MASTER trial | Monoclonal antibody-based quadruplet regimen (Dara-KRd) with MRD–based response-adapted therapy in patients with NDMM

Update: Find the latest report on the MASTER trial, here.

The MM Hub was delighted to be present at the 61^st American Society of Hematology (ASH) Annual Meeting held in Orlando, FL, US, from 7–10 December 2019. On Monday 9^th 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 criteria 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

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

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

AE, adverse event; IRR,  infusion-related reaction
	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