Patients eligible for transplant

VRD induction for ASCT: Results from the phase III GEM2012/MENOS65 trial

In September 2019, the results of the phase III PETHEMA/GEM2012/MENOS65 (NCT01916252) were published in Blood1 by Laura Rosinol from Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, ES, and colleagues.

Multiple myeloma (MM) is an incurable disease, so it is crucial for patients to remain in remission for as long as possible through high-quality and sustained responses to treatment. For this, many patients undergo transplantation in order to improve their survival outcomes.1 Induction and consolidation therapies prior to, and following, transplantation  are crucial for its efficacy and success. Multiple regimens have been investigated with the aim of identifying the best combination to serve as the standard of care (SOC) in MM. In this ongoing open-label trial, the efficacy and safety of bortezomib, lenalidomide, and dexamethasone (VRD) as induction therapy prior to autologous stem cell transplantation (ASCT) and as consolidation after transplant was evaluated for its potential to act as the new SOC, in patients with newly diagnosed MM (NDMM).

Study design & baseline characteristics
  • N= 458 patients with NDMM, aged 18-65, with Eastern Cooperative Oncology Group (ECOG) status ≤ 2 or 3 if status due to myeloma
  • Excluded patients; with:
    • Non-secretory MM without measurable plasmacytomas
    • Peripheral neuropathy of grade ≥ 2 in the 21 days prior to inclusion
    • Hypersensitivity to bortezomib, boric acid, mannitol, or lenalidomide

Table 1. Baseline characteristics

Total cohort

N= 458

Median age (range)

58 (31-65)

Male patients, %

52.4

ECOG performance status, %

0

1

2

3

Unknown

 

42.6

39.7

13.5

3.5

0.7

M-protein, %

IgG

IgA

Light chain

IgD

Non-secretory

 

59.6

23.4

15.1

0.7

1.3

ISS stage, %

I

II

III

Unknown

 

39.1

36.2

23.4

1.3

High-risk cytogenetics (del17p, t(4;14) and/or t(14;16), %

20.1

Study design stages:
  1. Induction therapy with VRD (n= 458)
  2. Conditioning therapy prior to ASCT
  3. ASCT (n= 397)
  4. Consolidation therapy with VRD post ASCT (n= 384)
  • VRD induction treatment: six cycles of 28-days
    • Bortezomib: 1.3mg/m2 subcutaneously on days 1, 4, 8, and 11
    • Lenalidomide: 25mg/day on days 1 and 21
    • Dexamethasone: 40mg on days 1-4 and 9-12
  • ASCT conditioning: started after the third VRD induction cycle
    • Busulfan: 9.6mg/kg intravenously by a 3-hour infusion on days -5, -4, and -3 plus melphalan at 140mg/m2
    • Or; melphalan: at 200mg/m2
  • VRD consolidation: two cycles three months post-ASCT at same dosing as induction stage
Assessments:
  • Responses were assessed at the beginning of each induction and consolidation cycle and after induction, ASCT, and consolidation
  • Minimal residual disease (MRD) assessed by next-generation sequencing (NGS) was assessed after induction, ASCT, and consolidation
Key findings
Efficacy & MRD
  • Treatment response in the intention-to-treat (ITT) population were assessed by an external independent committee at different treatment stages, as shown below in Table 2

Table 2. Efficacy and MRD results at different treatment stages in ITT population

(ITT; N= 458)

After VRD induction, %

After ASCT, %

After VRD consolidation, %

Overall response rate (ORR)

83.4

81.2

80.6

Complete response (CR)

33.4

44.1

50.2

Very good partial response (VGPR)

33.2

31.0

25.3

Partial response (PR)

16.8

6.1

5

Stable disease (SD)

4.4

1.3

0.2

Progressive disease (PD)

6.8

0.9

0.2

Not evaluable

5.5

16.6

19

MRD detection (median 3 x 10-6 sensitivity)

MRD-negative

28.8

42.1

45.2

MRD-positive

57.6

36.5

34.3

Missing data

13.5

21.4

20.5

The ORR in patients with high-risk cytogenetics including del17p, t(4;14) and/or t(14;16) was 81.% with 34.8% of patients achieving CR, 35.9% VGPR, and 10.9% PR

  • The depth of response increased with each cycle of VRD induction therapy, as seen by the higher rate of patients achieving VGPR:
    • VGPR by cycle 3: 55.6%
    • VGPR by cycle 4: 63.8%
    • VGPR by cycle 5: 70.4%
  • The depth of response also increased as patients progressed to the next treatment stages as seen by the increased CR rate from the VRD induction stage (33.4%), post-ASCT (44.1%), and following VRD consolidation (50.2%; Table 2)
  • MRD negativity at a median of 3 x 10-6 was achieved in the ITT population by 28.8% of patients after VRD induction, 42.1% post-ASCT and 45.2% after VRD consolidation (Table 2)
 Safety

Table 3. Safety analysis

Hematological

Treatment stage

Induction, any grade, %

Induction, grade 3–4, %

Consolidation grade 3–4,%

Neutropenia

31.9

12.9

10.5

Thrombocytopenia

25.3

25.3

9.9

Non-hematological

 

Treatment stage

Induction, any grade, %

Induction, grade 3–4, %

-

Peripheral neuropathy

38

3.9

-

Infection

28.2

9.2

-

Skin toxicity

19.9

3.1

-

Pneumonia

5.2

2.2

-

  • Treatment discontinuation due to ≥1 TEAEs during VRD induction occurred in 3.1% of patients (n= 14)
  • Dose modifications during VRD induction occurred for:
    • Bortezomib: 32.1%
    • Lenalidomide: 26.4%
    • Dexamethasone: 11.4%
Conclusions

Induction therapy with VRD prior to ASCT in patients with NDMM was well tolerated and led to good responses with an ORR of 83.4%. With every additional VRD induction cycle and treatment stage the depth of responses increased. These results indicate that VRD presents a good pre-transplantation SOC strategy for patients with NDMM and even for those with high-risk cytogenetics. 

References
  1. Rosiñol L. et al. Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplantation in multiple myeloma. Blood. 2019 Sep 4. DOI: 10.1182/blood.2019000241
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