|Year : 2016 | Volume
| Issue : 1 | Page : 9-14
|Multiple myeloma: Diagnosis and management issues in patients with pre-existing chronic kidney disease
Srilatha Vadlamudi, Siva Nagendra Reddy Annapareddy
Department of Nephrology, NRI Medical College, Chinakakani, Guntur District, Andhra Pradesh, India
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|Date of Web Publication||15-Jan-2016|
| Abstract|| |
Multiple myeloma is one of the most common malignancies encountered in clinical practice. Renal involvement in myeloma is a well-recognized entity. Although rare, another special situation that a nephrologist can encounter is myeloma occurring in a patient with preexisting chronic kidney disease (CKD) due to other etiologies. Anemia, bone pains and hypercalcemia, which commonly indicate the diagnosis of myeloma in the general population, are not useful in the presence of CKD. The sensitivity and specificity of serum free light chain assay is decreased in the presence of renal failure. Chemotherapy-related adverse effects are high compared with that in patients without CKD; this is attributed to the decreased clearance of drugs and the additive effect of chemotherapy-related adverse effects to the complications of CKD. Autologous and allogenic bone marrow transplantation can be attempted in this group of patients with non-myeloablative-conditioning regimens. Combined bone marrow and renal transplantation remains a viable option in this group of patients to increase life expectancy and quality of life.
|How to cite this article:|
Vadlamudi S, Annapareddy SN. Multiple myeloma: Diagnosis and management issues in patients with pre-existing chronic kidney disease. Saudi J Kidney Dis Transpl 2016;27:9-14
|How to cite this URL:|
Vadlamudi S, Annapareddy SN. Multiple myeloma: Diagnosis and management issues in patients with pre-existing chronic kidney disease. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2019 Dec 9];27:9-14. Available from: http://www.sjkdt.org/text.asp?2016/27/1/9/174046
| Introduction|| |
Multiple myeloma (MM) accounts for 10% of all hematological malignancies.  Renal involvement is common in MM, occurring in 50% of patients. Most of the patients respond to chemotherapy while approximately 2-12% become dialysis dependent.  Although rare, another special situation that a nephrologist can encounter is MM occurring in a patient with pre-existing chronic kidney disease (CKD) due to other etiologies. MM in a patient with preexisting CKD is elusive to diagnosis as the clinical symptoms and signs that commonly aid the diagnosis of MM are not useful in the presence of CKD. Patients may present with acute deterioration of renal function, resistant anemia or pathological fractures. Diagnosis of underlying plasma cell dyscrasia is important, particularly when a patient has transplant prospects. Unidentified disease may lead to graft loss and the patient may need both bone marrow and kidney transplant. In this article, we discuss the diagnostic and management issues in patients with MM and pre-existing CKD.
| Clinical Features of MM|| |
The clinical features of MM and their prevalence are shown in [Table 1].
| Diagnostic Problems with MM in CKD|| |
Most of the common symptoms that help the clinician in the diagnosis of MM are not helpful in patients with pre-existing CKD. Anemia occurs in 80% of patients with MM  and remains one of the most important clues for the diagnosis of myeloma. It is usually normocytic and normochromic and related to the replacement of bone marrow by tumor cells and inhibition of hematopoiesis by factors produced by the tumor cells.  Anemia is not useful in the diagnosis of MM in patients with CKD as it is present in both conditions. Diagnosis can be suspected only when erythropoietin (EPO) resistance is documented. EPO resistance is defined as failure to achieve hemoglobin targets with an EPO dose of 150- 300 IU/kg body weight administered intravenously (i.v.) thrice a week.  Diagnosis of EPO resistance takes time and there are several other reasons for EPO resistance, delaying the diagnosis of myeloma.
