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
HR, 95% CI, p value	0.54 0.36–0.82 p= 0.0027		NR		NR
d, dexamethasone; HR, hazard ratio; len, lenalidomde; NR, not reported; P, pomalidomide; PFS, progression free survival; V, bortezomib

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
d, dexamethasone; P, pomalidomide; PFS, progression free survival; V, bortezomib

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 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
AEs, adverse events; d, dexamethasone P, pomalidomide; V, bortezomib

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.