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Multiple Myeloma

(Myelomatosis; Plasma Cell Myeloma)

By

James R. Berenson

, MD, Institute for Myeloma and Bone Cancer Research

Last full review/revision Oct 2021| Content last modified Nov 2021
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Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing pain and/or fractures, renal insufficiency, hypercalcemia, anemia, and recurrent infections. Diagnosis typically requires demonstration of M-protein (sometimes present in urine and not serum but rarely absent entirely) and/or light-chain proteinuria, and excessive plasma cells in the bone marrow. Specific treatment most often includes some combination of conventional chemotherapy, corticosteroids, and one or more of the newer agents such as proteasome inhibitors (eg, bortezomib, carfilzomib, ixazomib), immunomodulating agents (eg, lenalidomide, thalidomide, pomalidomide), or monoclonal antibodies (eg, daratumumab, isatuximab, elotuzumab). High-dose melphalan followed by autologous peripheral blood stem cell transplantation may also be used.

The incidence of multiple myeloma is 2 to 4/100,000. Male:female ratio is 1.6:1, and the median age is about 65 years. Prevalence in Blacks is twice that in Whites. Etiology is unknown, although chromosomal and genetic factors, radiation, and chemicals have been suggested.

Pathophysiology

The M-protein (monoclonal immunoglobulin protein) produced by the malignant plasma cells is IgG in about 55% of myeloma patients and IgA in about 20%. Of patients producing either IgG or IgA, 40% also have Bence Jones proteinuria, which is free monoclonal kappa (κ) or lambda (λ) light chains in the urine. In 15 to 20% of patients, plasma cells secrete only Bence Jones protein. IgD myeloma accounts for about 1% of cases and is more frequent among patients of Asian descent. Rarely, patients have no M-protein in blood and urine, although the currently used serum free light chain assay now demonstrates monoclonal light chains in many of these formerly so-called nonsecretory patients.

Diffuse osteoporosis Osteoporosis Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more Osteoporosis or discrete osteolytic lesions develop, usually in the pelvis, spine, ribs, femur, humerus, and skull. Lesions are caused by bone replacement by expanding plasmacytomas or by cytokines that are secreted by malignant plasma cells that activate osteoclasts and suppress osteoblasts. The osteolytic lesions are usually multiple; occasionally, they are solitary intramedullary masses. Increased bone loss may also lead to hypercalcemia Hypercalcemia Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism, vitamin... read more . Extraosseous solitary plasmacytomas are unusual but may occur in any tissue, especially in the upper respiratory tract.

Because of lack of normal antibodies and other immune dysfunction, some patients have increased susceptibility to bacterial infection. Viral infections, especially herpes zoster infections Herpes Zoster Herpes zoster is infection that results when varicella-zoster virus reactivates from its latent state in a posterior dorsal root ganglion. Symptoms usually begin with pain along the affected... read more Herpes Zoster , are increasingly occurring as a result of newer treatment modalities, especially use of the proteasome inhibitors bortezomib, ixazomib, and carfilzomib and monoclonal antibodies such as daratumumab, elotuzumab, and isatuximab. Amyloidosis Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more Amyloidosis occurs in 10% of myeloma patients, most often in patients with lambda-type M-proteins.

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Symptoms and Signs

Persistent bone pain (especially in the back or thorax), renal failure, and recurring bacterial infections are the most common problems on presentation, but many patients are identified when routine laboratory tests show an elevated total protein level in the blood, proteinuria, or unexplained anemia or renal failure. Pathologic fractures (ie, fractures that occur with minimal or no trauma) are common, and vertebral collapse may lead to spinal cord compression Spinal Cord Compression Various lesions can compress the spinal cord, causing segmental sensory, motor, reflex, and sphincter deficits. Diagnosis is by MRI. Treatment is directed at relieving compression. (See also... read more Spinal Cord Compression and paraplegia. Symptoms of anemia predominate or may be the sole reason for evaluation in some patients, and a few patients have manifestations of hyperviscosity syndrome Symptoms and Signs Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins. Manifestations may include hyperviscosity, bleeding, recurring infections... read more . Peripheral neuropathy, carpal tunnel syndrome (especially with associated amyloid disease), abnormal bleeding, and symptoms of hypercalcemia (eg, polydipsia, dehydration) are common. Patients may also present with renal failure. Lymphadenopathy and hepatosplenomegaly are unusual.

