While treatment with ixazomib , lenalidomide , and dexamethasone ( ixazomib-Rd ) was shown to improve progression-free survival , recent long-term findings from the phase III TOURMALINE-MM1 trial published in the Journal of Clinical Oncology show the triple combination therapy may not prolong overall survival ( OS ) compared with only Rd in patients with relapsed or refractory multiple myeloma ( MM ).

According to the study ’ s senior author , Paul Richardson , MD , of the Dana- Farber Cancer Institute in Boston , Massachusetts , the median OS values reported in both arms of the study are the longest reported in phase III studies where lenalidomide and dexamethasone are used in this patient population . “ This just points to the remarkable clinical benefit of the immunomodulatory platform in these patients ,” he said .

However , Dr . Richardson suggests , the lack of OS benefit with ixazomib-Rd isn ’ t necessarily a negative finding . “ I think it points to the real equipoise of these trials in the modern setting because obviously patients get outstanding salvage therapies , so that impacts on OS ,” he said . “ It doesn ’ t mean that ixazomib has ‘ failed ,’ it means that the impact of subsequent therapies has dramatically improved outcome .”

Patients with MM were eligible for enrollment in the multicenter , late-stage TOUR- MALINE-MM1 trial if their disease had relapsed , become refractory , or relapsed and become refractory after one to three prior therapies . Randomization was stratified by number of prior therapies ( one vs . two or three ), prior exposure to a proteasome inhibitor ( yes vs . no ), and International Staging System disease stage ( I or II vs . III ).

Treatment consisted of randomly assigned ixazomib-Rd ( n = 360 ) or placebo-Rd ( n = 362 ). Ixazomib 4 mg or a matching placebo was administered on days one , eight , and 15 . In both arms , patients also received lenalidomide 25 mg on days one through 21 as well as dexamethasone 40 mg on days one , eight , 15 , and 22 . Treatment was administered in 28-day cycles until either disease progression or unacceptable toxicity .

At the time of data cutoff , a total of 16 patients in the ixazomib-Rd arm and 15 patients in the placebo-Rd group were still on their assigned treatment . Approximately 71.4 % ( n = 257 ) and 69.9 % of patients in the intention-to-treat ( ITT ) analysis received subsequent therapy in the ixazomib-Rd and placebo-Rd arms , respectively .

With a median follow-up of approximately 85 months in both arms , the median OS was 53.56 months for ixazomib-Rd and 51.6 months placebo-Rd in the ITT analysis .

Overall , there was no significant difference in OS between the two arms ( hazard ratio [ HR ] = 0.939 ; 95 % CI 0.784-1.125 ; p = 0.495 ).

Treatment with ixazomib-Rd demonstrated a treatment benefit in prespecified subgroups , including patients with del ( 17p ) ( HR = 0.916 ; 95 % CI 0.516-1.626 ), highrisk cytogenetics ( HR = 0.870 ; 95 % CI 0.580-1.305 ), and expanded high-risk cytogenetics ( HR = 0.862 ; 95 % CI 0.660-1.124 ). ( See FIGURE )

There was also a larger OS benefit with ixazomib-Rd compared with placebo-Rd in patients who :

• were refractory to any ( HR = 0.794 ; 95 % CI 0.538-1.172 ) or last ( HR = 0.742 ; 95 % CI 0.460-1.198 ) treatment line

• were between 65 and 75 years old ( HR = 0.757 ; 95 % CI 0.559-1.027 )

• had International Staging System stage 3 disease ( HR = 0.779 ; 95 % CI 0.487-1.247 )

FIGURE . Overall Survival in Patients With Cytogenetic Risk Factors

A

Probability of Survival

1.0

0.8

0.6

0.4

0.2

0 6

12 18

24 30

HR ( 95 % CI ) Log-rank test P

36

Group Ixazomib-Rd Placebo-Rd

B

Probability of Survival

No . at risk : Ixazomib-Rd Placebo-Rd

C

Probability of Survival

1.0

0.8

0.6

0.4

0.2

1.0

0.8

0.6

0.4

0.2

75 62

73 56

66 50

60 45

42 48

No . of Events / Patients Median ( 95 % CI ), months 28 / 36 42.2 ( 27.56 to 56.74 ) 25 / 33 29.4 ( 16.99 to 44.22 )

Time Since Random Assignment ( months )

55 39

48 32

HR ( 95 % CI ) Log-rank test P

54 60

66

72

0.916 ( 0.516 to 1.626 ) . 764

43 27

40 24

35 21

30 19

29 18

26 17

20 16

78 84

90

0.870 ( 0.580 to 1.305 ) . 500

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time Since Random Assignment ( months )

Group Ixazomib-Rd Placebo-Rd

HR ( 95 % CI ) Log-rank test P

17 12

10 3

2 0 0 0

96

0 0

No . of Events / Patients Median ( 95 % CI ), months 112 / 155 44.6 ( 35.88 to 53.55 ) 117 / 154 33.4 ( 28.98 to 42.97 )

0.862 ( 0.660 to 1.124 ) . 273

• had two or three prior therapies ( HR = 0.845 ; 95 % CI 0.642-1.114 )

The researchers found no new or additional safety concerns associated with the treatments during the study ’ s seven-year follow-up period . The only grade ≥3 treatment-emergent adverse events that occurred with a ≥5 % higher incidence in patients treated with ixazomib-Rd versus placebo-Rd were thrombocytopenia ( 21.3 % vs . 10.3 %) and diarrhea ( 10.0 % vs . 3.1 %). No differences were found between the two treatment arms in terms of quality of life . ●

Study authors report relationships with Millennium Pharmaceuticals , which sponsored this trial .

Reference

Richardson PG , Kumar SK , Masszi T , et al . Final overall survival analysis of the TOURMALINE-MM1 phase III trial of ixazomib , lenalidomide , and dexamethasone in patients with relapsed or refractory multiple myeloma [ published online ahead of print , 2021 Jun 11 .] J Clin Oncol . doi : 10.1200 / JCO . 21.00972 .

No . at risk :

0

Ixazomib-Rd 155 150 137 125 111 95 83 77 68 58 53 47 39 34 17 5 0 Placebo-Rd

154

6

142

12

126

18

113

24

101

30

83

36

71

42

66

48 Time Since Random Assignment ( months )

Overall survival in patients with ( A ) del ( 17p ), ( B ) high-risk cytogenetics , and ( C ) expanded high-risk cytogenetics ( intent-to-treat population ). High-risk cytogenetic features were detected by FISH ( fluorescence in situ hybridization ) and defined as at least one of del ( 17p ), t ( 4 ; 14 ), and t ( 14 ; 16 ). Standardrisk cytogenetics were defined as the absence of high-risk features in evaluable samples . Expanded high-risk cytogenetics included at least one of del ( 17p ), t ( 4 ; 14 ), t ( 14 ; 16 ), and 1q21 amplification . Cutoff values for defining the presence of cytogenetic abnormalities were based on the false-positive rates ( technical cutoffs ) of the FISH probes that were used . Cutoff points were 5 % positive cells for del ( 17p ), and 3 % positive cells for t ( 4 ; 14 ), t ( 14 ; 16 ), and 1q21 amplification .

58

54

53

60

47

66

41

72

38

78

30

84

13

90

4

96

0

30 ASH Clinical News August 2021