New and noteworthy research from the medical literature landscape

Results from a prespecified interim analysis from the phase III ALCYONE study found that the addition of daratumumab to standard care ( bortezomib , melphalan , prednisone [ VMP ]) halved the risk of disease progression or death , compared with standard of care alone . However , while toxicity profiles were similar between the two treatment regimens , the addition of daratumumab was associated with more frequent grade 3 or 4 infections , the authors reported in The New England Journal of Medicine .

“[ This combination ] was associated with a 50-percent lower risk of disease progression or death among patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic cell transplantation ( HCT ),” wrote María‐Victoria Mateos , MD , from the University Hospital of Salamanca in Spain , and co-authors .

The multicenter , randomized , open-label , activecontrolled study enrolled 706 patients from 162 sites in 25 countries between February 9 , 2015 , and July 14 , 2016 . ALCYONE included patients with newly diagnosed myeloma who were not eligible for high-dose chemotherapy with HCT because of coexisting conditions or age ≥65 years , but had adequate hepatic and renal function and an Eastern Cooperative Oncology Group performance status score of 0-2 .

Patients were randomized 1:1 based on International Staging System ( I , II , or III ), geographic region ( Europe vs . other ), and age (< 75 years vs . ≥75 years ). All patients received a maximum of nine , six-week cycles of VMP with or without daratumumab :

• VMP : bortezomib 1.3 mg / m 2 subcutaneously on days 1 , 4 , 8 , 11 , 22 , 25 , 29 , and 32 of cycle 1 , and days 1 , 8 , 22 , and 29 thereafter ; melphalan 9 mg / m 2 twice-daily ; and prednisone 60 mg / m 2 twice-daily on days 1-4 ( n = 356 )

• D-VMP : VMP regimen plus daratumumab 16 mg / kg intravenously once-weekly during cycle 1 , every 3 weeks for cycles 2-9 , and once-monthly thereafter ( n = 350 )

The median age in both cohorts and the entire patient population was 71 years ( range = 40-93 years ).

The study protocol specified that all patients in the control cohort discontinue treatment after nine cycles , but patients in the D-VMP group could continue daratumumab monotherapy .

The median duration of treatment was 14.7 months in the daratumumab group and 12.0 months in the control cohort ( ranges not provided ). Most patients in each group ( 276 D-VMP patients [ 79.8 %] and 220 VMP patients [ 62.1 %]) completed all nine cycles of VMP , and 17 in each group were still receiving VMP at last follow-up .

During the first nine treatment cycles , 19.4 percent of daratumumab-treated patients and 33.1 percent of the control cohort discontinued treatment , most often due to disease progression ( n = 23 / 350 [ 6.6 %] vs . 47 / 356

[ 13.3 %]; p values not reported ). After cycle nine , the most common reasons for daratumumab discontinuation were progressive disease ( n = 30 / 350 [ 8.7 %]) and death ( n = 2 / 350 [ 0.6 %]).

As of June 12 , 2017 ( clinical cutoff ), more patients in the control group experienced disease progression or death ( 143 patients [ 40.2 %] vs . 88 patients [ 25.1 %]), which translated to a 50-percent reduction in the risk of these outcomes in patients who received daratumumab ( hazard ratio [ HR ] = 0.50 ; 95 % CI 0.38-0.65 ; p < 0.001 ). Median progression-free survival ( PFS ; primary endpoint ) was significantly longer in the D-VMP group : not reached versus 18.1 months in the control group ( 95 % CI 16.5-19.9 ; p < 0.001 ). The 18-month rate of PFS also was higher among the daratumumab group : 71.6 percent vs . 50.2 percent ( p < 0.001 ).

“ The superiority of daratumumab with [ VMP ] was consistent across all subgroups , including [ participants ] 75 years of age or older and those with a poor prognosis ,” the authors wrote . They added that “ although the [ risk ] for disease progression or death in the daratumumab group was higher among patients with a high-risk cytogenetic profile than among those with a standard-risk cytogenetic profile ( 0.78 vs . 0.39 ), the results still favored the daratumumab group over the control group .”

