General MM

Daratumumab for smoldering multiple myeloma — results from the phase II CENTAURUS study

Although most patients with high- and intermediate-risk smoldering multiple myeloma (SMM) progress to malignant multiple myeloma (MM), the standard of care (SoC) treatment for the condition is still active monitoring. It has been hypothesized that by treating SMM, the onset of MM could be delayed.1 The MM Hub have previously covered this controversial topic in the form of expert debates such as that held at the 5th World Congress on Controversies in Multiple Myeloma (COMy), between Sundar Jagannath and Mario Boccadoro, available here, and a discussion between Maria Victoria Mateos and Francesca Gay, available at the end of this article.

A number of trials have attempted to determine if there is a more effective treatment for SMM besides observation. Firstly, the phase III, randomized QuiRedex study (NCT00480363) evaluated the effectiveness of lenalidomide plus dexamethasone (Rd) at delaying progression of SMM to symptomatic MM. Rd reduced the proportion of patients who developed MM (39% vs 86%) and improved overall survival (OS) compared to observation, however treatment-emergent adverse events (TEAEs) were a major concern. The most commonly observed Grade 3 adverse events (AEs) associated with the treatment regimen were infection, asthenia, neutropenia, and skin rash. Although no Grade 4 AEs were apparent following treatment induction, one patient died as a result of a respiratory infection.2

Secondly, the clinical benefit of lenalidomide monotherapy is being investigated in the ongoing E3A06 study (NCT01169337), which has uncovered the value of lenalidomide over observation alone in high-risk SMM patients.3 The MM Hub reported the interim results of the study presented at the 2019 American Society of Clinical Oncology (ASCO) meeting and a summary can be found here. Data from these studies highlight that earlier intervention in SMM could be clinically beneficial, though the toxicities associated with the Rd regimen have led to the search for a safer therapeutic intervention.

The anti-CD38 monoclonal antibody, daratumumab (dara), demonstrated deep and durable responses in patients with heavily pre-treated relapsed and/or refractory MM in the GEN501 (NCT00574288) and SIRIUS (NCT01985126) clinical trials.4,5 The CENTAURUS (NCT02316106) study set out to determine whether these positive outcomes would translate in patients with intermediate- or high-risk SMM. C. Ola Landgren of the Memorial Sloan Kettering Cancer Center, US, and colleagues recently reported the data from the phase II, open label CENTAURUS study investigating the efficacy and safety of three dara dosing schedules for patients with SMM. We hereby present a summary.

The MM Hub previously covered the topic of SMM as an educational theme, read more here.

Study design
  • Patients aged ≥ 18 years, diagnosed with intermediate- or high-risk SMM for < 5 years (n = 123) were randomly assigned (1:1:1) to receive dara (16mg/kg intravenously) in one of three distinct dosing regimens in 8-week cycles:

    • Extended intense (intense; n = 41): weekly in Cycle 1, every two weeks in Cycles 2 and 3, every four weeks in Cycles 4—7, and every eight weeks in Cycles 8—20

    • Extended intermediate (intermediate; n = 41): weekly in Cycle 1 and every eight weeks in Cycles 2—20

    • Short (n = 41): weekly for one cycle

  • Co-primary endpoints: complete response (CR) rate including CR rate > 15%, and progressive disease (PD)/death rate per patient-year

    • CR rate evaluated six months after randomization of last patient (cut-off: February 8, 2017) and PD/death rate calculated 12 months after last randomization (cut-off August 8, 2017)

  • Secondary endpoints: progression-free survival (PFS), overall response rate (ORR), OS, and biochemical or diagnostic PFS

Results

Patient characteristics

  • Patients (N = 255) were screened from 47 sites across Europe, North America, the Middle East and the Asia Pacific region

  • Of these patients, 132 were ineligible for the study

    • The leading rationale for patient exclusion was presentation of active MM

  • 123 eligible patients were enrolled and randomized to an intense, intermediate or short dara dosing schedule (Table 1)

Table 1. Baseline demographics and disease characteristics by dara dosing schedule

Dara dosing schedule

Intense (n = 41)

Intermediate (n = 41)

Short (n = 41)

Median age, years (range)

65.0 (34–79)

62.0 (31–81)

59.0 (39–78)

ECOG performance status score, %

0

1

 

78.0

22.0

 

82.9

17.1

 

85.4

14.6

Risk factors at screening, %

< 2

≥ 2

 

19.5

80.5

 

19.5

80.5

 

17.1

82.9

plasma cells in bone marrow, %

≥ 10% to < 20%

≥ 20% to < 40%

≥ 40% to < 60%

 

43.9

36.6

19.5

 

41.5

41.5

17.1

 

51.2

31.7

17.1

Median (range) time from SMM diagnosis to randomization, months

6.47 (0.4–46.2)

5.52 (0.7–46.7)

7.43 (1.0–56.0)

