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Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease
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clinical investigation
© 2015 International Society of Nephrology
Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease Camille Cohen1, Bruno Royer2, Vincent Javaugue3, Raphael Szalat4, Khalil El Karoui1, Alexis Caulier2, Bertrand Knebelmann1, Arnaud Jaccard5, Sylvie Chevret6, Guy Touchard3, Jean-Paul Fermand4, Bertrand Arnulf4 and Frank Bridoux3 1
Department of Nephrology, Necker Hospital, Paris, France; 2Department of Hematology, CHU Amiens, Amiens, France; 3Department of Nephrology, CHU Poitiers, Centre National de Référence Maladies Rares: Amylose AL et Autres Maladies à Dépôts d'Immunoglobulines Monoclonales, Poitiers, France; 4Department of Immunology and Hematology, Saint Louis Hospital, Paris, France; 5Department of Hematology, CHU Limoges, Centre National de Référence Maladies Rares: Amylose AL et Autres Maladies à Dépôts d'Immunoglobulines Monoclonales, Limoges, France and 6Department of Biostatistics and Informatics, Saint Louis Hospital, Paris, France
Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain, heavy chain, or both along basement membranes. While renal involvement is prominent, treatment strategies, such as the impact of novel anti-myeloma agents, remain poorly defined. Here we retrospectively studied 49 patients with MIDD who received a median of 4.5 cycles of intravenous bortezomib plus dexamethasone. Of these, 25 received no additional treatment, 18 also received cyclophosphamide, while 6 also received thalidomide or lenalidomide. The hematological diagnoses identified 38 patients with monoclonal gammopathy of renal significance, 10 with symptomatic multiple myeloma, and 1 with Waldenstrom macroglobulinemia. The overall hematologic response rate, based on the difference between involved and uninvolved serum-free light chains (dFLCs), was 91%. After median follow-up of 54 months, 5 patients died and 10 had reached end-stage renal disease. Renal response was achieved in 26 patients, with a 35% increase in median eGFR and an 86% decrease in median 24-h proteinuria. Predictive factors were pre-treatment eGFR over 30 ml/min per 1.73 m2 and post-treatment dFLC under 40 mg/l; the latter was the sole predictive factor of renal response by multivariable analysis. Thus, bortezomib-based therapy is a promising treatment strategy in MIDD, mainly when used early in the disease course. dFLC response is a favorable prognostic factor for renal survival. Kidney International advance online publication, 15 July 2015; doi:10.1038/ki.2015.201 Correspondence: Bertrand Arnulf, Department of Immunology and Hematology, Saint Louis Hospital, 1 Avenue Claude Vellefaux, 75010 Paris, France. E-mail: [email protected] or Frank Bridoux, Department of Nephrology, CHU Poitiers, Centre National de Référence Maladies Rares: Amylose AL et Autres Maladies à Dépôts d’Immunoglobulines Monoclonales, 2 Rue de la Milétrie 86021 Poitiers, France. E-mail: [email protected] Received 1 February 2015; revised 23 April 2015; accepted 14 May 2015 Kidney International
KEYWORDS: bortezomib; free light chains; monoclonal gammopathy of renal significance; monoclonal immunoglobulin; monoclonal immunoglobulin deposition disease
Randall-type monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of monoclonal gammopathies, characterized by linear non-organized Congo red-negative monoclonal immunoglobulin (Ig) deposits along basement membranes. As immunoglobulinic light-chain (AL) amyloidosis, MIDD is a multisystemic disease with prominent renal manifestations, but heart, liver, or peripheral nerve involvement may be encountered. In the kidney, deposits are invariably observed along tubular basement membranes, and in most cases in the mesangium, glomerular basement membranes, and around arteriolar myocytes. According to the composition of deposits, three categories are distinguished: light-chain deposition disease (LCDD), heavy-chain deposition disease (HCDD), and light- and heavy-chain deposition disease (LHCDD).1–6 Kappa light chains (LCs) are involved in about two-thirds of LCDD cases, with an overrepresentation of the VκIV subgroup.7 The usual presentation is with progressive kidney failure and glomerular symptoms, including nephrotic syndrome in half of patients. Uncommonly, MIDD may manifest with slowly progressive kidney disease without significant proteinuria.8 MIDD may occur during symptomatic plasma-cell or B-cell disorder, but also in patients with monoclonal gammopathy of undetermined significance or smoldering multiple myeloma.5 Recently, the concept of monoclonal gammopathy of renal significance (MGRS) was introduced to depict the association between renal disorders and small B cell clones secreting nephrotoxic monoclonal Ig.9 Early diagnosis and rapid hematological response are considered to be main factors that influence renal prognosis in MGRS.10 Therapeutic management of MIDD remains ill defined. Before the era of novel anti-myeloma agents, the overall 1
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C Cohen et al.: Bortezomib in MIDD
Table 1 | Baseline clinical data and treatment modalities All Patients, n Age, years Male/female ratio
49 64 (55–71) 1.2
LCDD 35 (71.5%) 63 (54–68) 0.9
Hematological data MGRS, n (%) Symptomatic myeloma, n (%) Waldenström macroglobulinemia, n (%) Abnormal FLC, n (%) Serum κ FLC excess, n (%) Serum κ level (mg/l) Serum λ FLC excess, n (%) Serum λ level (mg/l)
38 (78) 10 (20) 1 (2) 47/47 (100) 35 (74) 421 (143–1560) 12 (26) 761 (199–1072)
27 (77) 7 (20) 1 (3) 35/35 (100) 28 (80) 791 (147–2200) 7 (20) 639 (208–883)
Renal manifestations Serum creatinine (μmol/l) Hematuria, n (%) Nephrotic syndrome, n (%) 24-h Proteinuria, g Albuminemia, g/l Hypertension, n (%) Hemodialysis at diagnosis, n (%)
190 36 8 1.5 35 36 9
232 (165–422)* 23 (66) 3 (8.6)* 1.5 (0.9–4.8) 37 (32–42)* 23 (66) 8 (22.9)
Extrarenal manifestations Cardiac involvement, n (%) Liver involvement, n (%) Treatment modalities Number of cycles, n BD, n (%) CyBorD, n (%) BTD, n (%) BRD, n (%) HDM/ASCT, n (%)
(143–238) (73.4) (16.3) (1.0–4.3) (31–41) (73.4) (18.4)
5 (10) 1 (2)
4.5 25 18 5 1 18
(3–6) (51) (36.7) (10) (2) (36.7)
5 (14) 0
4 (3–6) 20 (57) 12 (34) 3 (8.6) 1 (2.9) 13 (37)
HCDD 12 (24.5%) 67 (59–74) 3
11 (91.2) 1 (8.3) 0 10/10 (100) 6 (60) 164 (142–360) 4 (40) 1260 (1118–1585)
155 11 5 2 30 11 1
(134–177) (91.7) (41.7) (1–5.4) (25–33) (91.7) (8.33)
0 1 (8.3)
6 6 5 1
(5–6) (50) (41.7) (8.33) 0 3 (25)
LHCDD 2 (4%) 54 (55–56) 1
0 2 (100) 0 2/2 (100) 1 (50) 367 1 (50) 704
156 (139–173) 2 (100) 0 3 (2.5–3.5) 36 (34–38) 2 (100) 0
0 0
6.5 (5–8) 0 1 (50) 1 (50) 0 2 (100)
Abbreviations: BD, bortezomib+dexamethasone; BRD, bortezomib+lenalidomide+dexamethasone; BTD, bortezomib+thalidomide+dexamethasone; CyBorD, cyclophosphamide+ bortezomib+dexamethasone; HCDD, heavy-chain deposition disease; HDM/ASCT, high-dose melphalan followed by autologous stem cell transplantation; LCDD, light-chain deposition disease; LHCDD, light- and heavy-chain deposition disease; MGRS, monoclonal gammopathy of renal significance; FLC, serum-free light chains. *Po0.05, comparison between LCDD and HCDD.
prognosis was poor. In a large series of 34 patients, treatment with alkylating agents resulted in median renal and patient survival of 22 and 54 months, respectively.3 Moreover, insufficient suppression of the underlying clonal disorder resulted in frequent disease recurrence with graft loss in more than 50% of patients.11–15 More recently, several groups have shown encouraging results with high-dose melphalan followed by autologous stem cell transplantation (HDM/ ASCT),16 and anecdotal case reports have suggested the efficacy of the proteasome inhibitor bortezomib on renal and patient outcomes in LCDD and HCDD.17–22 Although recent recommendations advocated the use of bortezomib as firstline treatment in MIDD,10 the efficacy and safety of novel anti-myeloma agents have not been evaluated so far. To this aim, we retrospectively reviewed 49 patients with biopsyproven MIDD treated with bortezomib-based combinations. RESULTS Baseline renal and hematologic data
Forty-nine patients (twenty-seven males and twenty-two females, median age 64 years) with MIDD (LCDD: n = 35, HCDD: n = 12, LHCDD: n = 2) were included (Table 1). 2
Median baseline serum creatinine was 190 μmol/l (143– 238). Twenty-four patients (49%) presented with chronic kidney disease (CKD) stages 1–3, and 25 patients (51%) with CKD stages 4–5, including 9 patients (18.4%) who required hemodialysis. In all, 36 patients (73.4%) had hematuria and 36 (73.4%) had hypertension. Proteinuria 40.5 g/day (median 2.5 g (1.3–5.2)) was detected in 39 patients (80%), including 8 (16%) with nephrotic syndrome. Ten patients (LCDD n = 8, HCDD n = 2) had proteinuria o0.5 g/24 h. In the whole cohort, median 24-h proteinuria was 1.5 g (1.0– 4.3), with median serum albumin of 35 g/l (30.5–41). Patients with HCCD had significantly lower serum albumin levels (30 (25–33) vs. 36.9 g/l (32–42), Po0.05) and presented more frequently with nephrotic syndrome (41.7% vs. 8.6%, Po0.05) than those with LCDD. Bone marrow studies showed 410% plasma cell infiltration in 33 patients and lymphoplasmocytic infiltration consistent with Waldenström macroglobulinemia in one. A serum monoclonal component (IgG: n = 20; IgA: n = 3; IgM: n = 3, IgD: n = 1; LC only: n = 22) was detected in all patients (Table 1). All 47 tested patients (including all HCDD cases) showed abnormal free light chain (FLC) ratio, with raised κ (n = 35, 74.5%) or Kidney International
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C Cohen et al.: Bortezomib in MIDD
Table 2 | Renal pathological data Number of patients, n Light microscopy, n (%) Nodular glomerulosclerosis Tubular atrophy/interstitial fibrosis Mild/moderate Severe Arteriosclerosis Mild/moderate Severe Associated cast nephropathy Immunofluorescence, n (%) Linear TBM deposits Linear GBM deposits Light-chain isotype (κ/λ) Heavy-chain isotype/subclass Electron microscopy, n (%) GBM deposits TBM deposits
All
LCDD
HCDD
LHCDD
48
34 (71%)
12 (25%)
2 (4%)
31 (64.6)
20 (59)
10 (83)
2 (100)
26 (54) 17 (35.4)
16 (48) 14 (42)
8 (66.6) 3 (25)
2 (100) 0
30 (62.5) 3 (6.25) 3 (6.25)
22 (65) 2 (6) 3 (8.8)
7 (58) 1 (8.3) 0
2 (100) 0 0
48 (100) 22 (46)
35 (100) 11 (32) 23/11
12 (100) 10 (83)* γ1 (n = 9), γ4 (n = 1), α (n = 2)
2 (100) 2 (100)* 1/1 γ1 (n = 2)
7/9 9/9
NA NA
10/12 12/12
3/3 3/3
Abbreviations: GBM, glomerular basement membrane; HCDD, heavy-chain deposition disease; LCDD, light-chain deposition disease; LHCDD, light- and heavy-chain deposition disease; NA, not available; TBM, tubular basement membrane. *Po0.05, comparison between LCDD and HCDD or LHCDD.
