Relapsed/refractory patients

IMW 2019 | OPTIMISMM: Subgroup analysis by prior exposure to bortezomib

The phase III OPTIMISMM trial (NCT01734928) evaluated the efficacy and safety of pomalidomide (P), bortezomib (V) and dexamethasone (d, PVd) compared to Vd alone in patients with relapsed/refractory multiple myeloma (RRMM). Patients enrolled in OPTIMISMM were all previously exposed to lenalidomide (len) and 70% were len-refractory.1

The full trial results showed PVd significantly improved progression-free survival (PFS) compared to Vd alone (PVd vs Vd: 11.2 vs 7.1 months, p< 0.0001) with an overall response rate (ORR) of 82.2% in the PVd arm compared to 50% in the Vd arm (p< 0.0001). Additionally, the authors demonstrated an improvement in PFS in patients who had received only one prior line of therapy; including those who were len-refractory (Table 1).1

Table 1. PFS in patients who received one prior line of therapy1

 

Total cohort

Len-refractory

Len non-refractory

 

PVd

n= 111

Vd

n= 115

PVd

n= 64

Vd

n= 65

PVd

n= 47

Vd

n= 50

Median PFS, months

20.73

11.63

17.84

9.49

22.01

11.96

Hazard ratio (HR), 95% CI, p value

0.54

0.36–0.82

p= 0.0027

Not reported (NR)

NR

 

Full results from the OPTIMISMM trial were recently published in Lancet Oncology and are available on the Multiple Myeloma (MM) Hub here.

Subgroup analysis, IMW 20192

During the XVII International Myeloma Workshop (IMW), Boston, US, Meletios Dimopoulos, National and Kapodistrian University of Athens, Athens, GR, presented a subgroup analysis of the OPTIMISMM trial comparing PVd to Vd as second-line treatment following frontline len treatment in patients who were, or were not, exposed to V.2

Of the intention-to-treat (ITT) population (n= 559), 226 had received only one prior line of treatment. Of these, 134 (59%) received V as part of induction treatment (subsequently randomized to PVd [n= 67] or Vd [n= 67]), compared to 92 (41%) who did not (subsequently randomized to PVd [n= 44] or Vd [n= 48]). 

  • Baseline characteristics:
    • Similar between patients who had received prior V and those who had not
    • More patients with prior V exposure had received a stem cell transplant
    • Patients without prior V were older and more frequently refractory to len
  • Treatment duration was much longer in the PVd arm compared to Vd, but was comparable between prior V exposure and no prior exposure
  • Median cycles of treatment were also similar between patients with and without prior V exposure in both study arms
  • Discontinuation of treatment most commonly occurred due to progressive disease (PD)
  • Discontinuation due to PD was more common in patients who had not received prior V, who were subsequently treated with Vd (PVd vs Vd; 31.8% vs5%)
Efficacy2
  • PVd reduced the risk of progression or death by 53% in V-exposed patients (hazard ratio [HR]: 0.47, p= 0.0068)
  • PVd also significantly improved ORR when compared to Vd irrespective of prior exposure to V (with prior V; p< 0.001, without prior V; p= 0.002)
  • Full efficacy results are shown in Table 2

Table 2. PFS and best response by prior exposure to V

 

With prior V

Without prior V

 

PVd (n= 67)

Vd (n= 67)

PVd (n= 44)

Vd (n= 48)

Median PFS (months), 95% CI

17.8

15.1–20.8

12

7.9–21.1

20.7

8.3–not evaluable

9.5

6.3–16.2

HR, 95% CI, p value

0.47

0.26–0.82

p= 0.0068

0.62

0.35–1.11

p= 0.1055

Response rates by prior V exposure (%)

ORR

89.6

49.3

90.9

62.5

Complete response (CR)/ stringent CR (sCR)

19.4

3

15.9

10.4

Very good partial response (VGPR)

43.3

13.4

43.2

20.8

Partial response (PR)

26.9

32.8

31.8

31.3

Stable disease (SD)

9

37.3

9.1

31.3

PD

1.5

4.5

0

2.1

Not evaluable

0

9

0

4.2

Duration of response (DoR), months

20.7

13.8

20

14.8

Safety2

The most common treatment-emergent adverse events (AEs) were neutropenia, infections and thrombocytopenia (Table 3). The safety profile of PVd was equivalent to those of each of the individual drugs.

Table 3. Safety by prior V exposure

 

With prior V

Without prior V

 

PVd (n= 67)

Vd (n= 64)

PVd (n= 44)

Vd (n= 46)

Median cycles of treatment

15

9

13.5

9

Grade III/IV hematologic adverse events (AEs), %

Neutropenia

45

11

23

9

Thrombocytopenia

24

27

14

13

Anemia

10

8

11

4

Grade III/IV non-hematologic AEs, %

Infections

27

16

32

15

Pneumonia

7

5

11

7

Peripheral sensory neuropathy

10

0

7

9

Fatigue

10

3

5

2

Hyperglycemia

9

3

7

15

Diarrhea

4

5

11

7

Syncope

4

2

2

9

Conclusion2

The results of this subgroup analysis indicate that second-line treatment with PVd was effective in len-pre-treated patients with RRMM, regardless of prior exposure to V.

This analysis supports the use of P-based regimens after one prior line of treatment in patients with RRMM immediately after exposure to len and V.

References
  1. Richardson P.G. et al., Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OTIMISMM): a randomized, open-label, phase 3 trial. Lancet Onc. 2019 May 13. DOI: 10.1016/S1470-2045(19)30152-4
  2. Dimopoulos M. et al., Pomalidomide + Bortezomib + Dexamethasone After One Prior Line of Therapy in Bortezomib-Pretreated Multiple Myeloma; Subanalysis of OPTIMISMM. XVII International Myeloma Workshop. 2019 Sep 14. Abstract #OAB-047
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