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Daratumumab plus VRd in transplant-eligible patients with newly diagnosed MM

May 14, 2020

The combination of bortezomib, lenalidomide, and dexamethasone (VRd), a standard induction regimen for patients with newly diagnosed multiple myeloma (NDMM), improved progression free survival (PFS) and overall survival (OS) in NDMM patients undergoing autologous stem cell transplant (ASCT). The phase II GRIFFIN study (MMY2004,  NCT02874742 ) evaluated whether the addition of daratumumab to VRd (D-VRd), a monoclonal CD38 antibody, followed by ASCT, could further enhance the depth of response in this setting. Previously reported  results of the safety run-in phase of the study  demonstrated that the regimen is safe and well-tolerated, with the depth of response improving over time. Peter Voorhees and colleagues recently published in  Blood the updated efficacy and safety results of the trial. 1

Study design

The multicenter, randomized, open-label, active-controlled study enrolled patients between December 20, 2016, and April 10, 2018. Key eligibility criteria included:

  • 18-70 years of age
  • NDMM defined by International Myeloma Working Group (IMWG) criteria
  • Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2
  • Eligible for high-dose therapy and ASCT

Patients stratified by International Staging System (ISS) disease stage and creatinine clearance were randomized 1:1 to receive D-VRd or VRd. Patients in both treatment groups received four 21-day induction cycles and two 21-day consolidation cycles of oral lenalidomide (25 mg daily on Days 1–14), subcutaneous bortezomib (1.3 mg/m 2on Days 1, 4, 8 and 11), and oral dexamethasone (20 mg on Days 1, 2, 8, 9, 15, and 16).

Patients in the D-VRd group received intravenous daratumumab (16 mg/kg) on Days 1, 8, and 15 of cycles 1–4 and Day 1 of post-ASCT consolidation cycles (cycles 5– 6). From cycle 7 until disease progression or ≤ 2 years, all patients received oral lenalidomide (10 mg daily on Days 1-21, increasing to 15 mg after 3 cycles, if tolerated) as maintenance therapy (28-day cycles). Additionally, patients in the D-VRd group received intravenous daratumumab (16 mg/kg) on Day 1 every 8 weeks or every 4 weeks. Following the completion of study maintenance therapy, patients can continue on lenalidomide.

Patients underwent stem cell mobilization after 4 cycles of induction therapy, followed by high-dose therapy (HDT; melphalan 200 mg/m 2) and ASCT. Consolidation therapy began 60-100 days after transplantation and maintenance therapy within 14 days of post-consolidation disease evaluation.

Study endpoints included:

  • Primary: stringent complete response (sCR) rate after completion of post-ASCT consolidation
  • Secondary: minimal residual disease (MRD)-negativity rate (< 1 x 10 5of nucleated cells) assessed by next-generation sequencing (NGS), and safety

Results

Patients characteristics

  • Out of 292 screened patients, 16 took part in the safety run-in phaseand 207 were randomized in the second part of the study to:
    • The D-VRd group: 104 patients, with 99 patients receiving ≥ 1 dose of the treatment and completing ≥ 1 disease assessment included in the primary efficacy analysis
    • The VRd group: 103 patients, with 102 patients receiving ≥ 1 dose of the treatment, including 97 with completing ≥ 1 disease assessment included in the primary efficacy analysis
  • The baseline patient characteristics were similar between the groups and are presented in Table 1

Table 1.Baseline patient and disease characteristics

D-VRd, daratumumab + VRd; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; VRd, bortezomib, lenalidomide, and dexamethasone

*ECOG performance status was assessed in 101 patients from the D-VRd group and 102 patients from the VRd group

cytogenetic risk profile was assessed in 98 patients from the D-VRd group and 97 patients from the VRd group

 

D-VRd (n = 104)

VRd (n = 103)

Age, years

Median (range)

< 65, %

 

59 (29–70)

73.1

 

61 (40–70)

72.8

ECOG performance status, %*

0

1

2

 

38.6

50.5

10.9

 

39.2

51.0

9.8

ISS disease stage, %

I

II

III

Missing

 

47.1

38.5

13.5

1.0

 

48.5

35.9

13.6

1.9

Cytogenetic risk profile, %

Standard risk

High risk

 

83.7

16.3

 

85.6

14.4

  • The median duration of treatment in the D-VRd group and the VRd group was 21.9 months (range, 1.1–29.7) and 19.5 months (range, 0.5–29.7), respectively
  • Less patients discontinued treatment in the D-VRd group compared to the VRd group (16.3% vs7%), with the main reasons for discontinuation including
    • progressive disease (6.7% vs7%)
    • patient withdrawal (3.8% vs7%)
    • adverse events (2.9% vs7%)
    • investigator discretion (2.9% vs7%)

Efficacy

  • Responses were significantly better in the D-VRD group compared to the VRd group. Results of primary analysis after a median follow up of 13.5 months are presented in Table 2
  • Responses deepened over time, after a median follow up of 22.1 months (0–30.0)
    • sCR was 62.6% in the D-VRd group and 45.4% in the VRd group (odds ratio, 1.98; 95% CI, 1.12–3.49; p = 0.0177)
    • Complete response (CR) or better was 79.8% in the D-VRd group and 60.8% in the VRd group (odds ratio, 2.53; 95% CI, 1.33–4.81; p = 0.0045)

