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New Data in Myeloma Care
How New Data May Change Myeloma Care in 2018 and Beyond

Released: January 29, 2018

Expiration: January 28, 2019

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Treatment paradigms in myeloma are undergoing a dramatic shift due to newly available information, including better disease definitions, acceptance of potential benefit from early intervention, development of new classes of agents leading to highly effective combinations, and the advent of various immunotherapeutic approaches. In this commentary, I discuss a few interesting new studies presented at the 2017 ASH annual meeting.

New Data in Smoldering Myeloma
Historically, observation has been the standard approach for smoldering myeloma as these patients are asymptomatic and accurate methods for assessing the risk of progression to active disease were lacking. However, the 2014 changes in the definition of active myeloma to include smoldering myeloma (SMM) at very high risk of progression based on biomarkers, but without any end-organ damage, represented a fundamental shift in the treatment philosophy in myeloma. This is reflected in the repertoire of clinical trials in the setting of SMM, including the CESAR and Centaurus trials, both of which had data presented at ASH 2017.

The phase II CESAR trial enrolled 90 patients with high-risk SMM to assess treatment with carfilzomib/lenalidomide/dexamethasone along with stem cell transplantation. At the end of consolidation, all patients (n = 35) achieved a CR and 60% achieved MRD negativity. Although these efficacy results are preliminary, the data are promising. The definition of smoldering disease was based on the Mayo and Spanish risk models, which included patients with a M-protein component ≥ 3 g/dL (serum), ≥ 10% bone marrow plasma cells, > 95% aberrant plasma cells by immunophenotype, and/or immunoparesis. It is of great interest that nearly one quarter of screened patients were considered to have active bone disease, based on positive imaging studies, and were excluded from the trial, which highlights the importance of the new definitions of active disease (> 1 focal lesion in bone by MRI, ≥ 60% clonal plasma cells in the bone marrow, or a serum free light chain ratio ≥ 100).

The phase II Centaurus trial examined different treatment and dose schedules of single-agent daratumumab in patients with SMM according to the 2014 diagnostic criteria (N = 123). These data suggested excellent efficacy for daratumumab in this setting, with an ORR of more than 50% for patients treated with the long or intermediate course of therapy, with an acceptable adverse event profile.

New Data in Newly Diagnosed Myeloma
The approval of new monoclonal antibodies, such as daratumumab and elotuzumab, have ushered in a new era for treatment of newly diagnosed and relapsed myeloma. The lack of overlapping toxicities allows daratumumab to be added to various standard-of-care treatment regimens in the relapsed/refractory setting. For patients with newly diagnosed myeloma, the phase III ALCYONE trial enrolled patients ineligible for autologous stem cell transplantation to assess the efficacy and safety of the addition of daratumumab to standard treatment with bortezomib/melphalan/prednisone (VMP). Results of this trial demonstrated an increased response rate (91% vs 74%), depth of response (MRD negativity: 22% vs 6%), and improved PFS (median: not reached vs 18.1 months) with the addition of daratumumab to VMP vs VMP alone.

These findings open up the possibility of other quadruple combinations, and several of them are being tested in clinical trials including combinations of carfilzomib/lenalidomide/dexamethasone and bortezomib/lenalidomide/dexamethasone (VRd) with daratumumab and VRd with elotuzumab. The demonstration of high response rates with these 4-drug regimens may offer several opportunities to move the field forward, including the potential to eliminate the need for steroids and to limit the duration of therapy, especially in patients who achieve MRD-negative disease.

New Data in Relapsed/Refractory Myeloma
Finally, multiple immune-therapeutic approaches have shown dramatic responses in patients with relapsed or refractory myeloma. CAR T-cell therapy, in particular, has been of immense interest in hematologic malignancies, including myeloma, and results of several trials have been presented so far.

Although CAR T-cells targeting CD19 have been developed and approved for relapsed or refractory large B-cell lymphoma and are in development for many other hematologic malignancies, this is not an optimal target for myeloma. However, CAR T-cells specific to BCMA—a TNF receptor superfamily expressed on myeloma tumor cells, nonmalignant plasma cells, and some mature B-cells—has demonstrated activity in myeloma. Multiple trials with BCMA-targeted CAR T-cells were presented at ASH 2017. One such trial was the phase I trial of bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed or refractory myeloma after ≥ 3 previous lines of therapy or those with double-refractory disease. In this report of updated results, bb2121 demonstrated significant activity for these patients who failed all available therapies. At a median follow-up of 40 weeks, 56% of patients achieved CR and 9 of 10 evaluable patients achieved MRD negativity at the higher doses tested. These responses appear to be durable, with some patients remaining in response beyond 1 year.

The results with the other anti-BCMA CAR T-cell approaches, including different BCMA targeting constructs, treatment with or without a chemotherapy conditioning regimen, and in combination with CAR T-cells targeting different antigens, also appear to be of significant clinical benefit.

These early-phase trials are very promising, but clearly, more work needs to be done to better identify the patients with myeloma who are most likely to benefit from CAR T-cell therapy and to delineate the potential for intervention earlier in the disease course, particularly for patients with high-risk disease. In addition, logistical concerns remain. Significant effort is required for the apheresis and ex-vivo manipulation of each patient’s T-cells. Furthermore, the time delay between T-cell collection and infusion of the CAR T-cell product can be difficult for a patient with aggressive disease. To ameliorate some of these concerns, off-the-shelf immune approaches such as a BCMA-targeted bispecific T-cell engager, or BiTE, may offer some advantages and are also being tested in clinical trials.

Your Thoughts
What do you think about the new data in myeloma discussed here and presented at the 2017 ASH annual meeting? Do you plan to integrate any new management strategies for your patients with myeloma based on the findings presented at ASH this past December? Please share your experiences and insights by joining the conversation in the comments box below and responding to the question at the right of your screen.

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In your current clinical practice, do you consider your patients diagnosed with SMM candidates for systemic therapy?
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