Diagnosis

  • Complete blood count (CBC) with platelets, peripheral blood smear, erythrocyte sedimentation rate (ESR), and chemistry panel (blood urea nitrogen [BUN], creatinine, calcium, uric acid, lactate dehydrogenase [LDH])

  • Serum and urine protein (on a 24-hour urine collection) electrophoresis followed by immunofixation; quantitative immunoglobulins; serum free light chains

  • X-rays (skeletal survey) and either a positron emission tomography (PET)-CT scan or whole-body MRI

  • Bone marrow examination, including conventional cytogenetics and fluorescent in situ hybridization studies (FISH)

Multiple myeloma is suspected in patients > 40 years with persistent unexplained bone pain, particularly at night or at rest, other typical symptoms, or unexplained laboratory abnormalities (such as elevated blood protein or urinary protein, hypercalcemia, renal insufficiency, or anemia) or x-rays showing a pathologic fracture or lytic lesions. Laboratory evaluation includes routine blood tests, LDH, serum beta-2 microglobulin, urine and serum immune and protein electrophoresis, serum free light chains. Patients should also undergo a skeletal survey and, because they are more sensitive to bone disease than x-rays, either a PET-CT scan or whole-body MRI. A bone marrow examination is also required along with conventional cytogenetics and FISH studies (for review, see [1, 2] Diagnosis references Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing... read more Diagnosis references ).

Routine blood tests include CBC, ESR, and chemistry panel. Anemia is present in 80% of patients, usually normocytic-normochromic anemia with formation of rouleaux, which are clusters of 3 to 12 red blood cells that occur in stacks. White blood cell and platelet counts are usually normal. ESR usually is > 100 mm/hour; BUN, serum creatinine, LDH, beta-2 microglobulin, and serum uric acid may be elevated. Anion gap is sometimes low. Hypercalcemia is present at diagnosis in about 10% of patients.

Immune and protein electrophoresis is done on a serum sample and on a urine sample concentrated from a 24-hour collection to quantify the amount of urinary M-protein. Serum electrophoresis identifies M-protein in about 80 to 90% of patients. The remaining 10 to 20% are usually patients with only free monoclonal light chains (Bence Jones protein) or IgD. They almost always have M-protein detected by urine protein electrophoresis.

Immunofixation electrophoresis can identify the immunoglobulin class of the M-protein (IgG, IgA, or uncommonly IgD, IgM, or IgE) and can often detect light-chain protein if serum immunoelectrophoresis is falsely negative; immunofixation electrophoresis is done even when the serum test is negative if multiple myeloma is strongly suspected.

Serum free light-chain analysis with delineation of kappa and lambda ratios or differences between the involved and uninvolved light chains helps confirm the diagnosis and can also be used to monitor efficacy of therapy and provide prognostic data.

Serum level of beta-2 microglobulin is measured if the diagnosis is confirmed or very likely and along with serum albumin is used to stage patients as part of the international staging system (see table Revised International Staging System for Multiple Myeloma Revised International Staging System for Multiple Myeloma Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing... read more Revised International Staging System for Multiple Myeloma ). Beta-2 microglobulin is a small protein on the membrane of all cells. Its concentration varies directly with tumor mass and severity of renal dysfunction.

