Big coffee interview | Professor Chen Wenming: How should patients with multiple myeloma with renal insufficiency be treated?

Renal insufficiency is one of the most common complications of multiple myeloma (MM), and about 30% of newly diagnosed MM (NDMM) patients are accompanied by renal insufficiency.

For patients with MM with renal insufficiency, rapid-acting drugs are needed to control MM, inhibit the secretion of light chains, reverse the damaged renal function, and improve the prognosis of patients.

Therefore, for MM patients with renal insufficiency, the choice of therapeutic drugs is very important.

Recently, Professor Chen Wenming from Beijing Chaoyang Hospital affiliated to Capital Medical University published a special article titled "How do I treat multiple myeloma patients with renal insufficiency" in the "Chinese Journal of Hematology" expert talks column, and shared Typical cases of MM with renal insufficiency and opinions on the treatment of such patients.

Yimaitong is fortunate to invite Professor Chen Wenming to accept an interview, combining clinical research progress and clinical experience, to share the status of diagnosis and treatment of patients with MM with renal insufficiency and the choice of treatment options.

Yimaitong: What are the clinical manifestations of patients with multiple myeloma with renal insufficiency? Professor Chen Wenming's three common clinical manifestations of multiple myeloma are anemia, bone disease and kidney disease.

Many patients were first diagnosed in the nephrology department because of kidney disease.

Early renal damage caused by MM is mainly manifested as proteinuria, some patients may have hematuria, and further aggravated patients may develop renal insufficiency.

Proteinuria is mainly due to the free light chains secreted by MM cells, which have a small molecular weight and can be excreted in urine to form light chain proteinuria; in addition, free light chains can be concentrated at the distal end of the renal tubule to form a cast and block the distal end Renal tubules, leading to renal tubular renal insufficiency; free light chains may also cause renal amyloidosis or renal light chain deposition disease.

Therefore, in terms of composition, proteinuria in patients with MM nephropathy can be pure free light chain, albumin with or without light chain, or mixed (both albumin and globulin) proteinuria With or without light chain.

In addition, patients may also experience changes in urine output, which can be used to determine the extent and location of kidney damage.

If the patient’s kidney is damaged in the distal renal tubules, resulting in dysfunction of urine concentration, the patient may experience increased nocturia.

Although some patients have proteinuria, the urine output may be normal if the kidneys are not significantly damaged.

If the renal tubules are severely blocked, the patient may experience reduced urine output, and urinary excretion disorders may also cause the patient to develop edema symptoms.

Yimaitong: How to distinguish MM with renal insufficiency from renal insufficiency caused by other diseases? Professor Chen Wenming has many causes of renal insufficiency, including glomerulonephritis, diabetic nephropathy, hypertensive nephropathy, drug-related nephropathy, etc.
Myeloma-related nephropathy is just one of them.

MM nephropathy mainly manifests as light chain type proteinuria or albumin-based proteinuria.

In addition, MM nephropathy mainly causes renal tubular lesions.
The glomeruli are generally not lesions.
Therefore, the patient's blood pressure is normal, the kidney size is normal (it may be larger when accompanied by amyloidosis), and the cortical thickness is normal.

Glomerulonephritis, diabetic nephropathy, and hypertensive nephropathy are often caused by insufficient blood supply to the kidneys to cause glomerular atrophy, leading to shrinkage of the kidney and thinning of the cortex.
At the same time, patients have mixed proteinuria, often accompanied by high blood pressure.

Based on these clinical features, it is not difficult to identify MM nephropathy clinically.

Yimaitong: There are more and more treatment drugs for multiple myeloma.
How should patients with renal insufficiency choose drugs? Professor Chen Wenming currently, the treatment drugs for multiple myeloma mainly include proteasome inhibitors, immunomodulators, monoclonal antibodies, cytotoxic drugs, small molecule drugs and glucocorticoids.

The proteasome inhibitors currently used internationally include bortezomib, ixazomib and carfilzomib.

The excretion of bortezomib is basically not affected by renal function, and bortezomib has a fast onset of action and relatively small side effects.
Therefore, bortezomib can be the first choice for patients with impaired renal function. Preliminary research data of ixazomib showed that patients with renal insufficiency should adjust the dose according to the creatinine clearance rate.
The latest study found that ixazomib may not necessarily need to be adjusted.
It can be seen that ixazomib is more affected by renal function.
small.

Internationally, there are few clinical data on the application of carfilzomib to patients with renal insufficiency, but the cardiotoxicity of carfilzomib may be stronger than that of bortezomib and ixazomib, plus MM with renal amyloidosis Patients may have different degrees of cardiac amyloidosis, and the use of carfilzomib is relatively unsafe.

Therefore, for MM patients with renal insufficiency, bortezomib is the first choice, followed by ixazomib, and finally carfilzomib.

The main immunomodulators are thalidomide, lenalidomide and pomalidomide.

The use of thalidomide is not affected by renal function, so patients with renal insufficiency can use thalidomide.

Both lenalidomide and pomalidomide need to be metabolized by the kidneys.
Therefore, patients with renal insufficiency will slow down the excretion of the drug, and increase hematological toxicity and bone marrow suppression toxicity.
Therefore, the dosage needs to be adjusted appropriately according to the creatinine clearance rate.

The monoclonal antibody currently on the market, the anti-CD38 monoclonal antibody (daratumumab), has good curative effect, quick onset, and can quickly reduce the light chain to further reduce kidney damage, and daratumumab is not metabolized by the kidneys , So patients with renal insufficiency can use it normally.

Small molecule drugs include anthracyclines, nitrosoureas and the like.

The most commonly used clinically are cyclophosphamide and anthracyclines (such as doxorubicin, etc.
).