Bone pain is another common symptom of MM, occurring in 70% of the patients.  In patients with CKD, bone pains are commonly implicated to renal osteodystrophy and, as such, are not useful for the treating physician to suspect myeloma. Short of bone biopsy, which is an invasive procedure and hence not practiced routinely, the cause for bone pain cannot be diagnosed accurately. Even in patients presenting with a solitary lytic lesion and pathological fracture, the diagnosis is confounded by the brown tumors due to hyper-parathyroidism.
Hypercalcemia is a common metabolic abnormality occurring in 30% of patients with MM;  however, it is not useful in patients with CKD due to usage of calcium and vitamin D analogues. Only persistent hypercalcemia after discontinuation of drugs is useful for the diagnosis of MM. Elevation of serum total proteins and hyper-globulinemia are also not useful for the diagnosis of MM as they are masked by the hypoproteinemia present in CKD. Hence, the diagnosis of MM in CKD requires a high index of suspicion due to the many confounding factors.
In the presence of CKD, there are issues related to the investigations used for the diagnosis of plasma cell dyscrasias. Urine protein electrophoresis and immune-fixation can give abnormal results in the presence of renal failure in view of anuria in some patients or altered filtration of paraproteins in renal failure.
Serum free light chain assays have high sensitivity and specificity compared with serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), serum and urine immune-fixation. In this assay, monoclonal gammopathy is suggested by the presence of an abnormal kappa to lambda ratio (ref range 0.26-1.65).  Patients with renal failure have elevated kappa to lamda ratios without any evidence of monoclonal gammopathy due to altered clearance of kappa and lambda chains. 
In normal subjects, the preferential route for light chain clearance is the kidney. Kappa chains are monomeric and hence cleared rapidly from circulation compared with lambda chains, leading to a median kappa to lambda ratio of 0.6. In patients with renal failure, the reticuloendothelial system becomes the preferential mode of clearance and the half-lives of kappa and lambda are altered, giving a median kappa to lambda ratio of 1.8. 
Studies have shown that the concentration of polyclonal free light chains increase progressively as the glomerular filtration ratio (GFR) declines. Therefore, the specificity of serum free light chain assays in diagnosing myeloma may be reduced as the elevation may just reflect renal failure rather than monoclonal gammopathy. 
Hutchinson et al conducted a study to evaluate the serum free light assay as a diagnostic tool for detecting monoclonal free light chains and the underlying MM in patients with dialysis-dependent acute kidney injury. They concluded that the reference range of 0.26-1.65 must be increased in patients with renal failure to improve the specificity of the test.  Increasing the reference (0.31-3.1) increased the specificity to 99% from 93% without reducing sensitivity. Interpretation of the reference range between 1.6 and 3.1 is difficult because it could be due to renal failure or monoclonal gammopathy. 
| Problems with the Existing Staging Systems of Myeloma in CKD|| |
The two staging systems of MM, namely the Durie Salmon and the International Staging System, are not useful when myeloma occurs in a patient with pre-existing CKD. The Durie Salmon system is based on hemoglobin, serum calcium, bone lesions and quantification of M protein. Of these variables, calcium and hemoglobin are influenced by CKD and hence are not useful for staging when myeloma occurs in a patient with CKD.
The International Staging System, which is based on beta 2 microglobulin and albumin, is not useful as both these variables are altered in renal failure. Serum beta 2 microglobulin is the single most important predictor for survival and can substitute for staging.  Because the beta 2 microglobulin levels increase in patients with renal failure, these levels cannot be used as markers for survival when myeloma occurs in a patient with CKD. 