λ (n = 12, 25.5%) levels. Two patients without available FLC tests had measurable serum monoclonal IgG. Hematological diagnosis was MGRS in 38 patients (78%), symptomatic multiple myeloma in 10 patients (20%; κ LC only myeloma: n = 4), and Waldenström macroglobulinemia in 1 case. Western blot analysis, available in seven HCDD patients, showed a serum monoclonal IgG1 (n = 6) or IgG4 (n = 1) featuring CH1 deletion in all cases. Extrarenal involvement
By transthoracic echocardiography, six patients had thickened interventricular septum (median diastolic thickness 15.5 mm (15–16.8)), suggestive of MIDD-associated hypertrophic cardiomyopathy. Median baseline serum Nt-proBNP and troponin T levels were 5,428 pg/ml (4817–21,500) and 0.5 μg/l (0.25–0.57), respectively. Two patients had carpal tunnel syndrome. Extrarenal Ig deposition was histologically proven in two patients. Linear κLC deposits were observed along bronchiolar and arteriolar basement membranes by light microscopy (LM) and immunofluorescence in a patient with obstructive pulmonary disease and diffuse bilateral lung cysts. In a HCDD patient with liver cholestasis and cytolysis, liver biopsy revealed thickening of sinusoidal walls with amorphous linear γHC deposits in Disse’s spaces. Renal pathologic findings
The diagnosis of MIDD was assessed by kidney biopsy in 48 patients and by bronchial biopsy in 1 case (Table 2). By LM, the most common renal lesions were diffuse tubular basement membrane thickening (n = 36, 75%), and nodular glomerulosclerosis (n = 31, 64.6%) that was observed more Kidney International
frequently in HCDD patients (Figures 1a and b, and 2a). In all, 16 patients (32.6%) had mesangial hypertrophy and 33 patients (67%) showed arteriolar lesions, including intimal fibrosis (n = 27) and/or deposits in the media of arterioles (n = 6). Moderate-to-severe interstitial fibrosis was present in 17 (35.4%) patients. Three LCDD patients with symptomatic myeloma had numerous casts within distal tubule lumens that stained positive with the same anti-LC conjugate as tubular and glomerular deposits. By immunofluorescence, monotypic linear Ig deposits (κ, n = 23; λ, n = 11, γ, n = 10; α, n = 2; γ+λ, n = 1; γ+κ, n = 1) were observed along tubular basement membranes in all cases. In all, 22 patients (46%) also displayed monotypic glomerular mesangial and/or capillary wall deposits (Figure 1c and d) and 10 patients (20%) had linear deposits around arteriolar myocytes. In the 10 γHCDD patients, analysis of γHC subclasses revealed monoclonal γ1 (n = 9) or γ4 (n = 1) deposits, featuring CH1 deletion in all cases (Figure 2b and c). Ultrastructural studies, available in 12 patients, showed linear punctate powdery electron-dense deposits along tubular basement membranes (n = 12), with amorphous mesangial and/or glomerular basement membrane deposits (n = 9), and arteriolar deposits in 3 cases (Figures 1e and f, and 2d). All 10 patients with baseline proteinuria o0.5 g/day showed predominant tubulointerstitial lesions, with diffuse thickening of tubular basement membranes and monotypic linear κ (n = 7), λ (n = 1), or γ1 (n = 2) deposits, associated with moderate-to-severe interstitial fibrosis. Seven had severe vascular involvement, with diffuse arteriosclerosis (n = 6) and/or widespread arteriolar Ig deposits (n = 4). Nodular glomerulosclerosis, only focal, was observed in six cases. 3
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C Cohen et al.: Bortezomib in MIDD
a
b
c
d
e
f
Figure 1 | Pathology of light-chain deposition disease. (a, b) Light microscopy, Toluidine blue staining (original magnification × 400). (a) Section of renal cortex showing a glomerulus with ischemic changes and diffuse mesangial expansion, (b) whereas in another case typical nodular mesangial glomerulosclerosis was observed. (c, d) Immunofluorescence microscopy (original magnification × 400). (c) Linear κ light-chain deposits in the mesangium, along tubular basement membranes and Bowman’s capsule. No staining was observed with λ light chain (d), α, γ, and μ heavy chains (not shown). (e, f) Electron microscopy. (e) Linear electron-dense deposits involving the outer aspect of tubular basement membrane (arrows). Original magnification × 12,000 (bar = 1 μm). (f) Diffuse linear non-organized electron-dense deposits on the inner aspect of the glomerular basement membranes (arrows). Original magnification × 10,000 (bar = 1 μm).
a
b
c
d
Figure 2 | Kidney biopsy from a patient with α heavy-chain deposition disease. (a) Light microscopy, Periodic acid–Schiff staining (original magnification × 400). Section of renal cortex showing nodular mesangial glomerulosclerosis with diffuse mesangial nodular deposits, double contours of the glomerular basement membranes, mesangiolysis with aneurysmal dilatation of the capillary lumens (arrows), and moderate mesangial hypercellularity. (b, c) Immunofluorescence microscopy with anti-α (b) and anti-κ (c) conjugates (original magnification × 400). Linear α heavy-chain deposits were observed in the mesangium and along tubular basement membranes (b), whereas no significant staining was detected with κ (c) and λ light chains, or γ and μ heavy chains (not shown). (d) Electron microscopy, original magnification × 6,000 (bar = 2 μm). Diffuse linear electron-dense deposits along the inner aspect of the glomerular basement membrane (asterisks).
Treatment-related toxicity
Bortezomib-based regimens were well tolerated. Six patients developed grade 1 peripheral neuropathy, but none required treatment discontinuation. After three cycles of CyBorD, a 85-year-old patient on chronic hemodialysis developed central neurologic symptoms that fully recovered after treatment disruption.
Treatment schedules
All patients received bortezomib-based therapy, as front-line in 38 cases (77.5%). Bortezomib (1.3 mg/m2 IV) was administered either biweekly on days 1–4–8–11 (21-day cycle, n = 30), or weekly on days 1–8–15–22 (28-day cycle, n = 19). Patients received a median of 4.5 cycles (3–6). The following combinations were used: bortezomib+dexamethasone (BD, n = 25), cyclophosphamide+bortezomib+dexamethasone (CyBorD, n = 18), bortezomib+thalidomide+dexamethasone (n = 5), and bortezomib+lenalidomide+dexamethasone (n = 1). HDM/ASCT with melphalan (200 mg/m2: n = 6; 140 mg/m2: n = 12) was performed in 13 patients with MGRS and 5 patients with symptomatic myeloma (Table 1). Compared with the rest of the cohort, patients who received HDM/ASCT were significantly younger (median age = 56 (51–63) vs. 67 (59– 75) years, Po0.05), but baseline median serum creatinine (200 μmol/l (158–405) vs. 226 μmol/l (134–321), P = 0.33) and frequency of symptomatic multiple myeloma (28% vs. 16%, P = 0.46) were not significantly different. 4
Responses and outcomes
After bortezomib-based treatment, the overall hematological response rate was 91% (40/44 evaluable patients). Of these, 31 patients (70.4%) achieved complete response (n = 5), or very good partial response (VGPR; n = 26). Hematological response rate was similar between patients with MGRS or symptomatic myeloma, and between patients with LCDD, HCDD, or LHCDD, respectively (Table 3). Among 38 patients treated with bortezomib as first-line therapy, only one who had achieved VGPR experienced hematological and renal relapse after 4.4 years. Among 11 patients who received bortezomib as second-line therapy, 4 (including 1 in VGPR, 1 in partial response, and 2 with stable disease after treatment) subsequently relapsed with a median time to progression of 8.8 years (8.2–9.7). Hematological (100% vs. 85%, P = 0.13) and renal (61% vs. 48%, P = 0.6) responses, as well as time to progression (8.4 vs. 8.1 years), were not significantly different among patients who received or not HDM/ASCT (Table 3). Kidney International
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C Cohen et al.: Bortezomib in MIDD
Table 3 | Hematological and renal responses All (n = 49)
LCDD (n = 35)
HCDD (n = 12)
LHCDD (n = 2)
a
Hematological response, n (%) CR VGPR PR NR
5 26 9 4
Renal response, n (%)
26 (53)
Data at last follow-up Serum creatinine, μmol/l 24 h Proteinuria, g ESRD, n (%) Chronic hemodialysis, n (%) Kidney transplantation, n (%) Death, n (%) Tolerance Peripheral neuropathy, n (%) Follow-up, months
167 0.2 10 8 2 5
(11.5) (59) (20.5) (9)
(140–263) (0.2–0.8) (20.4) (16.3) (4.1) (10)
3 19 7 3
(9.7) (61.3) (22.6) (9.7)
18 (51)
168 0.2 9 7 2 3
(144–259) (0.2–0.9) (25.7) (20) (5.7) (8.5)
6 (12.5)
3 (8.6)
54 (10–84)
60 (7–84)
2 5 2 1
(18.2) (45.5) (18.2) (9.1)
7 (58)
132 0.2 1 1
(112–164) (0.1–0.7) (8.3) (8.3) 0 2 (16.7)
3 (25) 22 (11–32)
2 (100)
2 (100)
122 (113–132) 0.1 (0.0–0.7) 0 0 0 0
0 6 (4.8–7.2)
Abbreviations: CR, complete response; ESRD, end-stage renal disease; HCDD, heavy-chain deposition disease; LCDD, light-chain deposition disease; LHCDD, light- and heavychain deposition disease; NR, no response; PR, partial response; VGPR, very good partial response. a Evaluable in 44 patients (LCDD: n = 31, HCDD: n = 11, LHCDD: n = 2).
