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 that cause 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 additional medications such as proteasome inhibitors (eg, bortezomib, carfilzomib, ixazomib), immunomodulating agents (eg, lenalidomide, thalidomide, pomalidomide), or monoclonal antibodies (eg, daratumumab, isatuximab, elotuzumab). Antibody- and T-cell-based approaches to targeting of B-cell maturation antigen have shown efficacy. High-dose melphalan followed by autologous peripheral blood stem cell transplantation may also be used.
(See also Overview of Plasma Cell Disorders.)
In the United States, the lifetime risk of getting multiple myeloma is 1 in 132 (0.76%) (1). The median age is about 70 years. Prevalence in Black people is twice that in White people. There is a slight male predominance. Etiology is unknown, although chromosomal and genetic factors, radiation, and chemicals have been suggested.
The American Cancer Society estimates that in 2023 in the United States there will be about 35,730 new cases of multiple myeloma diagnosed and about 12,590 deaths are expected to occur (1).
Загальні джерела літератури
1. American Cancer Society. Key Statistics About Multiple Myeloma. Atlanta, Ga., American Cancer Society; 2023.
Pathophysiology of Multiple Myeloma
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. IgM and IgD myeloma account for about 1% of cases each; IgD myeloma is more frequent among patients of Asian descent. IgE myeloma is exceedingly rare. 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 or discrete osteolytic lesions are often present, with the most common sites being 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, leading to bone loss. The osteolytic lesions are usually multiple; occasionally, they are solitary intramedullary masses. Increased bone loss may also lead to hypercalcemia. Extraosseous solitary plasmacytomas are unusual but may occur in any tissue, especially in the upper respiratory tract.
In many patients, renal failure is present at diagnosis or develops during the course of the disorder. Renal failure has many causes, and most commonly, it results from deposition of light chains in the distal tubules (myeloma-related kidney disease) or hypercalcemia.
Patients often develop anemia usually due to kidney disease or suppression of erythropoiesis by cancer cells but also may be due to other unrelated causes, including iron deficiency or vitamin B12 deficiency.
Because of lack of normal antibodies and other immune dysfunction, some patients have increased susceptibility to bacterial infection. Viral infections, especially herpes zoster infections, occur as a result of treatment modalities such as proteasome inhibitors (eg, bortezomib, ixazomib, carfilzomib) and monoclonal antibodies (eg, daratumumab, elotuzumab, isatuximab).
Amyloidosis occurs in 10% of myeloma patients, most often in patients with lambda-type M-proteins.
Variant expressions of multiple myeloma occur (see table Variant Expressions of Multiple Myeloma).
Symptoms and Signs of Multiple Myeloma
Persistent bone pain (especially in the back or thorax), renal failure, and recurrent 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.
Symptoms of anemia predominate or may be the sole reason for evaluation in some patients, and a few patients have manifestations of hyperviscosity syndrome.
Pathologic (fragility) fractures (ie, fractures that occur with minimal or no trauma) are common, and vertebral collapse may lead to spinal cord compression and paraplegia.
Peripheral neuropathy, carpal tunnel syndrome (especially with associated amyloid disease), abnormal bleeding, and symptoms of hypercalcemia (eg, polydipsia, dehydration) are common.
Lymphadenopathy and hepatosplenomegaly are unusual.
Diagnosis of Multiple Myeloma
Complete blood count (CBC) with platelets, peripheral blood smear, 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]).
Routine blood tests include CBC 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. 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 carried out 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. Most of the remaining 10 to 20% are patients with only free monoclonal light chains (Bence Jones protein) that can be detected using urine protein and immune electrophoresis. Rarely, patients have IgM, IgD, or IgE disease. Monoclonal protein is not evident at diagnosis in a small proportion of patients; however, during the course of the disease, more patients have evidence of monoclonal protein.
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). 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.
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.
Image courtesy of Michael J. Joyce, MD, and Hakan Ilaslan, MD.
