Written in Blood
Targeted Chemotherapy Improves Renal Outcomes in Patients With Plasma Cell Dyscrasias and C3 Glomerulopathy
Patients with monoclonal gammopathies often face a spectrum of renal manifestations , including C3 glomerulopathy ( C3G ), which may be attributable to the presence of the monoclonal immunoglobulin ( MIg ) produced by indolent B-cell clones . A large cohort study published in Blood confirmed the association between C3G and MIg and suggested that chemotherapy targeting the underlying B-cell clone could improve patients ’ renal outcomes .
Sophie Chauvet , MD , from the Department of Nephrology at the Georges-Pompidou European Hospital in Paris , France , and co-authors enrolled 50 patients between 2000 and 2014 who had biopsy-proven C3G ( a heterogenous group of rare glomerular diseases characterized by glomerular lesions ) and detectable MIg . Patients were excluded from the study if they had hepatitis B or C virus , antinuclear or anti-double-stranded DNA antibodies , or cryoglobulinemia .
Patients ’ hematologic diagnoses included monoclonal gammopathy of renal significance ( MGRS ; n = 30 ), smoldering multiple myeloma ( MM ; n = 15 ), chronic lymphocytic leukemia ( n = 3 ), and symptomatic MM ( n = 2 ). Most patients ( n = 42 , 86 %) presented with chronic kidney disease ( stage 3 = 31 %; stage 4 / 5 = 55 %).
A median of three months after diagnosis ( range = 1-20 months ), patients received the following treatments :
• chemotherapy ( n = 29 , including 22 patients who received a bortezomibbased regimen )
• “ conservative ” treatment with blockers of the renin-angiotensin system ( n = 13 )
• conventional immunosuppressive therapy ( including steroids , prednisone combined with rituximab , mycophenolate mofetil , azathrioprine , or cyclophosphamide ; n = 8 )
Five patients treated with chemotherapy experienced severe adverse events , including infectious pneumonitis ( n = 6 ), which led to three deaths . Two other deaths were reported , related to cardiac ( n = 1 ) and neurologic ( n = 1 ) complications . One patient treated with bortezomib developed neuropathy that required treatment discontinuation . “ Therapeutic choices should take into account renal elimination of antineoplastic drugs to limit their side effects ,” the authors noted .
Of the 37 evaluable patients , 18 achieved hematologic response ( assessed according to International Myeloma Working Group criteria ) after firstline therapy . Fifteen of these hematologic responders also had a renal response ( defined as proteinuria ≤0.5g / 24h , with albuminemia ≥30g / L and a < 10 % decrease in estimated glomerular filtration rate from baseline value ), whereas only five of 19 hematologic non-responders had a renal response ( 83 % vs . 28 %; p = 0.002 ).
Univariate analyses identified the following factors as being predictive of renal response :
• proteinuria at onset of treatment ( p = 0.005 )
• use of chemotherapy ( p = 0.001 )
• use of bortezomib-based regimen ( p = 0.0001 )
• time to treatment initiation ( p = 0.018 )
• hematologic response ( p = 0.0001 )
On multivariate analyses , however , only hematologic response was associated with renal response ( odds ratio = 9.0 ; 95 % CI 7.98-10.02 ; p = 0.035 ). See TABLE for more data about patients ’ hematologic and renal responses .
Though overall survival was similar among C3G patients with and without MIg , the presence of MIg negatively affected median renal survival of patients with C3G ( p < 0.003 ; hazard ratio [ HR ] = 2.92 ; 95 % CI 1.41-6.01 ).
Median renal survival ( defined as renal relapses ) was higher in patients treated with chemotherapy ( 48 months ) compared with conservative treatment ( 31 months ; HR = 0.27 ; 95 % CI 0.09-0.77 ; p = 0.01 ) but not significantly different from patients treated with immunosuppressive therapy ( 28 months ; HR = 0.41 ; 95 % CI 0.11-1.51 ; p = 0.18 ).
Renal survival was higher in patients who achieved a hematologic response compared with those who did not
“ Our results suggest that the use of novel anti-myeloma agents , such as bortezomib , represent a valuable therapeutic option in C3G / MIg .”
— SOPHIE CHAUVET , MD
( HR = 0.17 ; 95 % CI 0.12-0.66 ; p = 0.009 ). “ Renal response rate and renal survival were significantly higher in patients who rapidly achieved complete response or very good partial response with chemotherapy , suggesting a pathogenic role for the MIg in glomerular C3G deposition ,” they wrote . Renal survival was also significantly higher for chemotherapy-treated patients who achieved a hematologic response compared with hematologic non-responders ( p = 0.04 ). The following factors were associated with renal survival on univariate analysis :
TABLE . Hematologic and Renal Responses by Treatment Type
All Patients ( N = 50 )
Hematologic response 18 / 49 37 %
CR 9 ( 18 %)
VGPR 1 ( 2 %)
PR 8 ( 16 %)
No response 31 ( 63 %)
N / A 1 ( 2 %)
Severe AEs 6 ( 12 %)
Renal response 20 / 48 ( 42 %)
CR 6 ( 13 %)
PR 14 ( 29 %)
No response 28 ( 58 %)
N / A 2 ( 4 %)
Chemotherapy ( n = 29 )
17 / 29 59 %
8 ( 28 %)
1 ( 3 %)
8 ( 28 %)
12 ( 41 %)
Immunotherapy and
Conservative Therapy ( n = 21 ) p Value
1 / 20
0.0002
5 % 1
0.06
( 5 %) 0 1
0 0.01
19 ( 95 %)
− 1 ( 5 %)
5 ( 21 %)
19 / 27 ( 74 %)
6 ( 22 %)
13 ( 48 %)
9 ( 32 %)
2 ( 6 %)
CR = complete response ; VGPR = very good partial response ; PR = partial response ; N / A = not available ; AEs = adverse events
0.0002
1
0.21
( 5 %) 1 / 21
0.0001
( 5 %) 0 0.001
1
0.002
( 5 %) 19
0.0001
( 90 %) 0 −
1
• renal response ( p = 0.048 )
• hematologic response ( p = 0.028 )
• hematologic treatment ( p = 0.022 )
However , multivariate analyses found that only the absence of renal response was independently associated with renal survival ( p = 0.008 ).
“ Our results suggest that the use of novel anti-myeloma agents , such as bortezomib , represent a valuable therapeutic option in C3G / MIg ,” the authors concluded . “ Chemotherapy adapted to the origin of the underlying B-cell clonal disorder and to renal function and should be considered early in the disease course .”
The study is limited by its retrospective , multicenter design that included different treatment regimens . Future studies will also need to evaluate the efficacy and safety of chemotherapy combinations in patients with C3G and monoclonal gammopathy . ●
REFERENCE
Chauvet S , Frémeaux-Bacchi V , Petitprez F , et al . Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy . Blood . 2017 January 9 . [ Epub ahead of print ]
24 ASH Clinical News April 2017