Cyclophosphamide can be used safely under the condition of normal urine output, but its metabolites can easily cause hemorrhagic cystitis, and its use needs to be restricted when there is oliguria or anuria.

Anthracyclines have cardiotoxicity.
Because patients with renal amyloidosis are often accompanied by different degrees of cardiac amyloidosis, the use of anthracyclines is unsafe.

Therefore, for MM patients with renal insufficiency, cyclophosphamide is commonly used in clinical practice.

The last class of drugs is glucocorticoids, the most commonly used clinically at present are prednisone, methylprednisolone and dexamethasone.

Theoretically, dexamethasone has the strongest anti-tumor activity, but its sodium and water retention effect is also strong.
When patients with hypoproteinemia or severe edema use dexamethasone, sodium and water retention may increase the kidney and heart The burden of heart failure increases the risk of heart insufficiency, but if the patient does not have obvious amyloidosis, or if the heart function is normal, dexamethasone can be selected for treatment.

Prednisone needs to be metabolized by the liver in order to have drug activity, so prednisone can be used in patients with no liver disease, and the side effects of prednisone are relatively lighter than dexamethasone and methylprednisolone.

However, if patients with MM with renal insufficiency also have liver disease, the efficacy of prednisone will be weakened.
At this time, methylprednisolone or dexamethasone can be selected.

In summary, each drug has its unique characteristics and advantages.
In clinical work, an appropriate treatment plan should be selected according to the actual situation of the patient.

For MM patients with renal insufficiency, if a treatment plan is to be selected in advance, the four-drug combination of daretuzumab, bortezomib, thalidomide, and dexamethasone (D-VTd) is currently the best The choice of treatment can allow the patient to get relief as soon as possible; if the patient is also accompanied by arrhythmia, you can choose the three-drug combination of daratumomab, bortezomib, and dexamethasone (DVd).

If the patient has only simple proteinuria and no increase in creatinine, the D-VRd regimen (daratumomab, bortezomib, lenalidomide, dexamethasone) can be selected.

If the patient’s economic conditions are really limited, then bortezomib, thalidomide, dexamethasone (VTd) or a combination of bortezomib, lenalidomide, and dexamethasone (VRd) is also a very good treatment option .

Yimaitong: At present, daratumumab is mainly used for the treatment of relapsed and refractory MM, so what benefits can it be used in the first-line treatment of MM with renal insufficiency? Professor Chen Wenming Although daratumomab is mainly used clinically for patients with relapsed and refractory MM, it is actually used in the first-line treatment, especially for the first-line treatment of MM patients with renal insufficiency, which can provide patients with deep remission as soon as possible.
Reduce the further damage of light chain to tissues and organs. The combination of the latest drugs, such as the daratumomab combination regimen as a first-line treatment, sequential autologous hematopoietic stem cell transplantation, can enable about 60%-70% of patients to obtain minimal residual disease (MRD) negative (10-5) remission, It is a very good treatment plan.

Therefore, in the case of conditions, for MM patients with renal insufficiency or large proteinuria, daratumumab is a very good treatment option for the first-line treatment.

Yimaitong: In the process of symptomatic treatment of patients with MM with renal insufficiency, what should be paid attention to? In fact, Professor Chen Wenming, supportive treatment is very crucial in the course of disease treatment.

From the perspective of pathogenesis, MM patients with renal insufficiency are mainly renal tubular renal insufficiency.
The free light chain forms a cast that blocks the distal renal tubules.
The renal function can only be restored when the cast is removed.
Therefore, it is different from The limited intake of patients with glomerular renal insufficiency and supportive treatment for patients with renal insufficiency must be fluid and diuretic.
Even patients with anuria must be fluid and diuretic under the escort of dialysis.

The clinician must distinguish whether the patient's renal insufficiency is tubular or glomerular.

In addition, with regard to the need to limit sodium and potassium intake, renal insufficiency in patients with MM is often tubular renal insufficiency.
The patient does not have high blood pressure.
The previous diuretic conditions will lead to electrolyte loss.
If the dosage is restricted, it will appear.
Hyponatremia, hypokalemia, and electrolyte disturbances can easily cause arrhythmia.
In this case, maintaining electrolyte balance is particularly important.

Therefore, patients with MM with renal insufficiency do not need to restrict sodium and potassium intake.

In addition, protein intake is also a clinical concern.

Protein metabolites need to be excreted through the kidneys.
A high-protein diet may increase the burden on the kidneys.
Therefore, it is often clinically recommended that patients with renal insufficiency should have a low-protein diet.

However, it is generally not recommended for patients with MM with renal insufficiency to excessively limit protein intake.
Appropriate protein supplementation to reduce their own protein consumption is helpful for the recovery of the patient's body. Therefore, MM patients with renal insufficiency need to properly control protein intake only when creatinine is elevated, and normal diet is sufficient when creatinine is not high.

Professor Chen Wenming, Chief Physician, Professor, Doctor of Medicine, and Doctoral Supervisor, Director of the Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Director of Beijing Multiple Myeloma Medical Research Center, Director of the Department of Hematology, Capital Medical University, Consultant of the International Myeloma Working Group and China Multiple Myeloma Working Group Expert Committee Member of the Hematology Professional Committee of China Medical Education Association Member of the Standing Committee of the Hematology Branch of the Chinese Integrative Medicine Association Member of the Standing Committee of the Hematology Branch of the Chinese Geriatrics Society Member of the Hematology Branch of the Chinese Medical Association Hematopoietic Stem Cells Member of the Transplantation Group, Member of the Hematology and Tumor Branch of the Chinese Anti-Cancer Association