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 percentage 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 that can influence treatment choices and are associated with differences in survival.
Diagnosis and differentiation from other malignancies (eg, metastatic carcinoma, lymphoma, leukemia) and monoclonal gammopathy of undetermined significance typically require multiple criteria:
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.
Довідкові матеріали щодо діагностики
1. Sive J, Cuthill K, Hunter H, Kazmi M, Pratt G, Smith D and on behalf of British Society of Haematology: Guidelines on the diagnosis, investigation and initial treatment of myeloma: a British Society for Haematology/UK Myeloma Forum Guideline. Brit J Haematol 193:245–268, 2021. doi:10.1111/bjh.17410
2. Rajkumar SV: Multiple myeloma: 2022 update on diagnosis, risk-stratification and management. Am J Hematol 97(8):1086-1107, 2022. doi:10.1002/ajh.26590
Prognosis for Multiple Myeloma
Multiple myeloma is progressive and incurable, but median 5-year survival has improved to 58% as a result of advances in treatment (1). Unfavorable prognostic signs at diagnosis are higher stage, lower serum albumin levels, higher beta-2 microglobulin levels, elevated LDH levels, specific cytogenetic abnormalities in the tumor cells, and higher levels of malignant cells in the blood. Patients initially presenting with renal failure also do poorly unless kidney function improves with therapy, which typically happens with current treatment options.
Because multiple myeloma is ultimately fatal, patients are likely to benefit from discussions of end-of-life care that involve clinicians and appropriate family and friends. Points for discussion may include advance directives, the use of feeding tubes, and pain relief.
Довідковий матеріал щодо прогнозу
1. American Cancer Society: Multiple Myeloma: Early Detection, Diagnosis, and Staging. Survival Rates for Multiple Myeloma. Atlanta, Ga., American Cancer Society; 2023.
Treatment of Multiple Myeloma
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
The BCL-2 (BCL2 apoptosis regulator) inhibitor venetoclax for patients whose malignant cells show the t(11;14) genetic marker
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
Serum free light chain levels > 100 mg/L
Patients with these risk factors 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 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.
Лікування, спрямоване проти злоякісних клітин
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 agents, including cyclophosphamide, bendamustine, doxorubicin, and its analog, liposomal pegylated doxorubicin (doxorubicin liposomal), also are more effective when combined with an immunomodulatory drug (thalidomide, lenalidomide, or bortezomib). There is better survival when initial treatment includes both bortezomib and lenalidomide with corticosteroids. The addition of the monoclonal antibody daratumumab to bortezomib and dexamethasone as part of initial treatment appears to improve outcomes (1).
Response to treatment (see table Defining Response to Cancer Treatment) 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
Normalization of calcium levels among those presenting with elevated levels
Decrease in bone pain
Decrease in fatigue
Autologous peripheral blood stem cell transplantation 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, the newer treatment options are highly effective and may make transplantation less often necessary or unnecessary altogether. Recent clinical trials show longer progression-free survival, but no improvement in overall survival when patients undergo stem cell transplantation as part of initial therapy (2).
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 versus host disease.
Лікування рецидивної або рефрактерної мієломи
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. Monoclonal antibodies include daratumumab, isatuximab, and elotuzumab. These antibodies are more effective when combined with the immunomodulatory agents thalidomide, lenalidomide or pomalidomide, and dexamethasone. Daratumumab shows better results when combined with bortezomib and dexamethasone (3), and both daratumumab and isatuximab also show improved efficacy when added to carfilzomib and dexamethasone. However, treatment with any of these monoclonal antibodies and only dexamethasone is effective in many patients without the costs and adverse effects of additional medications.
The selective inhibitor of nuclear export (SINE) selinexor and the histone deacetylase inhibitor (HDACi) panobinostat are especially effective when combined with other active myeloma medications.