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X-rays include a skeletal survey (ie, plain x-rays of skull, long bones, spine, pelvis, and ribs). Punched-out lytic lesions or diffuse osteoporosis is present in 80% of cases. Radionuclide bone scans usually are not helpful. Whole-body MRI can provide more detail and is obtained if specific sites of pain or neurologic symptoms are present. PET-CT scans provide prognostic information and can help determine whether patients have solitary plasmacytoma or multiple myeloma.

Bone marrow aspiration and biopsy Bone marrow aspiration and biopsy Anemia is a decrease in the number of red blood cells (RBCs—as measured by the red cell count, the hematocrit, or the red cell hemoglobin content). In men, anemia is defined as hemoglobin read more Bone marrow aspiration and biopsy are done and reveal sheets or clusters of plasma cells; myeloma is diagnosed when >10% of the cells are of this type. However, bone marrow involvement is patchy; therefore, some samples from patients with myeloma may show <10% plasma cells. Still, the number of plasma cells in bone marrow is rarely normal. Plasma cell morphology does not correlate with the class of immunoglobulin synthesized. Chromosomal studies on bone marrow (eg, using cytogenetic testing methods such as FISH and immunohistochemistry) may reveal specific karyotypic abnormalities in plasma cells associated with differences in survival.

  • Clonal bone marrow plasma cells or plasmacytoma

  • M-protein in plasma and/or urine

  • Organ impairment (hypercalcemia, renal insufficiency, anemia, or bony lesions)

In patients without serum M protein, myeloma is indicated by Bence Jones proteinuria > 200 mg/24 hour or abnormal serum free light chain levels, osteolytic lesions (without evidence of metastatic cancer or granulomatous disease), and sheets or clusters of plasma cells in the bone marrow.

Diagnosis references

Prognosis

The disease is progressive and incurable, but median survival has recently improved to > 5 years as a result of advances in treatment. Unfavorable prognostic signs at diagnosis are lower serum albumin, higher beta-2 microglobulin levels, elevated LDH levels, and specific cytogenetic abnormalities in the tumor cells. Patients initially presenting with renal failure also do poorly unless kidney function improves with therapy (which typically happens with current treatment options).

Treatment

  • Conventional chemotherapy for symptomatic patients

  • Thalidomide, lenalidomide, or pomalidomide, and/or bortezomib, carfilzomib, or ixazomib, plus corticosteroids and/or conventional chemotherapy

  • Monoclonal antibodies, including elotuzumab, isatuximab, and daratumumab

  • Particularly for relapsed or refractory myeloma, selective inhibitor of nuclear export (SINE) selinexor, and the histone deacetylase inhibitor panobinostat

  • Particularly for relapsed or refractory myeloma, immune-based treatments that target B-cell maturation antigen (BCMA), which is highly expressed on myeloma cells

  • Maintenance therapy with corticosteroids, thalidomide, and/or lenalidomide, and proteasome inhibitors, especially oral ixazomib

  • Possibly autologous stem cell transplantation

  • Possibly radiation therapy to specific symptomatic areas that do not respond to systemic therapy

  • Treatment of complications (anemia, hypercalcemia, renal insufficiency, infections, and skeletal lesions (especially those associated with high risk of fracture)

Treatment of myeloma has improved in the past 2 decades, and long-term survival is a reasonable therapeutic target. Therapy involves direct treatment of malignant cells in symptomatic patients or those with myeloma-related organ dysfunction (anemia, renal dysfunction, hypercalcemia, or bone disease).

Risk factors for requiring rapid treatment of myeloma among patients initially presenting with organ dysfunction include > 60% plasma cells in bone marrow, > 1 lesion on MRI, and serum free light chain levels > 100 mg/L. These patients are considered to have active myeloma and require immediate treatment even though nearly all randomized clinical trials of early treatment of these patients have not yet shown an improvement in overall survival. Patients without these risk factors or end-organ dysfunction probably do not benefit from immediate treatment, which is usually withheld until symptoms or complications develop.