ECOG, Eastern Cooperative Oncology Group; SMM, smoldering multiple myeloma

Primary efficacy endpoints

  • Patient responses to the three dara dosing regimens were recorded at the primary analysis (clinical cut-off, August 8, 2017, median follow-up: 15.8 months; Table 2) and long-term follow-up (clinical cut-off June 29,2018, median 25.9 months)

    • Median duration of treatment (intense vs intermediate vs short), months: 25.8 vs 25.8 vs 1.6

    • Discontinuations (intense vs intermediate vs short): 7 vs 9 vs 2

      • Mainly due to PD

  • There were no significant differences in CR rate between dara dosing schedules (Table 2)

  • The co-primary endpoint of CR rate > 15% was not met in either analysis

  • The PD/death rates per patient year (Table 2) at longer follow-up show the study met the co-primary endpoint of median PFS ≥ 24 months

Table 2. Primary endpoint analysis of patients receiving intense, intermediate and short dosing schedules of dara at two follow-up periods

 

Intense (n = 41)

Intermediate (n = 41)

Short (n = 41)

Primary analysis, median 15.8 months follow-up

CR, %

90% CI

p value

2.4

0.1—11.1

0.9895

4.9

0.9—14.6

0.9569

0

-

-

PD/death rate*

80% CI

p value

0.055

0.014–0.096

< 0.0001

0.102

0.044–0.160

< 0.0001

0.206

0.118–0.295

0.0213

Long-term analysis, median 25.9 months follow-up

CR, %

90% CI

p value

4.9

0.9–14.6

0.9569

9.8

3.4–21.0

0.7567

0

-

-

PD/death rate*

80% CI

p value

0.059

0.025–0.092

< 0.0001

0.107

0.058–0.155

< 0.0001

0.150

0.089–0.211

< 0.0001

CR, complete response; CI, confidence interval; PD, progressive disease; PFS, progression-free survival

*Statistical significance

Secondary efficacy endpoints

  • OS data are immature; follow-up is ongoing

  • Median PFS was not reached in any treatment arm

  • PFS rates by diagnostic criteria (intense vs intermediate vs short) were:

    • 12 month: 95.1% vs 87.5% vs 84.0%

    • 24 month: 89.9% vs 82.0% vs 75.3%

  • ORR (intense vs intermediate vs short): 56.1% vs 53.7% vs 37.5%

Safety

  • The safety population consisted of 122 patients evaluated at the long-term follow-up

  • AEs were observed in 100% of patients in the intense and intermediate arms, and 92.5% in the short arm (Table 3)

  • Most infusion-related reactions were associated with the first infusion

  • AEs leading to discontinuations included pneumonia, thrombocytopenia, breast disorder, balance disorder, unstable angina and hypomania

Table 3. Summary of the safety data from patients receiving intense, intermediate and short dosing schedules of dara at the long-term follow-up

 

 

Intense (n = 41)

Intermediate (n = 41)

Short (n = 40)a

Median duration of treatment, months (range)

25.8 (1.0–33.1)

25.8 (1.9–33.1)

1.6 (0.1–1.9)

Grade 3/4 TEAEs, %

Hypertension

Hyperglycemia

 

43.9

7.3

2.4

26.8

4.9

4.9

15.0

2.5

0

Serious AEs, %

Pneumonia

31.7

4.9

14.6

2.4

10.0

2.5

Within the first eight weeks

12.2

0

10.0

Related to daratumumab

0

2.4

2.5

Discontinued treatment due to TEAE, %

7.3

2.4

5.0

Related to daratumumab

2.4

0

2.5

Any grade IRR rate, %

56.1

43.9

55.0

AE, adverse event; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event; URT, upper respiratory tract

aOne patient in the short arm was randomized but did not receive study treatment

Conclusions
  • Dara failed to induce a CR of > 15% in any regimen, yet improved PD/death rate and ORRs

  • The study suggests that dara may not be able to eradicate SMM but has some single agent activity

  • Extended treatment with dara could be more effective at delaying diagnostic and biochemical progression compared to short-term dosing

  • While the data from this study remain inconclusive, they suggest that dara is tolerable in intermediate- and high-risk SMM, providing the grounds for further investigation, particularly in combined dosing regimens

  • These data support an ongoing phase III study (NCT03301220) investigating whether dara prolongs PFS compared with active monitoring in participants with high-risk SMM

 



References
  1. Landgren CO. et al. Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS). Leukemia. 2020 Feb 5. DOI:10.1038/s41375-020-0718-z
  2. Mateos MV. et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Jul 8; 17(8):1127–36. DOI: 10.1016/S1470-2045(16)30124-3
  3. Lonial S. et al. E3A06: Randomized phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk smoldering multiple myeloma. Journal of Clinical Oncology. 2019 May 20; 8001–8001. DOI: 10.1200/JCO.2019.37.15_
  4. Lokhorst HM. et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015 Sept 24; 373:1207–19. DOI: 10.1056/NEJMoa1506348
  5. Lonial S. et al. Daratumumab monotherapy in patients with treatment refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9; 387(10027):1551–60. DOI: 10.1016/S0140-6736(15)01120-4
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