Twenty-six patients (53%) achieved renal response, with a decrease in median serum creatinine level from 190 (143– 238) μmol/l to 167 (140–263) μmol/l, and a median improvement in estimated glomerular filtration rate (eGFR) of 35%. Median 24-h proteinuria decreased from 1.5 (1.0–4.3) g to 0.2 (0.2–0.8) g (Table 3). Treatment modalities were not different in patients who achieved or not a renal response, including number of cycles (4 vs. 5, P = 0.45) and type of regimen (BD alone or CyBorD/BD+thalidomide/lenalidomide (42% vs. 59%, P = 0.39)), respectively. Renal response rate was similar in patients who received bortezomib as first-line therapy or at relapse, but it was significantly higher in patients with CKD stages 1–3 at diagnosis than in those with CKD stages 4–5 (71% and 36%, respectively, P = 0.02). Patients who did not achieve a renal response had significantly lower baseline eGFR compared with renal responders (20.6 (11.4–28.3) vs. 30.9 (18.7–40.1) ml/min per 1.73 m2, respectively, Po0.05). Five of the ten patients with baseline proteinuria o0.5 g/day had a renal response. Renal response occurred in all three patients with MIDD-associated cast nephropathy, with median serum creatinine level decreasing from 528 (373–644) μmol/l to 185 (165–308) μmol/l and 24-h proteinuria from 1.2 (0.7–3.2) g to 0.2 (0.1–0.2) g. Of the nine patients who required hemodialysis at diagnosis, three died and one was withdrawn from hemodialysis 22 months after completion of treatment. Two patients progressed to end-stage renal disease and were started on hemodialysis, 6 and 120 months after diagnosis. Three LCDD patients received a renal allograft, 20, 48, and 60 months after completion of bortezomib-based treatment. At the time of transplantation, two had sustained complete response and one had achieved VGPR. One patient developed chronic allograft rejection followed by graft loss after 3 years, Kidney International
without disease recurrence on graft biopsies at 12 and 30 months. In the two remaining patients, biopsies at 1 year did not reveal monoclonal Ig deposition on the allograft, which function was preserved at 1 and 2 years post transplantation, respectively. At the end of the follow-up, renal survival was higher in patients with a renal response than in those without (100% vs. 59%, respectively, P = 0.05, Figure 3). Renal outcome was strongly associated with hematological response (Table 4). All renal responders had achieved FLC response. Indeed, 22 out of 31 patients (71%) with posttreatment difference between involved and uninvolved serum free light chains (dFLC) o40 mg/l underwent renal response, whereas only 4 out of 18 (22%) patients with difference between involved and uninvolved serum free light chains (dFLC) 440 mg/l did (P = 0.001). Similarly, 23 out of 34 (67.7%) patients with 490% dFLC reduction had renal response, whereas only 3 out of 15 (20%) patients with o90% dFLC reduction did (P = 0.004). Renal response occurred in only two patients with partial response (i.e., 60% and 80% decrease in dFLC, respectively). The following parameters were selected for multivariate analysis of factors influencing renal response: age, baseline eGFR, 24-h proteinuria, dialysis requirement on diagnosis, symptomatic multiple myeloma, HDM/ASCT, 490% dFLC reduction, and post-treatment dFLC o40 mg/l. Only post-treatment dFLC o40 mg/l was independently associated with renal response (odds ratio = 1.04, 95% confidence interval = 0.99–1.09). Median follow-up was 54 (10–84) months. At the time of censoring, 21 patients had CKD stages 1–3, 22 patients had CKD stages 4–5, 8 of whom requiring dialysis, and 2 had received successful renal transplantation. Five patients, including four on chronic hemodialysis, had died after a 5
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C Cohen et al.: Bortezomib in MIDD
Overall survival (%)
Renal survival (%)
100 80 60 40 20 0 0
50
N at risk 40
22
100 150 200 Time (months) 8
4
80 60 40 20 0
250
2
0
20
40 60 80 100 120 Time (months)
N at risk 49
28
24
100
22
14
8
100
80 60 40
Renal response
20
P =0.05
No renal response
0 0
50
26 14
12 10
100 150 200 Time (months)
Overall survival (%)
Renal survival (%)
100
80 60 40
No renal response
0
250
N at risk
Renal response
P =0.03
20 0
20
40 60 80 100 120 Time (months)
26 23
18 12
13 12
N at risk 4 4
1 3
0 2
11 10
8 7
5 4
Figure 3 | Renal and patient survival. (a) Kaplan–Meier renal survival analysis. (b) Kaplan–Meier patient survival analysis. (c) Kaplan–Meier renal survival analysis, comparing patients with or without renal response. (d) Kaplan–Meier patient survival analysis, comparing patients with or without renal response. The nine patients who required dialysis at diagnosis were excluded from renal survival analysis.
Table 4 | Characteristics of renal responders Non-renal responders (n = 23) Age, years Male, n (%) Symptomatic myeloma, n (%) 24 h Proteinuria, g Baseline eGFR, ml/min per 1.73 m2 Baseline eGFRo30 ml/min, n (%) Dialysis at diagnosis, n (%) Baseline dFLC HDM/ASCT, n (%) dFLC o40 mg/l post treatment, n (%) dFLC reduction by 490% post treatment, n (%)
67 13 5 1 20.6 14 7 640 6 9 10
(59–73) (57) (22) (0.5–2.9) (11.4–28.3) (61) (30) (129–1831) (26) (39) (43)
Renal responders (n = 26)
P
61 (54–67) 14 (54) 5 (19) 1.5 (1–4.6) 30.9 (18.7–40.1) 9 (35) 1 (4) 299 (125–1292) 12 (46) 22 (85) 23 (88)
0.14 1 1 0.32 0.045 0.08 0.02 0.54 0.23 0.001 0.004
Abbreviations: dFLC, difference between involved and uninvolved free light chains; eGFR, estimated glomerular filtration rate; HDM/ASCT, high-dose melphalan followed by autologous stem cell transplantation.
