In a study involving patients with refractory multiple myeloma, the anti-CD38 antibody daratumumab in combination with bortezomib and dexamethasone resulted in longer progression-free survival and a ...higher rate of response than bortezomib and dexamethasone alone.
Multiple myeloma is associated with organ dysfunction, including bone lesions, anemia, renal insufficiency, and hypercalcemia.
1
,
2
Proteasome inhibitors (e.g., bortezomib) in combination with glucocorticoids are standard regimens for relapsed or relapsed and refractory multiple myeloma
3
(definitions of these terms are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org) and have contributed considerably to patient survival.
4
Nevertheless, almost all patients will have a relapse.
Daratumumab is a human IgGκ monoclonal antibody that targets CD38, which is highly expressed on myeloma cells and other hematopoietic cell types.
5
,
6
Daratumumab has direct and indirect antitumor activity and diverse . . .
Introduction: There is now 16 years' worth of established results of various trials demonstrating the bortezomib efficiency in the treatment of multiple myeloma. Over this time, the introduction of ...bortezomib has been a major break through in the treatment of multiple myeloma. Bortezomib can be administered in the outpatient setting with manageable toxicities.
Areas covered: A literature search was carried out using PubMed and Google Scholar. This review gives an overview of the critical role of the bortezomib in multiple myeloma and provides a comprehensive summary of key clinical benefit and safety data with the bortezomib. Initial toxicity profile has improved dramatically with introduction of subcutaneous administration and also, implementation of guidelines for early recognition and treatment. Triplet and quadruplets of bortezomib with agents possessing similar toxicities constitute a challenge.
Expert opinion: Bortezomib is an important part of current anti-myeloma therapy with a good clinical efficacy and manageable side effects. Although gastrointestinal disturbances and fatigue are the most common adverse effects, peripheral neuropathy and thrombocytopenia are the key dose-limiting toxicities of bortezomib-based combination regimens. Since these combinations are more effective, with faster disappearance of disease related symptoms and anti-inflammatory effects of bortezomib toxicities were not found to be augmented.
The addition of elotuzumab (a monoclonal antibody against SLAMF7) to lenalidomide plus dexamethasone produced a significant increase in progression-free survival as compared with lenalidomide plus ...dexamethasone alone.
Multiple myeloma, a malignant disease of monoclonal plasma cells, has a median overall survival of approximately 5 years.
1
Despite improvements in treatment outcomes with proteasome inhibitors and immunomodulatory drugs, most patients continue to have a relapse, and new treatment approaches are needed. Combination therapy may be key to overcoming drug resistance and improving long-term treatment outcomes. Lenalidomide, an immunomodulatory drug, in combination with dexamethasone is a standard regimen in patients with relapsed or refractory disease.
2
,
3
Three-drug combinations are emerging for patients with previously treated multiple myeloma
3
but may be limited by toxic effects. Agents with new mechanisms of action . . .
Extramedullary involvement (or extramedullary disease, EMD) represents an aggressive form of multiple myeloma (MM), characterized by the ability of a clone and/or subclone to thrive and grow ...independent of the bone marrow microenvironment. Several different definitions of EMD have been used in the published literature. We advocate that true EMD is restricted to soft-tissue plasmacytomas that arise due to hematogenous spread and have no contact with bony structures. Typical sites of EMD vary according to the phase of MM. At diagnosis, EMD is typically found in skin and soft tissues; at relapse, typical sites involved include liver, kidneys, lymph nodes, central nervous system (CNS), breast, pleura, and pericardium. The reported incidence of EMD varies considerably, and differences in diagnostic approach between studies are likely to contribute to this variability. In patients with newly diagnosed MM, the reported incidence ranges from 0.5% to 4.8%, while in relapsed/refractory MM the reported incidence is 3.4 to 14%. Available data demonstrate that the prognosis is poor, and considerably worse than for MM without soft-tissue plasmacytomas. Among patients with plasmacytomas, those with EMD have poorer outcomes than those with paraskeletal involvement. CNS involvement is rare, but prognosis is even more dismal than for EMD in other locations, particularly if there is leptomeningeal involvement. Available data on treatment outcomes for EMD are derived almost entirely from retrospective studies. Some agents and combinations have shown a degree of efficacy but, as would be expected, this is less than in MM patients with no extramedullary involvement. The paucity of prospective studies makes it difficult to justify strong recommendations for any treatment approach. Prospective data from patients with clearly defined EMD are important for the optimal evaluation of treatment outcomes.