Treatment of malignant cells

Conventional chemotherapy in the past was initial treatment of multiple myeloma, consisting of oral melphalan and prednisone given in cycles of 4 to 6 weeks for 8 to 12 cycles with monthly evaluation of response. However, superior outcomes have been achieved with the addition of either a proteasome inhibitor, such as bortezomib, carfilzomib, or ixazomib, or the immunomodulatory agents lenalidomide or thalidomide. Other chemotherapeutic drugs, including cyclophosphamide, bendamustine, doxorubicin, and its analog, liposomal pegylated doxorubicin, also are more effective when combined with an immunomodulatory drug (thalidomide, lenalidomide, or bortezomib). Studies suggest better survival when initial treatment includes both bortezomib and lenalidomide with corticosteroids. In addition, the addition of the monoclonal antibody daratumumab to bortezomib and dexamethasone as part of initial treatment appears to improve outcomes.

Response to treatment (see table Defining Response to Cancer Treatment Defining Response to Cancer Treatment Curing cancer requires eliminating all cells capable of causing cancer recurrence in a person's lifetime. The major modalities of therapy are Surgery (for local and local-regional disease) Radiation... read more ) is indicated by decreases in serum and urine M-protein, decreases in levels of the involved serum free light chain, increases in numbers of red blood cells, improvement in renal function among patients presenting with renal failure, and normalization of calcium levels among those presenting with elevated levels. Bone pain and fatigue should also decrease.

Autologous peripheral blood stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more may be considered for patients who have adequate cardiac, hepatic, pulmonary, and renal function, particularly those whose disease is stable or responsive after several cycles of initial therapy. However, studies suggest that the newer treatment options are highly effective and may make transplantation less often necessary or unnecessary altogether.

Allogeneic stem cell transplantation after nonmyeloablative chemotherapy (eg, low-dose cyclophosphamide and fludarabine) or low-dose radiation therapy can produce myeloma-free survival of 5 to 10 years in some patients. However, allogeneic stem cell transplantation with myeloablative or nonmyeloablative chemotherapy remains experimental because of the high morbidity and mortality resulting from graft vs host disease Complications Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more .

Treatment of relapsed or refractory myeloma

For patients with relapsed or refractory myeloma, combinations of a proteasome inhibitor (bortezomib, ixazomib, or carfilzomib) with an immunomodulatory agent (thalidomide, lenalidomide, or pomalidomide) and chemotherapy or corticosteroids may be used. These drugs are usually combined with other effective drugs that the patient has not yet been treated with, although patients with prolonged remissions may respond to retreatment with the same regimen that led to the initial remission. Patients who fail to respond to a given combination of drugs may respond when another drug in the same class (eg, proteasome inhibitors, immunomodulatory agents, chemotherapeutic drugs) is substituted.

Monoclonal antibodies targeting proteins on myeloma cells may also be highly effective in relapsed or refractory myeloma and include daratumumab, isatuximab, and elotuzumab. These antibodies are more effective when combined with lenalidomide or pomalidomide and dexamethasone. Daratumumab also shows better results when combined with bortezomib and dexamethasone, and both daratumumab and isatuximab have better efficacy than carfilzomib and dexamethasone.

Newer drugs shown to be effective include the selective inhibitor of nuclear export (SINE) selinexor, and the histone deacetylase inhibitor (HDACi) panobinostat. The newer drugs are especially effective when combined with other active myeloma drugs. Two effective immune treatments that target B-cell maturation antigen (BCMA) have recently become available. These drugs are the antibody drug conjugate belantamab mafotodin and the first cellular treatment for myeloma, the chimeric antigen receptor (CAR)-T cell therapy idecabtagene vicleucel.