The overall response rate was 90.9 percent in the daratumumab group and 73.9 percent in the control cohort ( p < 0.001 ). The authors also noted that a significantly greater portion of patients in the D-VMP group achieved minimal residual disease – negative status ( 78 [ 22.3 %] vs . 22 [ 6.2 %]; p < 0.001 ). See TABLE 1 for all response data .

The most common any-grade AEs ( occurring in ≥20 % of patients ) in the daratumumab and control cohorts were neutropenia ( 49.7 % and 52.5 %), thrombocytopenia ( 48.8 % and 53.7 %), peripheral sensory neuropathy ( 28.3 % and 34.2 %), anemia ( 28.0 % and 37.6 %), upper respiratory – tract infection ( 26.3 % and 13.8 %), diarrhea ( 23.7 % and 24.6 %), pyrexia ( 23.1 % and 20.9 %), and nausea ( 20.8 % and 21.5 %).

The most common grade 3 or 4 AEs ( occurring in ≥10 % of patients ) included neutropenia ( 39.9 %

TABLE 1 . Patient Response to Treatment Variable with D-VMP vs . 38.7 % with VMP ), thrombocytopenia ( 34.4 % vs . 37.6 %), and anemia ( 15.9 % vs . 19.8 %).

Daratumumab treatment was associated with a higher incidence of grade 3 or 4 infections , compared with VMP alone : 23.1 percent versus 14.7 percent .

Despite this increased risk of infection , the authors noted , AE-related discontinuations were lower in the daratumumab cohort ( 4.9 % vs . 9.0 %). “ Most infections , including pneumonia , resolved ( in 87.9 % of the patients in the daratumumab group and 86.5 % of those in the control group ), and rates of discontinuation of trial treatment owing to infections did not differ substantially between the two groups ( 0.9 % and 1.4 %, respectively ),” the authors reported .

After a median follow-up of 16.5 months ( range not reported ), 45 deaths occurred in the D-VMP group and 48 occurred in the control group . Death from infection occurred in five patients ( 1.4 %) in the daratumumab group and in four patients ( 1.1 %) in the control group .

Follow-up for long-term , overall survival is ongoing . The study ’ s findings are limited by its unblinded design , which may have introduced bias , and the allowance of continued monotherapy in the D-VMP arm . Janssen provided support for the study . The corresponding authors report financial support from Janssen , Celgene , Takeda , Amgen , and Bristol-Myers Squibb . MedErgy provided editorial support .

REFERENCE

Mateos MV , Dimopoulos MA , Cavo M , et al . Daratumumab plus bortezomib , melphalan , and prednisone for untreated myeloma . N Engl J Med . 2018 ; 378:518-28 .

Daratumumab Group ( n = 350 )

Control Group ( n = 356 ) p Value

ORR 318 ( 90.9 %) 263 ( 73.9 %) < 0.001 Best overall response

CR or better 149 ( 42.6 %)

Stringent CR 63 ( 18.0 %)

CR 86 ( 24.6 %)

VGPR or better 249 ( 71.1 %)

VGPR 100 ( 28.6 %)

PR 69 ( 19.7 %)

SD 20 ( 5.7 %)

87 ( 24.4 %)

25 ( 7.0 %)

62 ( 17.4 %)

177 ( 49.7 %)

90 ( 25.3 %)

86 ( 24.2 %)

76 ( 21.3 %)

Not evaluable 12 ( 3.4 %)

MRD-negative 78 ( 22.3 %)

15 ( 4.2 %)

22 ( 6.2 %)

ORR = overall response rate ; CR = complete response ; VGPR = very good partial response ; PR = partial response ; SD = stable disease ; PD = progressive disease ; MRD = minimal residual disease

< 0.001

–

–

< 0.001

–

–

–

–

–

< 0.001

26 ASH Clinical News June 2018