median of 3 (2–5.5) months from diagnosis. Causes of death were infection (n = 4) and epidermoid carcinoma of an unknown primary site (n = 1). The estimated overall survival at 10 years was significantly higher in renal responders comparatively to non-renal responders (100% vs. 78%, respectively, P = 0.03; Figure 3). DISCUSSION
We herein report the French experience of 49 patients with MIDD who received bortezomib-based regimens. To our knowledge, this is the largest series of MIDD patients treated with novel anti-myeloma agents. Clinical and demographic characteristics were similar to prior studies, with male preponderance, and a majority of patients in their seventh 6
decade. The diagnosis of MIDD was mostly assessed by kidney biopsy, showing the hallmark disease lesion, i.e., linear amorphous monoclonal Ig deposits along tubular basement membranes, commonly associated with glomerular and arteriolar deposits.2–6 Although most patients presented with glomerular symptoms, only 16.3% had nephrotic syndrome. Moreover, 10 patients had MIDD without significant proteinuria, a finding that was probably related to the predominance of ischemic tubulointerstitial lesions, with severe arteriolar involvement and only focal nodular glomerulosclerosis. These cases indicate that kidney biopsy should be considered in patients with monoclonal gammopathy and otherwise unexplained CKD, even in the absence of glomerular symptoms.8 The inclusion of this subgroup of Kidney International
C Cohen et al.: Bortezomib in MIDD
non-proteinuric MIDD patients accounts for the relatively low level of 24-h proteinuria in our study. When these 10 patients were excluded from analysis, median proteinuria was 2.5 g/day, a value close to those reported by Pozzi et al. (2.7 g/day) and Nasr et al. (4.1 g/day).4,5 In the present cohort, 78% of patients had an indolent underlying clonal disorder, consistent with MGRS. In previous series, the prevalence of multiple myeloma in MIDD ranged from 58 to 65% depending on the definition used for the diagnosis, but the prevalence of symptomatic disease, defined by the CRAB criteria,23 was usually not given.3–5 These data confirm that physicochemical peculiarities, rather than tumor mass, govern the nephrotoxic properties of monoclonal Ig in MIDD, as in most types of renal disorders in MGRS.6 In accordance with Nasr et al.,5 all patients tested for serum FLC had abnormal results, whereas a serum or urine monoclonal component was detected by electrophoresis/immunofixation in only 67% of cases. This suggests that serum FLC should be considered in the diagnostic workup of adults over 50 presenting with renal disease. Interestingly, all patients with HCDD had abnormal serum FLC levels at diagnosis. Of these, seven patients who achieved renal response after bortezomib therapy showed concomitant FLC response. Whether monitoring of serum FLCs is useful to assess treatment efficacy in HCDD remains to be confirmed in larger series. Recent expert consensus opinion recommends that chemotherapy in MIDD should be adapted to the nature of the B-cell clone secreting the neprotoxic monoclonal Ig. Consequently, bortezomib-based regimens should be used as first-line treatment in patients with plasma cell disorders.10 However, few data are currently available on the impact of this strategy on renal and patient outcomes. Only case reports underscored the efficacy and tolerance of bortezomib in HCDD and LCDD, including in patients with disease recurrence after renal transplantation or presenting with acute renal failure.17–22 In our experience, bortezomib-based combinations were highly efficient, with an overall hematological response rate of 91%, including VGPR or above in 70.4% of patients. Sustained hematological remissions were associated with survival of 100% at 85 months. By contrast, median patient survival was 494 and 54 months,3 in the largest series published before the era of novel anti-myeloma agents. Bortezomib therapy also resulted in a dramatic improvement in renal survival. Whereas median time to dialysis was 22 months in a large previous series,3 median renal survival was not reached in our cohort. Almost half of patients achieved a renal response, with only two patients progressing to end-stage renal disease. Moreover, we found that renal response was associated with significantly higher estimated renal and overall survival, suggesting that it represents a key issue in the management of MIDD. Renal response was observed even in patients with LCDD-associated cast nephropathy, in sharp contrast with the poor renal and overall survival reported by Lin et al. in this subgroup.3 These results are consistent with the efficacy of bortezomib-based regimens in myeloma cast Kidney International
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nephropathy, in which they induce rapid and often complete hematological response, resulting in renal improvement in more than 60% of patients not requiring dialysis.24–27 Of note, one patient with pure LCDD was withdrawn from hemodialysis 22 months after achievement of hematological response. Whether delayed renal response corresponds to slow catabolism of deposited Ig after clonal suppression, as recently suggested, remains to be confirmed.20,28 In the present series, renal response was independently associated with post-treatment dFLC o40 mg/l, suggesting that the quality of hematological response strongly influences renal prognosis in MIDD, as in AL amyloidosis.29 However, patients with CKD stages 1–3 at diagnosis had higher probability of renal response, compared with those with CKD stages 4–5. In the latter, the indication of chemotherapy should be carefully evaluated, depending on age, presence of extrarenal symptoms, and eligibility for a renal transplantation. Although few data are available on renal transplantation in MIDD, disease recurrence resulting in graft loss is nearly constant if the hematological disorder is not controlled.11 Three patients received a renal allograft, all with complete hematological response or VGPR at the time of transplantation. None experienced hematological relapse or disease recurrence, as demonstrated by follow-up transplant biopsies. Achieving sustained hematological remission appears therefore as a favorable prognosis factor of renal allograft survival in MIDD. Our data support the use of bortezomib-based combinations as first-line therapy, as hematological relapse was observed in only 1 out of 38 patients who received bortezomib as first-line therapy, compared with 4 of 11 patients who were given bortezomib as rescue therapy. Although bortezomib was administrated intravenously and twice weekly in most patients, tolerance profile was good, as only one patient required treatment discontinuation. Adaptation of treatment schedules in the more fragile patients, with subcutaneous injections or weekly administration, should be considered to reduce toxicity.30 In this retrospective series, bortezomib-based regimens were not standardized and the modalities of chemotherapy in MIDD remain to be defined. CyBorD, which does not require dosage adjustment in CKD patients, appears as a promising strategy, as it was well tolerated and induced high hematological and renal response rates. Recent studies in AL amyloidosis31–33 have shown the efficacy of the CyBorD regimen, including in patients with severe cardiac amyloidosis. HDM/ASCT was also safe in our cohort, although significant morbidity and treatment-related mortality has been reported in myeloma patients with CKD, particularly in those requiring dialysis.34,35 We did not observe any difference in terms of renal response or time to progression among patients who received or not HDM/ASCT. However, as hematological response rates were similar after HDM/ ASCT and bortezomib-based regimens, the indication of HDM/ASCT should be carefully weighted in MIDD patients with severe renal impairment.10 7
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In summary, bortezomib-based regimens may represent a promising treatment strategy in MIDD, particularly when used early in the disease course. Achievement of dFLC below 40 mg/l appears as a strong predictive factor of renal response. Treatment efficacy should be monitored using serial FLC measurements, as in AL amyloidosis. MATERIALS AND METHODS Patients Forty-nine patients referred to seven French university centers were retrospectively studied. Inclusion criteria were: (1) established diagnosis of MIDD, with (i) diffuse linear monoclonal Ig deposits along basement membranes of renal distal tubules, glomeruli, and/or around arteriolar myocytes by immunofluorescence, (ii) that stained positive for κ or λ LC only (LCDD), for γ or α heavy chain (HC) only (HCDD), or for both monoclonal LC and HC deposits (LHCDD), (iii) punctate powdery electron-dense deposits on tubular or glomerular basement membranes by electron microscopy when available; and (2) patients should have received at least one cycle of bortezomib-based therapy, as first line or at relapse. Demographics, clinical, and biological data were recorded at diagnosis, after completion of bortezomib therapy and at last followup. The following definitions were used: hypertension: systolic blood pressure 4140 mm Hg and/or diastolic blood pressure 490 mm Hg or use of anti-hypertensive drugs; nephrotic syndrome: 24-h proteinuria ⩾ 3 g and albuminemia ⩽ 30 g/l. eGFR was calculated using the modified Modification of Diet in Renal Disease equation.36 CKD was defined based on the Kidney Disease Outcomes Quality Initiative classification.37 The diagnosis of monoclonal gammopathy of undetermined significance and multiple myeloma was established according to the International Myeloma Working Group,23 and Waldenström macroglobulinemia was defined according to the international criteria.38 Hematological response was assessed according to the International Myeloma Working Group for patients with symptomatic myeloma.39 In patients with MGRS, the 2012 International Society of Amyloidosis criteria for hematological response were used.29 VGPR was defined by the achievement of dFLC of less than 40 mg/l, or by ⩾ 90% decrease in serum FLC level in patients with MGRS or myeloma, respectively. In two patients without available FLC results, hematological response was based on the monoclonal component serum level by electrophoresis.39 Renal response was defined according to the International Society of Amyloidosis criteria, by a 50% decrease (at least 0.5 g/day) of 24-h urine protein (urine protein must be 40.5 g/day pre-treatment) in the absence of a reduction in eGFR ⩾ 25%, or an increase in serum creatinine ⩾ 0.5 mg/dl.40 Patients with baseline proteinuria o0.5 g/day who achieved a 25% improvement in baseline eGFR value were considered as renal responders.8 The study was performed in accordance with the Declaration of Helsinki Principles and received approval by local ethics committees.
C Cohen et al.: Bortezomib in MIDD
specific for α, γ, and μ HC, and κ and λ LC (Dakopatts, Glostrup, Denmark). γHC subclasses were studied by indirect immunofluorescence using monoclonal antibodies specific for γ1, γ2, γ3, γ4 (clones NL16, GOM2, ZG4, RJ4, Unipath, Bedford, UK), and for the first (CH1) and second (CH2) γHC constant domains (clones TM15 and G7C, Abingdon Health, Birmingham, UK), with a polyclonal rabbit fluorescein isothiocyanate-conjugated anti-mouse IgG as secondary antibody (Immunotech, Marseille, France). Bronchial and liver biopsies were performed in one patient each, with LM and immunofluorescence studies using the same antibodies as described above. Kidney biopsy samples from 12 patients were available for ultrastructural studies. Ultra-thin sections were processed and examined under a JEOL JEM-1010 electron microscope (Jeol, Tokyo, Japan).41 Hematologic and immunologic studies Bone marrow smears and/or biopsy were performed in all patients. Serum and urine samples were systematically studied by conventional electrophoresis and immunofixation. In seven HCDD patients, western blotting analysis of the serum was performed as previously described.42 Serum FLCs were serially monitored in 47 patients (Binding Site, Birmingham, UK). Abnormal FLC ratio was defined as κ/λ ratio o0.26 or 41.65. Statistical analysis Data are expressed as medians with interquartiles for continuous variables and frequencies with percentages for qualitative variables. Fisher’s exact test and Mann–Whitney test were used for the comparison of qualitative and continuous variables, respectively. Survival analysis was performed by the Kaplan–Meier method using log-rank test for comparison of baseline groups. Statistical significance was assumed at Po0.05. Statistical analyses were carried out using GraphPad Prism version 5.1 (GraphPad Software, San Diego, CA). A multivariate logistic regression model was secondarily used to identify factors associated with renal response. DISCLOSURE
All the authors declared no competing interests.
AUTHOR CONTRIBUTIONS CC, BA, JPF, GT and FB designed the study. CC, BA and FB performed the study and wrote the manuscript. SC performed the multivariate analysis for predictive factors of renal response. All other authors provided data. REFERENCES 1.
2.
3.
Pathological studies All kidney biopsy samples were processed for LM and immunofluorescence microscopy, as previously described.41 By LM, sections were systematically stained with Congo red and examined under polarized light. Interstitial fibrosis, tubular atrophy, and vascular sclerosis were graded semi-quantitatively on a scale from 0 to 3+. Immunofluorescence studies were performed on 3 μm cryostat sections using polyclonal fluorescein isothiocyanate conjugates 8
4.
