Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of ...response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.
MM cells express high levels of CD38, while CD38 is expressed at relatively low levels on normal lymphoid and myeloid cells, and in some non-hematopoietic tissues. This expression profile, together ...with the role of CD38 in adhesion and as ectoenzyme, resulted in the development of CD38 antibodies for the treatment of multiple myeloma (MM). At this moment several CD38 antibodies are at different phases of clinical testing, with daratumumab already approved for various indications both as monotherapy and in combination with standards of care in MM. CD38 antibodies have Fc-dependent immune effector mechanisms, such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). Inhibition of ectoenzymatic function and direct apoptosis induction may also contribute to the efficacy of the antibodies to kill MM cells. The CD38 antibodies also improve host-anti-tumor immunity by the elimination of regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells. Mechanisms of primary and/or acquired resistance include tumor-related factors, such as reduced cell surface expression levels of the target antigen and high levels of complement inhibitors (CD55 and CD59). Differences in frequency or activity of effector cells may also contribute to differences in outcome. Furthermore, the microenvironment protects MM cells to CD38 antibody-induced ADCC by upregulation of anti-apoptotic molecules, such as survivin. Improved understanding of modes of action and mechanisms of resistance has resulted in rationally designed CD38-based combination therapies, which will contribute to further improvement in outcome of MM patients.
Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab ...has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma.
In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2 (20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3–6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting.
Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46–0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 22%; Kd, 38 25%).
KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit–risk profile.
Amgen.
With recent advances in myeloma therapy, patients can achieve long-term remissions, but eventually relapses will occur. Triple-class refractory myeloma (disease that is refractory to an ...immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody) and penta-refractory myeloma (disease that is refractory to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 antibody) are associated with a particularly poor prognosis, and novel treatments are desperately needed for these patients. Targeting B cell maturation antigen (BCMA), which is ubiquitously expressed on plasma cells, has emerged as a well-tolerated and highly efficacious strategy in patients with relapsed and refractory myeloma. Several mechanisms of targeting BCMA are currently under investigation, including antibody–drug conjugates, bispecific antibodies, and chimeric antigen receptor T cells and natural killer (NK) cells, all with unique side effect profiles. Early phase clinical trials showed unprecedented response rates in highly refractory myeloma patients, leading to the recent approvals of some of these agents. Still, many questions remain with regard to this target, including how best to target it, how to treat patients who have progressed on a BCMA-targeting therapy, and whether response rates will deepen if these agents are used in earlier lines of therapy. In this review, we examine the rationale for targeting BCMA and summarize the data for several agents across multiple classes of BCMA-targeting therapeutics, paying special attention to the diverse mechanisms and unique challenges of each therapeutic class.
Extramedullary multiple myeloma Bhutani, Manisha; Foureau, David M; Atrash, Shebli ...
Leukemia,
01/2020, Letnik:
34, Številka:
1
Journal Article
Recenzirano
Extramedullary multiple myeloma (EMM) is an aggressive subentity of multiple myeloma, characterized by the ability of a subclone to thrive and grow independent of the bone marrow microenvironment, ...resulting in a high-risk state associated with increased proliferation, evasion of apoptosis and treatment resistance. Despite improvement in survival for most patients with multiple myeloma over recent decades, outcomes are generally poor when EMM develops. Understanding the molecular underpinnings leading to homing of plasma cells in ecosystems outside the bone marrow will be crucial for therapeutically manipulating the microenvironment and targeting key signaling pathways. Herein, we discuss the evolutionary biology of EMM, underscore the importance of a uniform definition, discuss prognostic significance, and provide current and emerging treatment strategies for managing this rare subentity of multiple myeloma.
GPRC5D-Targeted CAR T Cells for Myeloma Mailankody, Sham; Devlin, Sean M.; Landa, Jonathan ...
The New England journal of medicine,
09/2022, Letnik:
387, Številka:
13
Journal Article
Recenzirano
In an early-phase study involving 17 patients with highly refractory multiple myeloma, CAR T-cell therapy with specificity for a G protein–coupled receptor that is expressed on myeloma cells produced ...a response in 71% of the patients.
Gain of chromosome 1q (+1q) is one of the most common recurrent cytogenetic abnormalities in multiple myeloma (MM), occurring in approximately 40% of newly diagnosed cases. Although it is often ...considered a poor prognostic marker in MM, +1q has not been uniformly adopted as a high-risk cytogenetic abnormality in guidelines. Controversy exists regarding the importance of copy number, as well as whether +1q is itself a driver of poor outcomes or merely a common passenger genetic abnormality in biologically unstable disease. Although the identification of a clear pathogenic mechanism from +1q remains elusive, many genes at the 1q21 locus have been proposed to cause early progression and resistance to anti-myeloma therapy. The plethora of potential drivers suggests that +1q is not only a causative factor or poor outcomes in MM but may be targetable and/or predictive of response to novel therapies. This review will summarize our current understanding of the pathogenesis of +1q in plasma cell neoplasms, the impact of 1q copy number, identify potential genetic drivers of poor outcomes within this subset, and attempt to clarify its clinical significance and implications for the management of patients with multiple myeloma.
This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, ...including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 n = 8, 10 n = 31, or 20 n = 6 mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ≥3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies. This trial was registered at www.clinicaltrials.gov as #NCT02283775.
•Isatuximab combined with pomalidomide/dexamethasone has a manageable safety profile with promising clinical activity.•Isatuximab 10 mg/kg (4 weekly doses followed by dosing every 2 weeks thereafter) has been selected for future combination studies.
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CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, ...deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up MFU approximately 28 months), including analyses of high-risk patient subgroups.
Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee.
At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel-related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report.
At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.
Teclistamab in Relapsed or Refractory Multiple Myeloma Moreau, Philippe; Garfall, Alfred L.; van de Donk, Niels W.C.J. ...
New England journal of medicine/The New England journal of medicine,
08/2022, Letnik:
387, Številka:
6
Journal Article
Recenzirano
Odprti dostop
In this phase 1–2 study involving patients with relapsed or refractory myeloma, a bispecific antibody (teclistamab) that mediates T-cell activation and subsequent lysis of myeloma cells expressing ...B-cell maturation antigen induced responses in 63% of the patients, including a complete response in nearly 40%.
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