rates by NGS with a threshold of 10-6
Key results
  • In total 81 patients have been enrolled onto the trial (see Table 1 for patient baseline characteristics)
  • Median follow-up of 7.4 months (2.1–20.0)

Table 1. Baseline characteristics

 

Enrolled patients with at least 2 cycles of induction

(N= 81)

Post-transplant patients

(N= 42)

Male

41 (51%)

22 (52%)

Median age (range)

≥70 years

61 (36–78)

18 (22%)

61 (36–78)

10 (24%)

Race/ethnicity

White

Minority

 

64 (79%)

17 (21%)

 

31 (74%)

11 (26%)

ECOG PS

0–1

2

 

64 (79%)

17 (21%)

 

29 (69%)

13 (31%)

ISS  

1

2

3

 

32 (40%)

33 (41%)

16 (20%)

 

14 (33%)

18 (43%)

10 (24%)

High-risk FISH

[t(4;14), t(14;16) or del17p]

23 (28%)

12 (29%)

High-risk FISH incl. +1q

[+1q, t(4;14), t(14;16), del17p]

42 (52%)

22 (52%)

LDH>ULN

15 (19%)

9 (21%)

R-ISS

1

2

3

 

25 (31%)

43 (53%)

13 (16%)

 

12 (29%)

21 (50%)

9 (21%)

ISS, International Staging System; FISH, fluorescent in situ hybridization; LDH, lactate dehydrogenase; R-ISS, revised International Staging System; ULN, upper limit of normal

Best MRD responses
  • MRD was trackable by NGS in 78/81 patients (96%) and 100% of the expected MRD datapoints were successfully obtained

The following results are presented as post induction, post transplant and at MRD-directed consolidation:

  • MRD-negative remission (< 10-5) rate was 40%, 73% and 82%
  • Rates of MRD < 10-6 were 27%, 47% and 63%
  • MRD-negative remission (< 10-5) rate by cytogenetic subset:
    • Standard-risk: 41%, 77% and 81%
    • High-risk: 38%, 67% and 83%
  • Rates of MRD < 10-6 by cytogenetic subset:
    • Standard-risk: 33%, 50% and 73%
    • High-risk: 14%, 42% and 42%
Best IMWG responses
  • After 2 cycles all patients had responded (partial response [PR] or very good partial response [VGPR])
    • Post-induction Cycle 2 (N= 81): 33% patients PR and 67% VGPR
    • Post-induction Cycle 4 (N= 70): 10% patients PR, 48% VGPR, 3% CR, and 39% stringent CR (sCR)
    • Post transplant (N= 42): 17% patients VGPR, 2% CR and 81% sCR
    • MRD-based consolidation (N= 42): 5% patients VGPR, and 95% sCR
  • 1 patient progressed at post-ASCT evaluation
  • sCR rate by cytogenetic subset can be seen in Table 2

Table 2. sCR rates

 

Post induction

Post transplant

MRD-based consolidation

All patients

39% (N= 70)

81% (N= 42)

95% (N= 42)

Standard risk

44% (N= 50)

79% (N= 29)

97% (N= 29)

High risk

25% (N= 20)

85% (N= 13)

91% (N= 13)

Observation and MRD surveillance
  • In total, 26 patients (19 standard risk and 7 high risk) have reached confirmed MRD-negativity and entered observation/MRD surveillance
  • With a median follow-up on observation of 4.9 months (0.2–12.2), no patients have relapsed or had resurgence of MRD
Safety summary
  • No patients discontinued therapy due to toxicity
  • Two patients died:
    • One patient died due to metapneumovirus pneumonia nine days after transplant
    • One patient died suddenly, unwitnessed, 58 days post transplant
  • There were 18 serious adverse events (SAEs): pneumonia (n= 5), fever and neutropenia (n= 2), pulmonary embolism (n= 1), atypical hemolytic uremic syndrome (n= 1), infusion-related reaction (IRR; n= 1), atrial fibrillation (n= 1), and other (n= 7)
  • The most common treatment-emergent AEs (including uncommon AEs of special interest) can be seen in Table 3

Table 3. Most common treatment-emergent AEs

 

All grades

Grade ≥3

Hematologic

Lymphopenia

Neutropenia

Thrombocytopenia

Anemia

 

 

31 (38%)

28 (35%)

16 (20%)

15 (19%)

 

19 (23%)

20 (25%)

4 (5%)

9 (11%)

Non-hematologic

Musculoskeletal pain

Infections

Fatigue

Rash/cutaneous AE

Nausea/vomiting

IRR

Constipation

Peripheral neuropathy

Dyspnea

Hypertension

Venous thromboembolism

 

50 (62%)

47 (58%)

45 (56%)

45 (56%)

41 (51%)

31 (38%)

26 (32%)

23 (28%)

19 (23%)

16 (20%)

7 (9%)

 

0

10 (12%)

1 (1%)

3 (4%)

0

2 (2%)

0

2 (2%)

1 (1%)

3 (4%)

1 (1%)

Conclusions
  • This is the first report of a monoclonal antibody-based quadruplet regimen with MRD-based response-adapted therapy in NDMM
  • Dara-KRd induction, ASCT and Dara-KRd consolidation guided by MRD was shown to be feasible, with an acceptable safety profile and leading to rapid responses with a high proportion of patients achieving CR/sCR
  • Study accrual is continuing with the aim of reaching 123 patients to further inform outcomes by cytogenetic subsets
References
  1. Costa LJ, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, autologous transplantation and post-transplant, response-adapted, measurable residual disease (MRD)-based Dara-Krd consolidation in patients with newly diagnosed multiple myeloma (NDMM). 2019 Dec 9; Abstract #860: ASH 61st Annual Meeting and Exposition, Orlando, FL

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