With the introduction of more effective novel therapies, the prognosis of multiple myeloma (MM) has improved significantly over the past decade, resulting with a significant proportion of patients ...achieving durable remissions that may reach even more than 10 years. Several studies demonstrated that the real prognostic value of complete remission (CR) relies on sustained undetectable minimal residual disease (MRD). Additionally, advances in MRD detection methods used for the detection of clonal plasma cells (cPC) inside or outside the bone marrow have also improved the value of MRD. The use of peripheral blood for MRD detection could be an effective method that overcomes the spatial heterogeneity and invasive intervention with recurrent bone marrow aspirations. During the last two decades, many groups have investigated the role of circulating plasma cells (CPCs) at diagnosis. As also presented by multiple groups during the recent ASH 2021 annual meeting, CPCs are becoming recognized as an independent prognostic factor. In addition, measurement of post-induction residual plasma cells in the stem cell graft is identified as another option for MRD assessment. Earlier studies in the era of less intensive induction regimens attempts to analyze the level of CPC contamination in the graft was shown to contribute to myeloma relapse and progression. According to these recent results, higher graft purity has been found to be in concordance with deeper responses. As expected, graft minimal residual disease (gMRD) may reflect the efficacy of induction as an additional response assessment tool. Although gMRD is a non-invasive approach, it has not gained sufficient support for routine use. In view of the hurdles related to monoclonal protein assessments, high-sensitivity cellular component measurement continues to possess its value as an end point for therapeutic efficacy. In this review, we will present a structural framework for MRD testing in peripheral blood stem cell autografts in MM and review the clinical integration into MM management.
Summary This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB ...features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition.
Patients treated with an induction regimen of melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance therapy had longer progression-free survival than those who did not receive ...maintenance therapy.
Melphalan–prednisone (MP) has long been the treatment of choice for patients with multiple myeloma who are older than 65 years of age.
1
The introduction of new agents in the past few years has substantially changed the treatment of multiple myeloma. MP plus either thalidomide or bortezomib is reported to improve progression-free survival and overall survival, as compared with MP alone,
2
,
3
and these combinations are now considered the new standards of care for elderly patients with newly diagnosed multiple myeloma who are ineligible for stem-cell transplantation.
1
Lenalidomide in combination with dexamethasone is effective in relapsed or refractory multiple myeloma
4
– . . .
Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier ...intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate >15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival PFS in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval CI, 0.014-0.096), 0.102 (80% CI, 0.044-0.160), and 0.206 (80% CI, 0.118-0.295), respectively, translating to a median PFS ≥24 months in all arms (P < 0.0001, <0.0001, and =0.0213, respectively). With longer follow-up (median follow-up, 25.9 months), CR rates were 4.9%, 9.8%, and 0% for intense, intermediate, and short dosing, respectively. PD/death rates for intense, intermediate, and short dosing were 0.059 (80% CI, 0.025-0.092), 0.107 (80% CI, 0.058-0.155), and 0.150 (80% CI, 0.089-0.211), respectively, again translating to a median PFS ≥ 24 months in all arms (P < 0.0001 for all arms). Twenty-four-month PFS rates were 89.9% (90% CI, 78.5-95.4%), 82.0% (90% CI, 69.0-89.9%), and 75.3% (90% CI, 61.1-85.0%) for intense, intermediate, and short dosing, respectively. Pharmacokinetic analyses indicated that intense dosing maintained target-saturating trough concentrations in most patients throughout weekly, every-2-week, and every-4-week dosing periods. No new safety signals were observed. These data provide the basis for an ongoing phase 3 study of daratumumab in SMM.
PDF