Even though the beta 2 microglobulin levels increase in renal failure, the heavy chain of this substance is not elevated and correlates with the tumor burden. In a study by Perosa et al,  it was shown that a staging system based on free beta 2 microglobulin, free heavy chain and IgM levels predicted prognosis in patients with and without renal failure.
| Management of MM in CKD|| |
Management of MM in a patient with preexisting CKD does not differ much from that in patients with CKD secondary to myeloma. The major issue is that if the patient undergoes transplantation with an undiagnosed disease, it leads to recurrence in the graft and graft loss.
| Issues Related to Chemotherapy in the Presence of CKD|| |
Traditional chemotherapy consisted of alkylating agents such as melphalan and steroids. Subsequently, many new drugs have been introduced such as thalidomide, lenalidomide and bortezomib. All the chemotherapyrelated adverse effects are increased in patients with CKD because decreased drug clearance can lead to more adverse effects even with a reduced dose; e.g,: myelosuppression with melphalan. Also, the adverse effect of a drug may become additive to the complication of CKD; e.g. peripheral neuropathy with thalidomide and bortezomib and hyperkalemia with thalidomide.
The following are the regimens regularly used to treat myeloma and their relevance to renal failure.
Melphalan 8-10 mg orally on Days 1-7 and prednisolone 60 mg on Days 1-7, repeated every six weeks, was established as the standard regimen for the treatment of MM in a trial involving 183 patients, which showed that the melphalan-prednisolone combination prolongs survival compared with melphalan alone.  Dose modification is required for melphalan in patients with CKD to reduce hematological toxicity. Approximately 75% of the dose with a GFR of 10-50 mL/min and 50% of the dose with a GFR <10 mL/min is to be administered.
The mechanism of action of thalidomide is not known but probably acts as an immunemodulator. Thalidomide 200 mg/day on Days 1-28 and dexamethasone 40 mg on Days 1, 8, 15 and 22 can be used for both primary and relapsed disease treatment.  Thalidomide can aggravate the peripheral neuropathy and hyperkalemia seen in patients with CKD.  The dose should be reduced to 50-100 mg/day when the GFR is <50 mL/min.
Lenalidomide is a 4-amino substituted analogue of thalidomide and is used in combination with dexamethasone for the treatment of MM. The normal dose is 25 mg/day orally on Days 1-21 and dexamethasone 40 mg orally on Days 1, 8, 15 and 22 of a 28-day cycle. However, the dose needs to be reduced in renal failure; 10 mg/day (GFR 30-50 mL/ min), 15 mg on alternate days (GFR <15 mL/ min) and 15 mg only on the days of dialyisis in end-stage renal disease.  There is an increased risk of myelosuppression in renal failure compared with that in normal patients. 
Bortezomib is a proteasome inhibitor used for the treatment of primary, relapsed and refractory myeloma. It causes apopotsis of the plasma cells and interferes with inflammatory pathways.  It can be combined with dexamethasone alone or with dexamethasone plus thalidomide or linaledomide or melphalan. The dose does not need to be reduced in renal failure. Peripheral neuropathy, which is seen in patients with chronic renal failure, may be aggravated with bortezomib therapy. The standard dose is 1.3 mg/m 2 on Days 1, 8, 15 and 22. In view of the high response rates documented in several studies, bortezomib is now the first line of choice for inducing remission.
| Role of Renal and Bone Marrow Transplantation|| |
Renal transplantation alone without treating MM is not recommended in view of recurrence. Renal transplant can be taken up only after induction of remission with chemotherapy ± stem cell transplant. Many centers recommend a disease-free interval of 3-5 years before proceeding for renal transplantation. 
However, majority of the patients with renal failure and MM do not receive autologous or allogenic bone marrow transplantation in view of increased morbidity and mortality. Majority of reviews exclude patients with serum creatinine of >2.5 mg/dL from stem cell transplant studies and therefore the benefits of stem cell transplant in patients with severe renal insufficiency are not clear. 