Maintenance therapy

Maintenance therapy has been tried with nonchemotherapeutic drugs, including interferon alfa, which prolongs remission but does not improve survival and is associated with significant adverse effects. Following a response to corticosteroid-based regimens, corticosteroids alone are effective as a maintenance treatment. Thalidomide may also be effective as a maintenance treatment, and studies show that lenalidomide alone or with corticosteroids is also effective maintenance treatment. However, there is some concern about secondary malignancy among patients receiving long-term lenalidomide therapy, especially after autologous stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more , and the risk of developing secondary cancers must be weighed against improved survival. In addition, the oral proteasome inhibitor ixazomib is effective as a single agent in the maintenance setting. Whether the combination of ixazomib with lenalidomide is more effective in this setting is yet unknown. The role of antibodies as maintenance therapy remains to be defined.

Treatment of complications

In addition to direct treatment of malignant cells, therapy must also be directed at complications, which include

  • Anemia

  • Hypercalcemia

  • Hyperuricemia

  • Infections

  • Renal insufficiency

  • Skeletal lesions

Anemia can be treated with recombinant erythropoietin (40,000 units subcutaneously once a week) among patients whose anemia is inadequately relieved by chemotherapy. If anemia causes cardiovascular or significant systemic symptoms, packed red blood cells are transfused Red blood cells (RBCs) Whole blood can provide improved oxygen-carrying capacity, volume expansion, and replacement of clotting factors and was previously recommended for rapid massive blood loss. However, because... read more . Plasma exchange Plasma exchange Apheresis refers to the process of separating the cellular and soluble components of blood using a machine. Apheresis is often done on donors where whole blood is centrifuged to obtain individual... read more is indicated if hyperviscosity Symptoms and Signs Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins. Manifestations may include hyperviscosity, bleeding, recurring infections... read more develops. Often patients are iron deficient for reasons unrelated to their myeloma and require intravenous iron. Patients with anemia should have periodic measurement of serum iron, transferrin, and ferritin levels to monitor iron stores as well as vitamin B12. levels

Hypercalcemia is treated with vigorous saluresis, IV bisphosphonates (preferably zoledronic acid) after rehydration, and sometimes with calcitonin or prednisone. Denosumab can also be used to treat hypercalcemia. Patients should avoid calcium-containing foods, calcium supplements, and vitamin D.

Hyperuricemia may occur in some patients with high tumor burden and underlying metabolic problems. However, most patients do not require allopurinol. Allopurinol or rasburicase is indicated for patients with high levels of serum uric acid or high tumor burden and a high risk of tumor lysis syndrome Tumor Lysis and Cytokine Release Syndromes Adverse effects are common in patients receiving any cancer therapy. Patients may also have adverse effects resulting from their cancer. Successfully managing these adverse effects is important... read more with treatment.

Infection is more likely during chemotherapy-induced neutropenia. In addition, infections with the herpes zoster Herpes Zoster Herpes zoster is infection that results when varicella-zoster virus reactivates from its latent state in a posterior dorsal root ganglion. Symptoms usually begin with pain along the affected... read more Herpes Zoster virus are occurring more frequently among patients treated with newer antimyeloma drugs, especially the proteasome inhibitors (bortezomib, carfilzomib, ixazomib) and the monoclonal antibodies (daratumumab, isatuximab, elotuzumab). Documented bacterial infections should be treated with antibiotics; however, prophylactic use of antibiotics is not routinely recommended.

Prophylactic use of antiviral drugs (eg, acyclovir, valganciclovir, famciclovir) is indicated for patients receiving a proteasome inhibitor (bortezomib, carfilzomib, ixazomib) or a monoclonal antibody (daratumumab, isatuximab, elotuzumab).