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27. Dimopoulos MA, Roussou M, Gkotzamanidou M et al. The role of novel agents on the reversibility of renal impairment in newly diagnosed symptomatic patients with multiple myeloma. Leukemia 2013; 27: 423–429. 28. Nambirajan A, Bhowmik D, Singh G et al. Monoclonal gammopathy of renal significance with light-chain deposition disease diagnosed postrenal transplant: a diagnostic and therapeutic challenge. Transpl Int 2015; 28: 375–379. 29. Palladini G, Dispenzieri A, Gertz MA et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012; 30: 4541–4549. 30. Moreau P, Pylypenko H, Grosicki S et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011; 12: 431–440. 31. Venner CP, Lane T, Foard D et al. Cyclophosphamide, bortezomib and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood 2012; 119: 4387–4390. 32. Mikhael JR, Schuster SR, Jimenez-Zepeda VH et al. Cyclophosphamidebortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood 2012; 19: 4391–4394. 33. Jaccard A, Comenzo RL, Hari P et al. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica 2014; 99: 1479–1485. 34. Badros A, Barlogie B, Siegel E et al. Results of autologous stem cell transplant in multiple myeloma patients with renal failure. Br J Haematol 2001; 144: 822–829. 35. Knudsen LM, Nielsen B, Gimsing P et al. Autologous stem cell transplantation in multiple myeloma: outcome in patients with renal failure. Eur J Haematol 2005; 75: 27–33. 36. Levey AS, Bosch JP, Lewis JB et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–470. 37. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1–S266. 38. Owen RG, Treon SP, Al-Katib A et al. Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin Oncol 2003; 30: 110–115. 39. Durie BGM, Harousseau JL, Miguel JS et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473. 40. Gertz MA, Comenzo R, Falk RH et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol 2005; 79: 319–328. 41. Bridoux F, Hugue V, Coldefy O et al. Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features. Kidney Int 2002; 62: 1764–1775. 42. Beaume A, Brizard A, Dreyfus B et al. High incidence of serum monoclonal Igs detected by a sensitive immunoblotting technique in B-cell chronic lymphocytic leukemia. Blood 1994; 84: 1216–1219.
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© 2015 International Society of Nephrology
Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease Camille Cohen1, Bruno Royer2, Vincent Javaugue3, Raphael Szalat4, Khalil El Karoui1, Alexis Caulier2, Bertrand Knebelmann1, Arnaud Jaccard5, Sylvie Chevret6, Guy Touchard3, Jean-Paul Fermand4, Bertrand Arnulf4 and Frank Bridoux3 1
Department of Nephrology, Necker Hospital, Paris, France; 2Department of Hematology, CHU Amiens, Amiens, France; 3Department of Nephrology, CHU Poitiers, Centre National de Référence Maladies Rares: Amylose AL et Autres Maladies à Dépôts d'Immunoglobulines Monoclonales, Poitiers, France; 4Department of Immunology and Hematology, Saint Louis Hospital, Paris, France; 5Department of Hematology, CHU Limoges, Centre National de Référence Maladies Rares: Amylose AL et Autres Maladies à Dépôts d'Immunoglobulines Monoclonales, Limoges, France and 6Department of Biostatistics and Informatics, Saint Louis Hospital, Paris, France
Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain, heavy chain, or both along basement membranes. While renal involvement is prominent, treatment strategies, such as the impact of novel anti-myeloma agents, remain poorly defined. Here we retrospectively studied 49 patients with MIDD who received a median of 4.5 cycles of intravenous bortezomib plus dexamethasone. Of these, 25 received no additional treatment, 18 also received cyclophosphamide, while 6 also received thalidomide or lenalidomide. The hematological diagnoses identified 38 patients with monoclonal gammopathy of renal significance, 10 with symptomatic multiple myeloma, and 1 with Waldenstrom macroglobulinemia. The overall hematologic response rate, based on the difference between involved and uninvolved serum-free light chains (dFLCs), was 91%. After median follow-up of 54 months, 5 patients died and 10 had reached end-stage renal disease. Renal response was achieved in 26 patients, with a 35% increase in median eGFR and an 86% decrease in median 24-h proteinuria. Predictive factors were pre-treatment eGFR over 30 ml/min per 1.73 m2 and post-treatment dFLC under 40 mg/l; the latter was the sole predictive factor of renal response by multivariable analysis. Thus, bortezomib-based therapy is a promising treatment strategy in MIDD, mainly when used early in the disease course. dFLC response is a favorable prognostic factor for renal survival. Kidney International advance online publication, 15 July 2015; doi:10.1038/ki.2015.201 Correspondence: Bertrand Arnulf, Department of Immunology and Hematology, Saint Louis Hospital, 1 Avenue Claude Vellefaux, 75010 Paris, France. E-mail: [email protected] or Frank Bridoux, Department of Nephrology, CHU Poitiers, Centre National de Référence Maladies Rares: Amylose AL et Autres Maladies à Dépôts d’Immunoglobulines Monoclonales, 2 Rue de la Milétrie 86021 Poitiers, France. E-mail: [email protected] Received 1 February 2015; revised 23 April 2015; accepted 14 May 2015 Kidney International
KEYWORDS: bortezomib; free light chains; monoclonal gammopathy of renal significance; monoclonal immunoglobulin; monoclonal immunoglobulin deposition disease
Randall-type monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of monoclonal gammopathies, characterized by linear non-organized Congo red-negative monoclonal immunoglobulin (Ig) deposits along basement membranes. As immunoglobulinic light-chain (AL) amyloidosis, MIDD is a multisystemic disease with prominent renal manifestations, but heart, liver, or peripheral nerve involvement may be encountered. In the kidney, deposits are invariably observed along tubular basement membranes, and in most cases in the mesangium, glomerular basement membranes, and around arteriolar myocytes. According to the composition of deposits, three categories are distinguished: light-chain deposition disease (LCDD), heavy-chain deposition disease (HCDD), and light- and heavy-chain deposition disease (LHCDD).1–6 Kappa light chains (LCs) are involved in about two-thirds of LCDD cases, with an overrepresentation of the VκIV subgroup.7 The usual presentation is with progressive kidney failure and glomerular symptoms, including nephrotic syndrome in half of patients. Uncommonly, MIDD may manifest with slowly progressive kidney disease without significant proteinuria.8 MIDD may occur during symptomatic plasma-cell or B-cell disorder, but also in patients with monoclonal gammopathy of undetermined significance or smoldering multiple myeloma.5 Recently, the concept of monoclonal gammopathy of renal significance (MGRS) was introduced to depict the association between renal disorders and small B cell clones secreting nephrotoxic monoclonal Ig.9 Early diagnosis and rapid hematological response are considered to be main factors that influence renal prognosis in MGRS.10 Therapeutic management of MIDD remains ill defined. Before the era of novel anti-myeloma agents, the overall 1
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Table 1 | Baseline clinical data and treatment modalities All Patients, n Age, years Male/female ratio
49 64 (55–71) 1.2
LCDD 35 (71.5%) 63 (54–68) 0.9
Hematological data MGRS, n (%) Symptomatic myeloma, n (%) Waldenström macroglobulinemia, n (%) Abnormal FLC, n (%) Serum κ FLC excess, n (%) Serum κ level (mg/l) Serum λ FLC excess, n (%) Serum λ level (mg/l)
38 (78) 10 (20) 1 (2) 47/47 (100) 35 (74) 421 (143–1560) 12 (26) 761 (199–1072)
27 (77) 7 (20) 1 (3) 35/35 (100) 28 (80) 791 (147–2200) 7 (20) 639 (208–883)
Renal manifestations Serum creatinine (μmol/l) Hematuria, n (%) Nephrotic syndrome, n (%) 24-h Proteinuria, g Albuminemia, g/l Hypertension, n (%) Hemodialysis at diagnosis, n (%)
190 36 8 1.5 35 36 9
232 (165–422)* 23 (66) 3 (8.6)* 1.5 (0.9–4.8) 37 (32–42)* 23 (66) 8 (22.9)
Extrarenal manifestations Cardiac involvement, n (%) Liver involvement, n (%) Treatment modalities Number of cycles, n BD, n (%) CyBorD, n (%) BTD, n (%) BRD, n (%) HDM/ASCT, n (%)
(143–238) (73.4) (16.3) (1.0–4.3) (31–41) (73.4) (18.4)
5 (10) 1 (2)
4.5 25 18 5 1 18
(3–6) (51) (36.7) (10) (2) (36.7)
5 (14) 0
4 (3–6) 20 (57) 12 (34) 3 (8.6) 1 (2.9) 13 (37)
HCDD 12 (24.5%) 67 (59–74) 3
11 (91.2) 1 (8.3) 0 10/10 (100) 6 (60) 164 (142–360) 4 (40) 1260 (1118–1585)
155 11 5 2 30 11 1
(134–177) (91.7) (41.7) (1–5.4) (25–33) (91.7) (8.33)
0 1 (8.3)
6 6 5 1
(5–6) (50) (41.7) (8.33) 0 3 (25)
LHCDD 2 (4%) 54 (55–56) 1
0 2 (100) 0 2/2 (100) 1 (50) 367 1 (50) 704
156 (139–173) 2 (100) 0 3 (2.5–3.5) 36 (34–38) 2 (100) 0
0 0
6.5 (5–8) 0 1 (50) 1 (50) 0 2 (100)
Abbreviations: BD, bortezomib+dexamethasone; BRD, bortezomib+lenalidomide+dexamethasone; BTD, bortezomib+thalidomide+dexamethasone; CyBorD, cyclophosphamide+ bortezomib+dexamethasone; HCDD, heavy-chain deposition disease; HDM/ASCT, high-dose melphalan followed by autologous stem cell transplantation; LCDD, light-chain deposition disease; LHCDD, light- and heavy-chain deposition disease; MGRS, monoclonal gammopathy of renal significance; FLC, serum-free light chains. *Po0.05, comparison between LCDD and HCDD.
