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 bortezomib-based 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 (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:

  • 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]

TABLE. Hematologic and Renal Responses by Treatment Type
  All Patients

(N=50)

Chemotherapy

(n=29)

Immunotherapy and Conservative Therapy

(n=21)

p Value
Hematologic response 18/49

37%

17/29

59%

1/20

5%

0.0002
CR 9

(18%)

8

(28%)

1

(5%)

0.06
VGPR 1

(2%)

1

(3%)

0 1
PR 8
(16%)
8
(28%)
0 0.01
No response 31

(63%)

12

(41%)

19

(95%)

0.0002
N/A 1

(2%)

1

(5%)

1
Severe AEs 6

(12%)

5

(21%)

1

(5%)

0.21
Renal response 20/48

(42%)

19/27
(74%)
1/21

(5%)

0.0001
CR 6

(13%)

6

(22%)

0 0.001
PR 14

(29%)

13

(48%)

1

(5%)

0.002
No response 28

(58%)

9

(32%)

19
(90%)
0.0001
N/A 2

(4%)

2

(6%)

0
CR = complete response; VGPR = very good partial response; PR = partial response; N/A = not available; AEs = adverse events

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