Prophylactic IV immune globulin may reduce the risk of infection but is generally reserved for patients with low uninvolved immunoglobulin levels and frequent recurrent infections. Pneumococcal vaccine Pneumococcal Vaccine Pneumococcal disease (eg, otitis media, pneumonia, sepsis, meningitis) is caused by some of the > 90 serotypes of Streptococcus pneumoniae (pneumococci). Vaccines are directed against many of... read more and influenza vaccine Influenza Vaccine Based on recommendations by the World Health Organization and the Centers for Disease Control and Prevention (CDC), vaccines for influenza are modified annually to include the most prevalent... read more are indicated to prevent infection. However, use of live vaccines is not recommended in these immunocompromised patients. However, the newer, nonviable recombinant zoster vaccine, unlike the earlier live-attenuated zoster vaccine, may be given to prevent herpes zoster.

Renal compromise can often be ameliorated with adequate hydration. Even patients with prolonged, massive Bence Jones proteinuria ( 10 to 30 g/day) may have intact renal function if they maintain a urine output > 2000 mL/day. Dehydration combined with high-osmolar IV contrast may precipitate acute oliguric renal failure in patients with Bence Jones proteinuria. Plasma exchange may be effective in some cases. Nephrotoxic drugs should be avoided.

Skeletal lesions require multiple supportive measures. Maintenance of ambulation and supplemental calcium and vitamin D help preserve bone density. Vitamin D levels should be measured at diagnosis and periodically, and dosing of vitamin D adjusted accordingly. Analgesics and palliative doses of radiation therapy (18 to 24 gray) can relieve bone pain. However, radiation therapy may cause significant toxicity and, because it suppresses bone marrow function, may impair the patient’s ability to receive cytotoxic doses of systemic chemotherapy.

Most patients, especially those with lytic lesions and generalized osteoporosis or osteopenia, should receive a monthly IV bisphosphonate (either pamidronate or zoledronic acid). Bisphosphonates reduce skeletal complications and lessen bone pain and may have an antitumor effect. For patients with potentially reversible renal failure resulting from myeloma but unrelated to hypercalcemia or with ongoing infusion reactions after bisphosphonate infusion, an option is monthly denosumab (given subcutaneously), which, unlike bisphosphonates, is not cleared by the kidneys and does not cause infusion reactions. Both bisphosphonates and denosumab may uncommonly cause osteonecrosis of the jaw. Maintaining excellent dental health and avoiding dental explants and implants are important to minimize the risk of this complication.

Key Points

  • Malignant plasma cells produce monoclonal immunoglobulin and invade and destroy bone.

  • Expanding plasmacytomas and cytokine secretion cause multiple, discrete, osteolytic lesions (usually in the pelvis, spine, ribs, and skull) and diffuse osteoporosis; pain, fractures, and hypercalcemia are common.

  • Anemia and renal failure are common.

  • Amyloidosis develops in about 10%, typically patients who produce excess lambda light chains.

  • Do serum and urine protein electrophoresis followed by immunofixation, quantitative immunoglobulins, and measurement of serum free light chains.

  • Do bone marrow aspiration and biopsy.

  • Symptomatic patients and those with organ dysfunction should be treated with drug therapy, which may include corticosteroids, chemotherapy drugs, proteasome inhibitors, immunomodulatory agents, monoclonal antibodies, selective inhibitors of nuclear export, histone deacetylase inhibitors, and cellular and antibody-based immune therapies targeting B-cell maturation antigen.

  • Stem cell transplantation is an option for some patients, but newer, highly effective treatment options may make it unnecessary in others.

More Information

The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

  • Bal S, Giri S, Godby KN, Costa LJ: New regimens and directions in the management of newly diagnosed multiple myeloma. Am J Hematol 96:367–378, 2021.

  • Gulla A, Anderson KC: Multiple myeloma: the (r)evolution of current therapy and a glance into the future. Haematologica 105:2358–2367, 2020.

  • Cook G, Morris CTCM: Evolution or revolution in multiple myeloma therapy and the role of the UK. Brit J Haematol 191:542–551, 2020.

  • Premkumar V, Bhutani D, Lentzsch S: Modern treatments and future directions for relapsed/refractory multiple myeloma patients. Clinical Lymphoma Myeloma Leuk20(11):736–743, 2020.

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