prognosis was poor. In a large series of 34 patients, treatment with alkylating agents resulted in median renal and patient survival of 22 and 54 months, respectively.3 Moreover, insufficient suppression of the underlying clonal disorder resulted in frequent disease recurrence with graft loss in more than 50% of patients.11–15 More recently, several groups have shown encouraging results with high-dose melphalan followed by autologous stem cell transplantation (HDM/ ASCT),16 and anecdotal case reports have suggested the efficacy of the proteasome inhibitor bortezomib on renal and patient outcomes in LCDD and HCDD.17–22 Although recent recommendations advocated the use of bortezomib as firstline treatment in MIDD,10 the efficacy and safety of novel anti-myeloma agents have not been evaluated so far. To this aim, we retrospectively reviewed 49 patients with biopsyproven MIDD treated with bortezomib-based combinations. RESULTS Baseline renal and hematologic data
Forty-nine patients (twenty-seven males and twenty-two females, median age 64 years) with MIDD (LCDD: n = 35, HCDD: n = 12, LHCDD: n = 2) were included (Table 1). 2
Median baseline serum creatinine was 190 μmol/l (143– 238). Twenty-four patients (49%) presented with chronic kidney disease (CKD) stages 1–3, and 25 patients (51%) with CKD stages 4–5, including 9 patients (18.4%) who required hemodialysis. In all, 36 patients (73.4%) had hematuria and 36 (73.4%) had hypertension. Proteinuria 40.5 g/day (median 2.5 g (1.3–5.2)) was detected in 39 patients (80%), including 8 (16%) with nephrotic syndrome. Ten patients (LCDD n = 8, HCDD n = 2) had proteinuria o0.5 g/24 h. In the whole cohort, median 24-h proteinuria was 1.5 g (1.0– 4.3), with median serum albumin of 35 g/l (30.5–41). Patients with HCCD had significantly lower serum albumin levels (30 (25–33) vs. 36.9 g/l (32–42), Po0.05) and presented more frequently with nephrotic syndrome (41.7% vs. 8.6%, Po0.05) than those with LCDD. Bone marrow studies showed 410% plasma cell infiltration in 33 patients and lymphoplasmocytic infiltration consistent with Waldenström macroglobulinemia in one. A serum monoclonal component (IgG: n = 20; IgA: n = 3; IgM: n = 3, IgD: n = 1; LC only: n = 22) was detected in all patients (Table 1). All 47 tested patients (including all HCDD cases) showed abnormal free light chain (FLC) ratio, with raised κ (n = 35, 74.5%) or Kidney International
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Table 2 | Renal pathological data Number of patients, n Light microscopy, n (%) Nodular glomerulosclerosis Tubular atrophy/interstitial fibrosis Mild/moderate Severe Arteriosclerosis Mild/moderate Severe Associated cast nephropathy Immunofluorescence, n (%) Linear TBM deposits Linear GBM deposits Light-chain isotype (κ/λ) Heavy-chain isotype/subclass Electron microscopy, n (%) GBM deposits TBM deposits
All
LCDD
HCDD
LHCDD
48
34 (71%)
12 (25%)
2 (4%)
31 (64.6)
20 (59)
10 (83)
2 (100)
26 (54) 17 (35.4)
16 (48) 14 (42)
8 (66.6) 3 (25)
2 (100) 0
30 (62.5) 3 (6.25) 3 (6.25)
22 (65) 2 (6) 3 (8.8)
7 (58) 1 (8.3) 0
2 (100) 0 0
48 (100) 22 (46)
35 (100) 11 (32) 23/11
12 (100) 10 (83)* γ1 (n = 9), γ4 (n = 1), α (n = 2)
2 (100) 2 (100)* 1/1 γ1 (n = 2)
7/9 9/9
NA NA
10/12 12/12
3/3 3/3
Abbreviations: GBM, glomerular basement membrane; HCDD, heavy-chain deposition disease; LCDD, light-chain deposition disease; LHCDD, light- and heavy-chain deposition disease; NA, not available; TBM, tubular basement membrane. *Po0.05, comparison between LCDD and HCDD or LHCDD.
λ (n = 12, 25.5%) levels. Two patients without available FLC tests had measurable serum monoclonal IgG. Hematological diagnosis was MGRS in 38 patients (78%), symptomatic multiple myeloma in 10 patients (20%; κ LC only myeloma: n = 4), and Waldenström macroglobulinemia in 1 case. Western blot analysis, available in seven HCDD patients, showed a serum monoclonal IgG1 (n = 6) or IgG4 (n = 1) featuring CH1 deletion in all cases. Extrarenal involvement
By transthoracic echocardiography, six patients had thickened interventricular septum (median diastolic thickness 15.5 mm (15–16.8)), suggestive of MIDD-associated hypertrophic cardiomyopathy. Median baseline serum Nt-proBNP and troponin T levels were 5,428 pg/ml (4817–21,500) and 0.5 μg/l (0.25–0.57), respectively. Two patients had carpal tunnel syndrome. Extrarenal Ig deposition was histologically proven in two patients. Linear κLC deposits were observed along bronchiolar and arteriolar basement membranes by light microscopy (LM) and immunofluorescence in a patient with obstructive pulmonary disease and diffuse bilateral lung cysts. In a HCDD patient with liver cholestasis and cytolysis, liver biopsy revealed thickening of sinusoidal walls with amorphous linear γHC deposits in Disse’s spaces. Renal pathologic findings
The diagnosis of MIDD was assessed by kidney biopsy in 48 patients and by bronchial biopsy in 1 case (Table 2). By LM, the most common renal lesions were diffuse tubular basement membrane thickening (n = 36, 75%), and nodular glomerulosclerosis (n = 31, 64.6%) that was observed more Kidney International
frequently in HCDD patients (Figures 1a and b, and 2a). In all, 16 patients (32.6%) had mesangial hypertrophy and 33 patients (67%) showed arteriolar lesions, including intimal fibrosis (n = 27) and/or deposits in the media of arterioles (n = 6). Moderate-to-severe interstitial fibrosis was present in 17 (35.4%) patients. Three LCDD patients with symptomatic myeloma had numerous casts within distal tubule lumens that stained positive with the same anti-LC conjugate as tubular and glomerular deposits. By immunofluorescence, monotypic linear Ig deposits (κ, n = 23; λ, n = 11, γ, n = 10; α, n = 2; γ+λ, n = 1; γ+κ, n = 1) were observed along tubular basement membranes in all cases. In all, 22 patients (46%) also displayed monotypic glomerular mesangial and/or capillary wall deposits (Figure 1c and d) and 10 patients (20%) had linear deposits around arteriolar myocytes. In the 10 γHCDD patients, analysis of γHC subclasses revealed monoclonal γ1 (n = 9) or γ4 (n = 1) deposits, featuring CH1 deletion in all cases (Figure 2b and c). Ultrastructural studies, available in 12 patients, showed linear punctate powdery electron-dense deposits along tubular basement membranes (n = 12), with amorphous mesangial and/or glomerular basement membrane deposits (n = 9), and arteriolar deposits in 3 cases (Figures 1e and f, and 2d). All 10 patients with baseline proteinuria o0.5 g/day showed predominant tubulointerstitial lesions, with diffuse thickening of tubular basement membranes and monotypic linear κ (n = 7), λ (n = 1), or γ1 (n = 2) deposits, associated with moderate-to-severe interstitial fibrosis. Seven had severe vascular involvement, with diffuse arteriosclerosis (n = 6) and/or widespread arteriolar Ig deposits (n = 4). Nodular glomerulosclerosis, only focal, was observed in six cases. 3
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a
b
c
d
e
f
Figure 1 | Pathology of light-chain deposition disease. (a, b) Light microscopy, Toluidine blue staining (original magnification × 400). (a) Section of renal cortex showing a glomerulus with ischemic changes and diffuse mesangial expansion, (b) whereas in another case typical nodular mesangial glomerulosclerosis was observed. (c, d) Immunofluorescence microscopy (original magnification × 400). (c) Linear κ light-chain deposits in the mesangium, along tubular basement membranes and Bowman’s capsule. No staining was observed with λ light chain (d), α, γ, and μ heavy chains (not shown). (e, f) Electron microscopy. (e) Linear electron-dense deposits involving the outer aspect of tubular basement membrane (arrows). Original magnification × 12,000 (bar = 1 μm). (f) Diffuse linear non-organized electron-dense deposits on the inner aspect of the glomerular basement membranes (arrows). Original magnification × 10,000 (bar = 1 μm).
a
b
c
d
Figure 2 | Kidney biopsy from a patient with α heavy-chain deposition disease. (a) Light microscopy, Periodic acid–Schiff staining (original magnification × 400). Section of renal cortex showing nodular mesangial glomerulosclerosis with diffuse mesangial nodular deposits, double contours of the glomerular basement membranes, mesangiolysis with aneurysmal dilatation of the capillary lumens (arrows), and moderate mesangial hypercellularity. (b, c) Immunofluorescence microscopy with anti-α (b) and anti-κ (c) conjugates (original magnification × 400). Linear α heavy-chain deposits were observed in the mesangium and along tubular basement membranes (b), whereas no significant staining was detected with κ (c) and λ light chains, or γ and μ heavy chains (not shown). (d) Electron microscopy, original magnification × 6,000 (bar = 2 μm). Diffuse linear electron-dense deposits along the inner aspect of the glomerular basement membrane (asterisks).
Treatment-related toxicity
Bortezomib-based regimens were well tolerated. Six patients developed grade 1 peripheral neuropathy, but none required treatment discontinuation. After three cycles of CyBorD, a 85-year-old patient on chronic hemodialysis developed central neurologic symptoms that fully recovered after treatment disruption.