Table 2.Primary analysis summary of responses by the end of consolidation

CI, confidence intervals; CR, complete response; D-VRd, daratumumab + VRd;  sCR, stringent CR; SD, stable disease; PD, progressive disease; PR, progressive response; VRD, bortezomib + lenalidomide + dexamethasone; VGPR, very good progressive response

Best response

D-VRd (n = 99)

VRd (n = 97)

Odds Ratio (95% CI)

P value

Overall response rate, %

sCR

CR

VGPR

≥VGPR

PR

SD

PD

99

42.4

9.1

39.4

90.9

8.1

1.0

0

91.8

32.0

10.3

30.9

73.2

18.6

7.2

1.0

8.7 (1.08–71.01)

1.57 (0.87–2.82)

 

 

 

0.016

0.068

 

 

0.0014

  • At a median follow up of 22.1 months, more patients had a negative MRD status in the D-VRd group compared with the VRd group (51% vs4%). The results are presented in Table 3
  • The subgroup analysis revealed an improved sCR rate by the end of post-ASCT consolidation and a higher MRD negativity with D-VRd vsVRd in all subgroups except for patients with ISS stage III disease or high-risk cytogenetic abnormalities
  • Median PFS was not reached in either group
    • Estimated 24-month PFS rate was 95.8% (95% CI, 89.2–98.4) in the D-VRd group and 89.8% (95% CI, 77.1–95.7) in the VRd group
  • Median OS was not reached in either group, with follow-up for long-term survival ongoing 

Table 3.MRD status at last follow-up after a median follow up of 22.1 months

CI, confidence interval; CR, complete response; D-VRd, daratumumab + VRd; ITT, intent-to-treat; MRD, minimal residual disease; VRd, bortezomib + lenalidomide + dexamethasone

*< 10 -5of malignant plasma cell

MRD-negative status, n (%)*

D-VRd

VRd

Odds ratio (95%, CI)

P value

ITT population

MRD negative

MRD negative with ≥ CR

 

53/104 (51.0)

49/104 (47.1)

 

21/103 (20.4)

19/103 (18.4)

 

4.07 (2.18–7.59)

3.89 (2.07–7.33)

 

< 0.0001

< 0.0001

In patients achieving ≥ CR

49/79 (62.0)

19/59 (32.2)

3.57 (1.72–7.44)

0.0006

MRD-evaluable population

53/77 (68.8)

21/65 (32.3)

4.47 (2.19–9.11)

< 0.0001

Safety

  • The most common grade 3/4 adverse events (AEs) were neutropenia, lymphopenia, thrombocytopenia, leukopenia, and pneumonia ( Table 4)
  • Serious AEs were more common in the VRd than the D-VRd group (51.0% vs5%), with pyrexia and pneumonia most frequently reported
  • 2% of patients in the D-VRd group and 20.6% in the RVd group had AEs leading to treatment discontinuation, most commonly peripheral sensory neuropathy (D-VRd, 5.1% and VRd, 3.9%)
  • Infections of any grade were more frequent in patients in the D-VRd group than in the VRd group (90.9% vs8%)
  • Stem cell mobilization and collection were performed successfully after the fourth induction cycle, although more patients in the D-VRd group needed plerixafor compared with the VRd group (69.5% vs3%)

Table 4.Grade 3/4 AEs reported in ≥ 3% of patients

AE, adverse event; D-VRd, daratumumab + VRd; NA, not applicable; VRd, bortezomib + lenalidomide + dexamethasone

*There were no grade 4 infusion-related reactions

AE, %

D-VRd (n = 99)

VRd (n = 102)

Hematologic

Neutropenia

Lymphopenia

Thrombocytopenia

Leukopenia

Anaemia

 

41.4

23.2

16.2

16.2

9.1

 

21.6

21.6

8.8

6.9

5.9

Non-hematologic

Pneumonia

Fatigue

Peripheral neuropathy

Diarrhea

Back pain

 

8.1

6.1

7.1

7.1

1.0

 

10.8

5.9

7.8

3.9

3.9

Infusion-related reaction*

6.1

NA

Conclusion

The study has demonstrated that the addition of daratumumab to VRd resulted in increased rates of sCR and MRD negativity, potential surrogate markers of PFS, in patients with transplant-eligible NDMM. The combination had no impact on stem cell mobilization and engraftment. The deepening of responses over time, and acceptable safety profile of the regimen suggest D-VRD could become a new standard of care for transplant-eligible NDMM. This possibility is currently being investigated in a phase III clinical trial PERSEUS (NCT03710603 ).

  1. Voorhees PM, Kaufman JL, Laubach JP, et al. Daratumumab, Lenalidomide, Bortezomib, & Dexamethasone for Transplant-eligible Newly Diagnosed Multiple Myeloma: GRIFFIN. Blood.2020;pii:blood.2020005288. DOI: 10.1182/blood.2020005288