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Multiple myeloma (MM) is a complex disease characterized by considerable genetic heterogeneity. The updated NCCN Guidelines for MM have added new “preferred” regimens for transplant and nontransplant candidates, and have moved some formerly “preferred” regimens to the “other” category. Supportive care has improved outcomes for patients, and new treatments in combination have extended survival for patients with MM. Novel agents on the horizon are poised to raise the bar even further.

The most recent NCCN Guidelines for Multiple Myeloma include a ranking of the many treatment options for various settings as “preferred,” “other,” and “useful in certain circumstances.” For patients eligible for autologous stem cell transplant (ASCT), the preferred regimen remains bortezomib/lenalidomide/dexamethasone (category 1) or bortezomib/cyclophosphamide/dexamethasone. Upfront ASCT also remains a preferred strategy for patients who are transplant-eligible, despite highly effective newer agents such as induction therapy. Double (tandem) ASCT may benefit patients with high-risk cytogenetics, such as 17p deletion. Lenalidomide maintenance is the standard posttransplant approach and results in improved progression-free and overall survivals. For relapsed disease, a host of new agents have been shown to improve outcomes, mostly in combination with bortezomib or lenalidomide, but their selection depends largely on response and tolerability to prior therapies.

The emergence of immunotherapy has changed the treatment strategy for multiple myeloma, both in the early disease setting and in relapsed/refractory disease. Although daratumumab has been routinely incorporated into various combination regimens, T-cell–redirecting approaches, such as bispecific T-cell engagers and CAR T-cell therapy, are emerging. In patients with highly refractory disease, these approaches have robustly impacted both progression-free and overall survival. Most of these agents target the B-cell maturation antigen. Drugs with new targets are also in development, which will further extend the value of immunotherapeutic strategies in myeloma.

The treatment of multiple myeloma (MM) has evolved over the past decade, yet it remains a chronic disease. Several trials of 4-drug induction regimens have resulted in deepening of disease response. With the emergence of multidrug regimens, questions have arisen regarding the role of autologous stem cell transplant (ASCT) in MM therapy and available treatment options after ASCT. Clinicians have also continued to improve the efficacy of maintenance therapies. In transplant-ineligible patients, the phases of treatment are less distinct; however, several regimens have demonstrated efficacy in this clinical setting. Future research should focus on individualizing treatment approaches.

Although recent advances in the treatment of multiple myeloma have improved survival, it remains a chronic disease that requires a long-term treatment strategy. The key to achieving the best outcomes for patients is delivering the best “package” of treatment at a given stage. This means using optimal combinations that maximize benefit based on what patients have received previously and minimize treatment-related toxicity. Sequencing of regimens also plays an important role. As new agents and new classes of drugs continue to be approved for multiple myeloma, future strategies will use more individualized approaches to treatment.

For patients with newly diagnosed multiple myeloma (MM), treatment with 4-drug regimens produce deep responses and should be considered for those with high-risk features. Daratumumab + lenalidomide and dexamethasone is standard treatment for newly diagnosed patients not eligible for autologous stem cell transplantation (ASCT). Although lenalidomide remains standard maintenance therapy, in some instances more intensive regimens can be considered. ASCT is more effective when given up-front rather than delayed, but delaying transplantation until disease progression is acceptable. CAR T-cell therapy can provide durable responses, and 2 agents are now FDA-approved for use in multiple myeloma. Bispecific T-cell engagers are also effective for relapsed myeloma, as is the BCL2 inhibitor venetoclax, especially for patients with t(11;14) disease. An emerging novel class of drugs, the CELMoDs (cereblon E3 ligase modulator), target cereblon.

The treatment of multiple myeloma is marked by many recent advances, but for newly diagnosed patients the standard of care for induction remains the combination of a proteasome inhibitor, immunomodulatory drug, and dexamethasone. The role of a 4-drug induction regimen is still being defined, but can be considered for patients with high-risk disease. For patients who are eligible to undergo stem cell transplant, this approach remains the preferred option, but transplant can be delayed until relapse if patients prefer. In those who are not eligible for transplant, based on impressive data with daratumumab/lenalidomide/dexamethasone, this triplet should be considered as initial therapy. In patients with relapsed disease, it is important to switch treatment to new drug classes; for this, multiple combinations can be recommended. Updated guidelines now include new drugs for refractory disease: selinexor and belantamab mafodotin, both listed as “other regimens” in the NCCN Guidelines, can be considered.

Patients with smoldering myeloma should undergo periodic risk assessment—if they are deemed at high risk for disease progression, clinical trials or lenalidomide with or without dexamethasone should be considered. The initial treatment of newly diagnosed myeloma should be based on the patient’s risk, fitness, and preferences. Induction with a quadruplet regimen, followed by autologous transplantation and maintenance therapy, remains the standard of care, especially for those with high-risk disease. For patients with standard-risk disease not undergoing immediate transplantation, triplet or quadruplet induction followed by maintenance is the standard. Appropriate treatment of relapsed disease depends on response to previous treatment, residual side effects, and comorbidities. T-cell–redirecting therapies and other novel agents have shown activity, even in heavily pretreated patients. Most patients will require multiple lines of therapy over the course of the disease.

Venous thromboembolism (VTE) is a major complication in all patients with cancer. Compared with the general population, patients with multiple myeloma (MM) have a 9-fold increase in VTE risk, likely because of their malignancy, its treatments, and other additional patient-related factors. In MM, thromboembolism events tend to occur within 6 months of treatment initiation, regardless of treatment regimen; however, the use of immunomodulatory agents such as thalidomide or lenalidomide, especially in combination with dexamethasone or multiagent chemotherapy, is known to create a significant risk for VTE. Currently, official recommendations for VTE prophylaxis in MM outlined in various national guidelines or multidisciplinary society panels are based on expert opinion, because data from randomized controlled trials are scarce. Large studies which have mainly focused on the efficacy of thromboprophylaxis in patients with cancer at higher risk for VTE either had a very low representation of patients with MM, or excluded them all together, limiting our ability to draw evidence-based conclusions on how to effectively protect MM population from VTE. In this brief perspective, we highlight some of the greatest challenges that have hampered the field concerning the availability of high-quality clinical trial data for the formulation of best VTE prophylaxis strategies in patients with newly diagnosed MM, as well as the rationale for the latest updates in the NCCN Guidelines on this topic.

Although oncology care has evolved, outcome assessment remains a key challenge. Outcome measurement requires identification and adoption of a succinct list of metrics indicative of high-quality cancer care for use within and across healthcare systems. NCCN established an advisory committee, the NCCN Quality and Outcomes Committee, consisting of provider experts from NCCN Member Institutions and other stakeholders, including payers and patient advocacy, community oncology, and health information technology representatives, to review the existing quality landscape and identify contemporary, relevant cancer quality and outcomes measures by reevaluating validated measures for endorsement and proposing new measure concepts to fill crucial gaps. This manuscript reports on 22 measures and concepts; 15 that align with existing measures and 7 that are new.