hematology and oncology
Multiple Myeloma
Treatment of Multiple Myeloma
Conventional chemotherapy for symptomatic patients Thalidomide,lenalidomide, orpomalidomide, and/orbortezomib,carfilzomib, orixazomib, plus corticosteroids and/or conventional chemotherapy Monoclonal antibodies, includingelotuzumab,isatuximab, anddaratumumab Particularly for relapsed or refractory myeloma, selective inhibitor of nuclear export (SINE)selinexor, and the histone deacetylase inhibitorpanobinostat 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) inhibitorvenetoclaxfor patients whose malignant cells show the t(11;14) genetic marker Maintenance therapy with corticosteroids,thalidomide, and/orlenalidomide, and proteasome inhibitors, especially oralixazomib 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. as part of initial treatment appears to improve outcomes ( Treatment references ). Response to treatment (see table) 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 Hematopoietic Stem Cell Transplantation None ) 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 Complications . For patients with relapsed or refractory myeloma, combinations of a proteasome inhibitor (bortezomib,ixazomib, orcarfilzomib) with an immunomodulatory agent (thalidomide,lenalidomide, orpomalidomide) 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. ( Treatment references ), and both The selective inhibitor of nuclear export (SINE)selinexorand the histone deacetylase inhibitor (HDACi)panobinostatare especially effective when combined with other active myeloma medications. 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. has been shown to be effective for treating patients whose myeloma cells show the genetic marker t(11;14) ( Treatment references ). 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. therapy, especially after Hematopoietic Stem Cell Transplantation . Thus, the risk of developing secondary cancers must be weighed against improved survival. The oral proteasome inhibitorixazomibis effective as a single agent as maintenance therapy. Whether the combination ofixazomibwithlenalidomideis more effective is unknown. The role of antibodies as maintenance therapy remains to be defined. 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 can be treated with recombinant erythropoietin among patients whose anemia is inadequately relieved by chemotherapy. If anemia causes cardiovascular or significant systemic symptoms, Red blood cells (RBCs) . Hypercalcemiais treated with vigorous saluresis, IV bisphosphonates (preferablyzoledronic acid) after rehydration, and sometimes withcalcitoninorprednisone.Denosumabcan also be used to treat hypercalcemia especially among patients with severe renal failure. Patients should avoid calcium-containing foods, calcium supplements, andvitamin D. is indicated for patients with high levels of serum uric acid or high tumor burden and a high risk of Tumor Lysis and Cytokine Release Syndromes with treatment. is more likely during chemotherapy-induced Neutropenia . In addition, infections with the 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 Renal compromisecan 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 lesionsrequire multiple supportive measures. Maintenance of ambulation and supplemental calcium andvitamin Dhelp preserve bone density.Vitamin Dlevels should be measured at diagnosis and periodically, and dosing ofvitamin Dadjusted 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 (eitherpamidronateorzoledronic 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 monthlydenosumab(given subcutaneously), which, unlike bisphosphonates, is not cleared by the kidneys and does not cause infusion reactions. Both bisphosphonates anddenosumabmay 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. 1.Abdallah N, Kumar SK.Daratumumabin untreated newly diagnosed multiple myeloma.Ther Adv Hematol2019;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 Med2022;387(2):132-147. doi:10.1056/NEJMoa2204925 3.Palumbo A, Chanan-Khan A, Weisel K, et al.Daratumumab,Bortezomib, andDexamethasonefor Multiple Myeloma.N Engl J Med2016;375(8):754-766. doi:10.1056/NEJMoa1606038 4.Sidiqi MH, Al Saleh AS, Kumar SK, et al.Venetoclaxfor the treatment of multiple myeloma: Outcomes outside of clinical trials.Am J Hematol2021;96(9):1131-1136. doi:10.1002/ajh.26269 