Treatment schedules
All patients received bortezomib-based therapy, as front-line in 38 cases (77.5%). Bortezomib (1.3 mg/m2 IV) was administered either biweekly on days 1–4–8–11 (21-day cycle, n = 30), or weekly on days 1–8–15–22 (28-day cycle, n = 19). Patients received a median of 4.5 cycles (3–6). The following combinations were used: bortezomib+dexamethasone (BD, n = 25), cyclophosphamide+bortezomib+dexamethasone (CyBorD, n = 18), bortezomib+thalidomide+dexamethasone (n = 5), and bortezomib+lenalidomide+dexamethasone (n = 1). HDM/ASCT with melphalan (200 mg/m2: n = 6; 140 mg/m2: n = 12) was performed in 13 patients with MGRS and 5 patients with symptomatic myeloma (Table 1). Compared with the rest of the cohort, patients who received HDM/ASCT were significantly younger (median age = 56 (51–63) vs. 67 (59– 75) years, Po0.05), but baseline median serum creatinine (200 μmol/l (158–405) vs. 226 μmol/l (134–321), P = 0.33) and frequency of symptomatic multiple myeloma (28% vs. 16%, P = 0.46) were not significantly different. 4
Responses and outcomes
After bortezomib-based treatment, the overall hematological response rate was 91% (40/44 evaluable patients). Of these, 31 patients (70.4%) achieved complete response (n = 5), or very good partial response (VGPR; n = 26). Hematological response rate was similar between patients with MGRS or symptomatic myeloma, and between patients with LCDD, HCDD, or LHCDD, respectively (Table 3). Among 38 patients treated with bortezomib as first-line therapy, only one who had achieved VGPR experienced hematological and renal relapse after 4.4 years. Among 11 patients who received bortezomib as second-line therapy, 4 (including 1 in VGPR, 1 in partial response, and 2 with stable disease after treatment) subsequently relapsed with a median time to progression of 8.8 years (8.2–9.7). Hematological (100% vs. 85%, P = 0.13) and renal (61% vs. 48%, P = 0.6) responses, as well as time to progression (8.4 vs. 8.1 years), were not significantly different among patients who received or not HDM/ASCT (Table 3). Kidney International
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Table 3 | Hematological and renal responses All (n = 49)
LCDD (n = 35)
HCDD (n = 12)
LHCDD (n = 2)
a
Hematological response, n (%) CR VGPR PR NR
5 26 9 4
Renal response, n (%)
26 (53)
Data at last follow-up Serum creatinine, μmol/l 24 h Proteinuria, g ESRD, n (%) Chronic hemodialysis, n (%) Kidney transplantation, n (%) Death, n (%) Tolerance Peripheral neuropathy, n (%) Follow-up, months
167 0.2 10 8 2 5
(11.5) (59) (20.5) (9)
(140–263) (0.2–0.8) (20.4) (16.3) (4.1) (10)
3 19 7 3
(9.7) (61.3) (22.6) (9.7)
18 (51)
168 0.2 9 7 2 3
(144–259) (0.2–0.9) (25.7) (20) (5.7) (8.5)
6 (12.5)
3 (8.6)
54 (10–84)
60 (7–84)
2 5 2 1
(18.2) (45.5) (18.2) (9.1)
7 (58)
132 0.2 1 1
(112–164) (0.1–0.7) (8.3) (8.3) 0 2 (16.7)
3 (25) 22 (11–32)
2 (100)
2 (100)
122 (113–132) 0.1 (0.0–0.7) 0 0 0 0
0 6 (4.8–7.2)
Abbreviations: CR, complete response; ESRD, end-stage renal disease; HCDD, heavy-chain deposition disease; LCDD, light-chain deposition disease; LHCDD, light- and heavychain deposition disease; NR, no response; PR, partial response; VGPR, very good partial response. a Evaluable in 44 patients (LCDD: n = 31, HCDD: n = 11, LHCDD: n = 2).
Twenty-six patients (53%) achieved renal response, with a decrease in median serum creatinine level from 190 (143– 238) μmol/l to 167 (140–263) μmol/l, and a median improvement in estimated glomerular filtration rate (eGFR) of 35%. Median 24-h proteinuria decreased from 1.5 (1.0–4.3) g to 0.2 (0.2–0.8) g (Table 3). Treatment modalities were not different in patients who achieved or not a renal response, including number of cycles (4 vs. 5, P = 0.45) and type of regimen (BD alone or CyBorD/BD+thalidomide/lenalidomide (42% vs. 59%, P = 0.39)), respectively. Renal response rate was similar in patients who received bortezomib as first-line therapy or at relapse, but it was significantly higher in patients with CKD stages 1–3 at diagnosis than in those with CKD stages 4–5 (71% and 36%, respectively, P = 0.02). Patients who did not achieve a renal response had significantly lower baseline eGFR compared with renal responders (20.6 (11.4–28.3) vs. 30.9 (18.7–40.1) ml/min per 1.73 m2, respectively, Po0.05). Five of the ten patients with baseline proteinuria o0.5 g/day had a renal response. Renal response occurred in all three patients with MIDD-associated cast nephropathy, with median serum creatinine level decreasing from 528 (373–644) μmol/l to 185 (165–308) μmol/l and 24-h proteinuria from 1.2 (0.7–3.2) g to 0.2 (0.1–0.2) g. Of the nine patients who required hemodialysis at diagnosis, three died and one was withdrawn from hemodialysis 22 months after completion of treatment. Two patients progressed to end-stage renal disease and were started on hemodialysis, 6 and 120 months after diagnosis. Three LCDD patients received a renal allograft, 20, 48, and 60 months after completion of bortezomib-based treatment. At the time of transplantation, two had sustained complete response and one had achieved VGPR. One patient developed chronic allograft rejection followed by graft loss after 3 years, Kidney International
without disease recurrence on graft biopsies at 12 and 30 months. In the two remaining patients, biopsies at 1 year did not reveal monoclonal Ig deposition on the allograft, which function was preserved at 1 and 2 years post transplantation, respectively. At the end of the follow-up, renal survival was higher in patients with a renal response than in those without (100% vs. 59%, respectively, P = 0.05, Figure 3). Renal outcome was strongly associated with hematological response (Table 4). All renal responders had achieved FLC response. Indeed, 22 out of 31 patients (71%) with posttreatment difference between involved and uninvolved serum free light chains (dFLC) o40 mg/l underwent renal response, whereas only 4 out of 18 (22%) patients with difference between involved and uninvolved serum free light chains (dFLC) 440 mg/l did (P = 0.001). Similarly, 23 out of 34 (67.7%) patients with 490% dFLC reduction had renal response, whereas only 3 out of 15 (20%) patients with o90% dFLC reduction did (P = 0.004). Renal response occurred in only two patients with partial response (i.e., 60% and 80% decrease in dFLC, respectively). The following parameters were selected for multivariate analysis of factors influencing renal response: age, baseline eGFR, 24-h proteinuria, dialysis requirement on diagnosis, symptomatic multiple myeloma, HDM/ASCT, 490% dFLC reduction, and post-treatment dFLC o40 mg/l. Only post-treatment dFLC o40 mg/l was independently associated with renal response (odds ratio = 1.04, 95% confidence interval = 0.99–1.09). Median follow-up was 54 (10–84) months. At the time of censoring, 21 patients had CKD stages 1–3, 22 patients had CKD stages 4–5, 8 of whom requiring dialysis, and 2 had received successful renal transplantation. Five patients, including four on chronic hemodialysis, had died after a 5
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C Cohen et al.: Bortezomib in MIDD
Overall survival (%)
Renal survival (%)
100 80 60 40 20 0 0
50
N at risk 40
22
100 150 200 Time (months) 8
4
80 60 40 20 0
250
2
0
20
40 60 80 100 120 Time (months)
N at risk 49
28
24
100
22
14
8
100
80 60 40
Renal response
20
P =0.05
No renal response
0 0
50
26 14
12 10
100 150 200 Time (months)
Overall survival (%)
Renal survival (%)
100
80 60 40
No renal response
0
250
N at risk
Renal response
P =0.03
20 0
20
40 60 80 100 120 Time (months)
26 23
18 12
13 12
N at risk 4 4
1 3
0 2
11 10
8 7
5 4
Figure 3 | Renal and patient survival. (a) Kaplan–Meier renal survival analysis. (b) Kaplan–Meier patient survival analysis. (c) Kaplan–Meier renal survival analysis, comparing patients with or without renal response. (d) Kaplan–Meier patient survival analysis, comparing patients with or without renal response. The nine patients who required dialysis at diagnosis were excluded from renal survival analysis.
Table 4 | Characteristics of renal responders Non-renal responders (n = 23) Age, years Male, n (%) Symptomatic myeloma, n (%) 24 h Proteinuria, g Baseline eGFR, ml/min per 1.73 m2 Baseline eGFRo30 ml/min, n (%) Dialysis at diagnosis, n (%) Baseline dFLC HDM/ASCT, n (%) dFLC o40 mg/l post treatment, n (%) dFLC reduction by 490% post treatment, n (%)
67 13 5 1 20.6 14 7 640 6 9 10
(59–73) (57) (22) (0.5–2.9) (11.4–28.3) (61) (30) (129–1831) (26) (39) (43)
Renal responders (n = 26)
P
61 (54–67) 14 (54) 5 (19) 1.5 (1–4.6) 30.9 (18.7–40.1) 9 (35) 1 (4) 299 (125–1292) 12 (46) 22 (85) 23 (88)
0.14 1 1 0.32 0.045 0.08 0.02 0.54 0.23 0.001 0.004
Abbreviations: dFLC, difference between involved and uninvolved free light chains; eGFR, estimated glomerular filtration rate; HDM/ASCT, high-dose melphalan followed by autologous stem cell transplantation.