Engraftment of recipient bone marrow with donor hematopoietic stem cells exerts its beneficial effects in two ways: (a) replacement of the malignant cells of recipient by donor stem cells: This occurs with the cyto-reductive effect of the intensive high-dose condition regimens such as myelo-ablative therapy and total body irradiation, which leads to the development of full chimerism. This cannot be used in patients with CKD due to high morbidity and mortality and (b) graft versus malignant effect: With the use of non-myeloablative conditioning regimens (fludarabine, reduced doses of irradiation and low dose of alkylating agents such as cyclophosphamide 5-5.7 g/m 2 ), only part of the recipient hematopoietic cells are replaced, which leads to the development of mixed chimerism. A patient is defined as mixed chimeria if 5-95% of hematopoietic cells are of donor origin. Mixed chimerism exerts its beneficial effects by graft vs malignant effect,  in which the donor hematopoietic cells attack and destroy the recipient malignant cells. Studies have shown that patients with CKD can be taken up for stem cell transplant with non-myeloablative conditioning regimens  that reduce the chemotherapy-related morbidity.
Animal models as well as some clinical studies have shown that kidney from the same donor can be transplanted without immunosuppression after bone marrow transplant due to induction of tolerance. Studies have shown that the tolerance continues even after the disappearance of chimerism and the development of a full donor chimeric status is not required for the induction of tolerance. Basing on this principle, combined bone and kidney transplantation was attempted in patients with MM and chronic renal failure with reduced intensity conditioning regimens. Three studies are reported in the literature about induction of tolerance following combined kidney and bone marrow transplantation.
The Stanford group has developed a total lymphoid irradiation regimen-based protocol for the induction of renal allograft tolerance in HLA identical kidney transplantation. Fifteen of the sixteen patients developed mixed chimerism and eight patients were off immunosuppression. Four patients continued immunosuppression because of rejection in three and recurrence of focal and segmental glomerulosclerosis in one.  However, this protocol failed when attempted in HLA-mismatched transplants.  Six patients who underwent simultaneous kidney and bone marrow transplant from HLA-identical siblings following a non-myeloablative conditioning regimen accepted their grafts in the long term. The conditioning regimen included cyclophosphamide 60 mg/kg/day intravenously on Days 4 and 5, thymic irradiation (700 cGy) on Day 1 and equine anti-thymocyte globulin 15-20 mg/kg body weight on Days 1, 3 and 5. Cyclosporine was given for two months post-operatively followed by donor leukocyte infusions. All the patients accepted grafts even when mixed chimerism was lost and there was development of anti-donor responses in vitro. 
In a study by Sachs et al, ten patients received combined kidney and bone marrow transplant from HLA-mismatched donors. The pre-conditioning regimen was the same as that for matched donors for the first three patients;  four to six patients received two additional doses of peri-transplant rituximab following acute humoral rejection and seven to ten patients received four doses of peri-transplant rituximab. All the ten patients developed chimerism following transplant, which was undetectable by Day 21, and no graft versus host disease occurred. Immunosuppression was discontinued in seven of the ten patients. One patient returned to dialysis due to the development of thrombotic microangiopathy and one other patient developed cellular rejection. The remaining patients accepted grafts without immunosuppression.  Thus, because patients with CKD tolerate chemotherapy poorly, combined kidney and bone marrow transplant is a viable option for this high-risk group in order to increase life expectancy and quality of life.
| Conclusions|| |
MM in CKD is elusive to diagnosis in view of confounding clinical features and laboratory investigations. Diagnosis is important as undiagnosed disease may lead to recurrence in the graft and graft loss following renal transplant. Patients with CKD are at high risk for chemotherapy-induced adverse events and doses must be reduced appropriately. Autologous or allogenic bone marrow transplant followed by renal transplant or simultaneous kidney and bone marrow transplant remains a viable option in this group of patients.
| Key Points|| |
- Myeloma can occur in patients with preexisting CKD and is elusive to diagnosis.
- Anemia, bone pains and hypercalcemia are not useful for diagnosis.
- Autologous and allogenic bone marrow transplant can be offered to these patients with non-myeloablative-conditioning regimens.
- Combined bone marrow and kidney transplant induces tolerance and offers cure to these patients.
Conflicts of interest: None
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Department of Nephrology, NRI Medical College, Chinakakani, Guntur District - 522 503, Andhra Pradesh
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