Three effective immune treatments that target B-cell maturation antigen (BCMA) are available. These treatments include cellular therapies for myeloma, the chimeric antigen receptor (CAR)-T cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel, and a bispecific antibody teclistamab that also targets CD3 on T cells. Although these treatments are effective, they can cause significant acute adverse effects (cytokine release syndrome, neurologic problems) and a high risk of ongoing severe infections.
The oral BCL-2 inhibitor venetoclax has been shown to be effective for treating patients whose myeloma cells show the genetic marker t(11;14) (4).
Підтримуюча терапія
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 lenalidomide alone or with corticosteroids is effective as maintenance treatment. However, there is some concern about secondary malignancies among patients receiving long-term lenalidomide therapy, especially after autologous stem cell transplantation. Thus, the risk of developing secondary cancers must be weighed against improved survival.
The oral proteasome inhibitor ixazomib is effective as a single agent as maintenance therapy. Whether the combination of ixazomib with lenalidomide is more effective is unknown.
The role of antibodies as maintenance therapy remains to be defined.
Лікування ускладнень
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 among patients whose anemia is inadequately relieved by chemotherapy. If anemia causes cardiovascular or significant systemic symptoms, packed red blood cells are transfused. Plasma exchange is indicated if the patient develops hyperviscosity, which rarely occurs in patients with myeloma. 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 especially among patients with severe renal failure. 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 with treatment.
Infection is more likely during chemotherapy-induced neutropenia. In addition, infections with the herpes zoster virus occur frequently among patients treated with certain antimyeloma drugs, especially the proteasome inhibitors (bortezomib, carfilzomib, ixazomib) and the monoclonal antibodies (daratumumab, isatuximab, elotuzumab). The newer B-cell maturation antigen (BCMA) directed treatments are associated with a very high risk of severe infection.
Documented bacterial infections should be treated with antibiotics. 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 and influenza vaccine are indicated to prevent infection but are not effective in most patients because of their disease- and treatment-related immune deficiency. Use of live vaccines is not recommended in immunocompromised patients. The nonviable recombinant zoster vaccine, unlike the earlier live-attenuated zoster vaccine, may be given to prevent herpes zoster but also is of limited effectiveness.
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. Rapid and aggressive treatment of the underlying myeloma to reduce the levels of the nephrotoxic monoclonal immunoglobulin is important to reverse this condition.
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.
Посилання на лікування
1. Abdallah N, Kumar SK. Daratumumab in untreated newly diagnosed multiple myeloma. Ther Adv Hematol 2019;10:2040620719894871. doi:10.1177/2040620719894871
2. Richardson PG, Jacobus SJ, Weller EA, et al. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. N Engl J Med 2022;387(2):132-147. doi:10.1056/NEJMoa2204925
3. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016;375(8):754-766. doi:10.1056/NEJMoa1606038
4. Sidiqi MH, Al Saleh AS, Kumar SK, et al. Venetoclax for the treatment of multiple myeloma: Outcomes outside of clinical trials. Am J Hematol 2021;96(9):1131-1136. doi:10.1002/ajh.26269
Ключові моменти
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.
Додаткова інформація
The following English-language resources 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. doi:10.1002/ajh.26080
Cowan AJ, Green DJ, Kwok M, et al: Diagnosis and management of multiple myeloma: A review. JAMA 327:464-477, 2022. doi: 10.1001/jama.2022.0003
Cook G, Morris CTCM: Evolution or revolution in multiple myeloma therapy and the role of the UK. Brit J Haematol 191:542–551, 2020. doi:10.1111/bjh.17148
Gulla A, Anderson KC: Multiple myeloma: the (r)evolution of current therapy and a glance into the future. Haematologica 105:2358–2367, 2020. doi:10.3324/haematol.2020.247015
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. doi:10.1016/j.clml.2020.06.023
Soekojo CY, Chng WJ: Treatment horizon in multiple myeloma. Eur J Haematol 109:425-440, 2022. doi: 10.1111/ejh.13840