median of 3 (2–5.5) months from diagnosis. Causes of death were infection (n = 4) and epidermoid carcinoma of an unknown primary site (n = 1). The estimated overall survival at 10 years was significantly higher in renal responders comparatively to non-renal responders (100% vs. 78%, respectively, P = 0.03; Figure 3). DISCUSSION
We herein report the French experience of 49 patients with MIDD who received bortezomib-based regimens. To our knowledge, this is the largest series of MIDD patients treated with novel anti-myeloma agents. Clinical and demographic characteristics were similar to prior studies, with male preponderance, and a majority of patients in their seventh 6
decade. The diagnosis of MIDD was mostly assessed by kidney biopsy, showing the hallmark disease lesion, i.e., linear amorphous monoclonal Ig deposits along tubular basement membranes, commonly associated with glomerular and arteriolar deposits.2–6 Although most patients presented with glomerular symptoms, only 16.3% had nephrotic syndrome. Moreover, 10 patients had MIDD without significant proteinuria, a finding that was probably related to the predominance of ischemic tubulointerstitial lesions, with severe arteriolar involvement and only focal nodular glomerulosclerosis. These cases indicate that kidney biopsy should be considered in patients with monoclonal gammopathy and otherwise unexplained CKD, even in the absence of glomerular symptoms.8 The inclusion of this subgroup of Kidney International
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non-proteinuric MIDD patients accounts for the relatively low level of 24-h proteinuria in our study. When these 10 patients were excluded from analysis, median proteinuria was 2.5 g/day, a value close to those reported by Pozzi et al. (2.7 g/day) and Nasr et al. (4.1 g/day).4,5 In the present cohort, 78% of patients had an indolent underlying clonal disorder, consistent with MGRS. In previous series, the prevalence of multiple myeloma in MIDD ranged from 58 to 65% depending on the definition used for the diagnosis, but the prevalence of symptomatic disease, defined by the CRAB criteria,23 was usually not given.3–5 These data confirm that physicochemical peculiarities, rather than tumor mass, govern the nephrotoxic properties of monoclonal Ig in MIDD, as in most types of renal disorders in MGRS.6 In accordance with Nasr et al.,5 all patients tested for serum FLC had abnormal results, whereas a serum or urine monoclonal component was detected by electrophoresis/immunofixation in only 67% of cases. This suggests that serum FLC should be considered in the diagnostic workup of adults over 50 presenting with renal disease. Interestingly, all patients with HCDD had abnormal serum FLC levels at diagnosis. Of these, seven patients who achieved renal response after bortezomib therapy showed concomitant FLC response. Whether monitoring of serum FLCs is useful to assess treatment efficacy in HCDD remains to be confirmed in larger series. Recent expert consensus opinion recommends that chemotherapy in MIDD should be adapted to the nature of the B-cell clone secreting the neprotoxic monoclonal Ig. Consequently, bortezomib-based regimens should be used as first-line treatment in patients with plasma cell disorders.10 However, few data are currently available on the impact of this strategy on renal and patient outcomes. Only case reports underscored the efficacy and tolerance of bortezomib in HCDD and LCDD, including in patients with disease recurrence after renal transplantation or presenting with acute renal failure.17–22 In our experience, bortezomib-based combinations were highly efficient, with an overall hematological response rate of 91%, including VGPR or above in 70.4% of patients. Sustained hematological remissions were associated with survival of 100% at 85 months. By contrast, median patient survival was 494 and 54 months,3 in the largest series published before the era of novel anti-myeloma agents. Bortezomib therapy also resulted in a dramatic improvement in renal survival. Whereas median time to dialysis was 22 months in a large previous series,3 median renal survival was not reached in our cohort. Almost half of patients achieved a renal response, with only two patients progressing to end-stage renal disease. Moreover, we found that renal response was associated with significantly higher estimated renal and overall survival, suggesting that it represents a key issue in the management of MIDD. Renal response was observed even in patients with LCDD-associated cast nephropathy, in sharp contrast with the poor renal and overall survival reported by Lin et al. in this subgroup.3 These results are consistent with the efficacy of bortezomib-based regimens in myeloma cast Kidney International
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nephropathy, in which they induce rapid and often complete hematological response, resulting in renal improvement in more than 60% of patients not requiring dialysis.24–27 Of note, one patient with pure LCDD was withdrawn from hemodialysis 22 months after achievement of hematological response. Whether delayed renal response corresponds to slow catabolism of deposited Ig after clonal suppression, as recently suggested, remains to be confirmed.20,28 In the present series, renal response was independently associated with post-treatment dFLC o40 mg/l, suggesting that the quality of hematological response strongly influences renal prognosis in MIDD, as in AL amyloidosis.29 However, patients with CKD stages 1–3 at diagnosis had higher probability of renal response, compared with those with CKD stages 4–5. In the latter, the indication of chemotherapy should be carefully evaluated, depending on age, presence of extrarenal symptoms, and eligibility for a renal transplantation. Although few data are available on renal transplantation in MIDD, disease recurrence resulting in graft loss is nearly constant if the hematological disorder is not controlled.11 Three patients received a renal allograft, all with complete hematological response or VGPR at the time of transplantation. None experienced hematological relapse or disease recurrence, as demonstrated by follow-up transplant biopsies. Achieving sustained hematological remission appears therefore as a favorable prognosis factor of renal allograft survival in MIDD. Our data support the use of bortezomib-based combinations as first-line therapy, as hematological relapse was observed in only 1 out of 38 patients who received bortezomib as first-line therapy, compared with 4 of 11 patients who were given bortezomib as rescue therapy. Although bortezomib was administrated intravenously and twice weekly in most patients, tolerance profile was good, as only one patient required treatment discontinuation. Adaptation of treatment schedules in the more fragile patients, with subcutaneous injections or weekly administration, should be considered to reduce toxicity.30 In this retrospective series, bortezomib-based regimens were not standardized and the modalities of chemotherapy in MIDD remain to be defined. CyBorD, which does not require dosage adjustment in CKD patients, appears as a promising strategy, as it was well tolerated and induced high hematological and renal response rates. Recent studies in AL amyloidosis31–33 have shown the efficacy of the CyBorD regimen, including in patients with severe cardiac amyloidosis. HDM/ASCT was also safe in our cohort, although significant morbidity and treatment-related mortality has been reported in myeloma patients with CKD, particularly in those requiring dialysis.34,35 We did not observe any difference in terms of renal response or time to progression among patients who received or not HDM/ASCT. However, as hematological response rates were similar after HDM/ ASCT and bortezomib-based regimens, the indication of HDM/ASCT should be carefully weighted in MIDD patients with severe renal impairment.10 7
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In summary, bortezomib-based regimens may represent a promising treatment strategy in MIDD, particularly when used early in the disease course. Achievement of dFLC below 40 mg/l appears as a strong predictive factor of renal response. Treatment efficacy should be monitored using serial FLC measurements, as in AL amyloidosis. MATERIALS AND METHODS Patients Forty-nine patients referred to seven French university centers were retrospectively studied. Inclusion criteria were: (1) established diagnosis of MIDD, with (i) diffuse linear monoclonal Ig deposits along basement membranes of renal distal tubules, glomeruli, and/or around arteriolar myocytes by immunofluorescence, (ii) that stained positive for κ or λ LC only (LCDD), for γ or α heavy chain (HC) only (HCDD), or for both monoclonal LC and HC deposits (LHCDD), (iii) punctate powdery electron-dense deposits on tubular or glomerular basement membranes by electron microscopy when available; and (2) patients should have received at least one cycle of bortezomib-based therapy, as first line or at relapse. Demographics, clinical, and biological data were recorded at diagnosis, after completion of bortezomib therapy and at last followup. The following definitions were used: hypertension: systolic blood pressure 4140 mm Hg and/or diastolic blood pressure 490 mm Hg or use of anti-hypertensive drugs; nephrotic syndrome: 24-h proteinuria ⩾ 3 g and albuminemia ⩽ 30 g/l. eGFR was calculated using the modified Modification of Diet in Renal Disease equation.36 CKD was defined based on the Kidney Disease Outcomes Quality Initiative classification.37 The diagnosis of monoclonal gammopathy of undetermined significance and multiple myeloma was established according to the International Myeloma Working Group,23 and Waldenström macroglobulinemia was defined according to the international criteria.38 Hematological response was assessed according to the International Myeloma Working Group for patients with symptomatic myeloma.39 In patients with MGRS, the 2012 International Society of Amyloidosis criteria for hematological response were used.29 VGPR was defined by the achievement of dFLC of less than 40 mg/l, or by ⩾ 90% decrease in serum FLC level in patients with MGRS or myeloma, respectively. In two patients without available FLC results, hematological response was based on the monoclonal component serum level by electrophoresis.39 Renal response was defined according to the International Society of Amyloidosis criteria, by a 50% decrease (at least 0.5 g/day) of 24-h urine protein (urine protein must be 40.5 g/day pre-treatment) in the absence of a reduction in eGFR ⩾ 25%, or an increase in serum creatinine ⩾ 0.5 mg/dl.40 Patients with baseline proteinuria o0.5 g/day who achieved a 25% improvement in baseline eGFR value were considered as renal responders.8 The study was performed in accordance with the Declaration of Helsinki Principles and received approval by local ethics committees.
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specific for α, γ, and μ HC, and κ and λ LC (Dakopatts, Glostrup, Denmark). γHC subclasses were studied by indirect immunofluorescence using monoclonal antibodies specific for γ1, γ2, γ3, γ4 (clones NL16, GOM2, ZG4, RJ4, Unipath, Bedford, UK), and for the first (CH1) and second (CH2) γHC constant domains (clones TM15 and G7C, Abingdon Health, Birmingham, UK), with a polyclonal rabbit fluorescein isothiocyanate-conjugated anti-mouse IgG as secondary antibody (Immunotech, Marseille, France). Bronchial and liver biopsies were performed in one patient each, with LM and immunofluorescence studies using the same antibodies as described above. Kidney biopsy samples from 12 patients were available for ultrastructural studies. Ultra-thin sections were processed and examined under a JEOL JEM-1010 electron microscope (Jeol, Tokyo, Japan).41 Hematologic and immunologic studies Bone marrow smears and/or biopsy were performed in all patients. Serum and urine samples were systematically studied by conventional electrophoresis and immunofixation. In seven HCDD patients, western blotting analysis of the serum was performed as previously described.42 Serum FLCs were serially monitored in 47 patients (Binding Site, Birmingham, UK). Abnormal FLC ratio was defined as κ/λ ratio o0.26 or 41.65. Statistical analysis Data are expressed as medians with interquartiles for continuous variables and frequencies with percentages for qualitative variables. Fisher’s exact test and Mann–Whitney test were used for the comparison of qualitative and continuous variables, respectively. Survival analysis was performed by the Kaplan–Meier method using log-rank test for comparison of baseline groups. Statistical significance was assumed at Po0.05. Statistical analyses were carried out using GraphPad Prism version 5.1 (GraphPad Software, San Diego, CA). A multivariate logistic regression model was secondarily used to identify factors associated with renal response. DISCLOSURE
All the authors declared no competing interests.
AUTHOR CONTRIBUTIONS CC, BA, JPF, GT and FB designed the study. CC, BA and FB performed the study and wrote the manuscript. SC performed the multivariate analysis for predictive factors of renal response. All other authors provided data. REFERENCES 1.
2.
3.
Pathological studies All kidney biopsy samples were processed for LM and immunofluorescence microscopy, as previously described.41 By LM, sections were systematically stained with Congo red and examined under polarized light. Interstitial fibrosis, tubular atrophy, and vascular sclerosis were graded semi-quantitatively on a scale from 0 to 3+. Immunofluorescence studies were performed on 3 μm cryostat sections using polyclonal fluorescein isothiocyanate conjugates 8
4.
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