New Therapies for Multiple Myeloma

Faced with data on new drug therapies for multiple myeloma, oncologists are anticipating the potential value of these drugs and considering how access to these interventions may affect treatment paradigms. Treatment strategies in multiple myeloma depend on several variables, including where patients are in disease progression, whether they are eligible for transplants, and what other comorbidities or risk factors may be present. Often, patients are started on a triplet regimen referred to as VRd, which includes Velcade, Revlimid, and the oral corticosteroid, dexamethasone. Higher risk patients or younger patients may also be given Kyprolis as an upfront treatment.

Complicating the therapeutic landscape is the changing nature of the patient population. Today, with newer and better interventions, patients are living longer but also becoming more progressively refractory to therapy. Higher proportions of these patients are also suffering from certain related conditions, such as extramedullary disease and plasma cell leukemia. In addition to contending with innovative upfront therapies, determining how to treat these more progressively refractory patients is an emerging challenge that presents novel therapeutic needs and opportunities.

Below is an analysis of some of the latest promising drug therapies for multiple myeloma.

Uptake for Darzalex will likely increase with an approved subcutaneous formulation

For multiple myeloma patients, the most frequent use of Janssen’s Darzalex, or daratumumab, has been in those who have already received other treatments. Though Darzalex has been approved by the U.S. Food and Drug Administration (FDA) as a frontline therapy – including in combination with Revlimid and dexamethasone – its adoption as an upfront drug for newly diagnosed multiple myeloma patients has yet to take hold. Perhaps the biggest barrier to uptake for this monoclonal antibody drug is the inconvenience associated with its administration.

Undergoing Darzalex treatment requires hours at infusion centers for the initial couple of doses and then approximately 90 minutes for subsequent doses. Patients may have a low tolerance for this type of inconvenience and prefer other treatment options. Once the subcutaneous formulation of Darzalex is approved by the FDA, allowing for much faster administration times, the drug will likely be utilized more frequently.

Bluebird Bio’s bb2121 and bb21217 show promise of CAR-T cell strategy

Bluebird Bio’s bb2121 and bb21217 are chimeric antigen receptor (CAR) T-cell therapies that target B-cell maturation antigens (BCMAs) on malignant myeloma cells. Data on bb2121 from the KarMMa trial has demonstrated an excellent response. These results, which were recently published in the New England Journal of Medicine, showed that more than 80% of multiple myeloma patients responded to the therapy when it was provided above a certain dose level. These data also showed that the drug is associated with very little cytokine release, meaning the cytotoxicity that occurs with high levels of cytokine release is largely circumvented with this drug.

Though bb2121 is associated with excellent response rates, with durations lasting up to 17 months, the drug is not a cure. Even those patients on the drug who become minimal residual disease (MRD) negative – having fewer than one myeloma cell per million bone marrow cells – eventually relapse. Nonetheless, a drug like this that is associated with a duration of response and median progression-free survival of 11 months in heavily relapsed patients is worth considering, and it is reasonable to assume that bb2121 will continue to move toward FDA approval.

Based on the observation that exhaustion markers have been upregulated in T-cells in CAR-T products, the goal with bb21217 has been to promote the memory phenotype to enhance self-renewal potential and maintain a longer-term immune response. Using the same construct as bb2121, Bluebird Bio cultured the T-cells with PI3-kinase inhibitor to create bb21217.

Binding of antigens to T-cells normally leads to downstream signaling of PI3-kinase, which is associated with more metabolically active T-cells. Researchers have thus hypothesized that coating the cells in PI3-kinase inhibitor could encourage a more central phenotype with a longer-term memory and activity that could persist over several months. The hope is that bb21217 will provide longer response and remission times than has been seen with bb2121.

So far in a phase 1 study of bb21217, responses have been observed at lower doses in 10 out of 12 patients, with surprisingly little neurotoxicity. It is likely, however, that higher doses will be even more effective. Corroborating the notion that a better memory phenotype may lead to a longer response rate, data on bb21217 show that 6 months into treatment, patients with more memory T-cells in their peripheral blood have a lower rate of disease progression.

Janssen’s JNJ-4528 CAR-T cell therapy may put pressure on Bluebird Bio

JNJ-4528 is a CAR-T cell therapy containing two BCMA-targeting single domain antibodies. The CARTITUDE-1 study on the impact of JNJ-4528 in relapse refractory multiple myeloma patients has demonstrated a highly acceptable safety profile, with grade 5 cytokine release occurring after 99 days of treatment. With bb21217, this level of cytokine release was observed after only about 2 weeks. The neurotoxicity associated with JNJ-4528 has been comparable to that of bb21217.

A patient on JNJ-4528 did pass away due to drug-related complications. However, given the otherwise favorable safety profile and the likelihood that we will learn to better manage cytokine release and to optimize CAR-T cell constructs to minimize the associated toxicity, this event is unlikely to prevent the progress of JNJ-4528.

Perhaps the most eye-catching data related to JNJ-4528 has been its impressive 100% response rate. It is important to note, however, that the follow-up for the JNJ-4528 drug occurred sooner than the follow-up for bb2121, which precludes a simple comparison of the results. In addition, while JNJ-4528 appears to be a robust product, it is likely a bit behind bb2121 in terms of getting to market.

Who will win the race in the bispecific T-cell engager (BiTEs) space?

There are several players in the bispecific T-cell engager (BiTE) space, including Amgen, Bristol Myers Squibb, and Regeneron. An important thing to consider with this treatment approach is whether a company is positioning its drug for earlier or later lines of therapy because the subcutaneous formulation of Darzalex is likely to significantly increase uptake of Darzalex as an upfront drug. Drugs positioned as upfront therapies will therefore compete with Darzalex, whereas the success of Darzalex will be irrelevant for those that are positioned as later therapies.

Amgen’s AMG 420 is thus far providing a solid overall response rate with some side effects that are not likely to prohibit the drug from moving forward. The half-life extended study that Amgen is undergoing with AMG 701 may be promising in terms of offering an alternative to taxing infusion strategies.

Bristol Myers Squibb’s CC-93269 has been showing solid overall response rates with deep complete remissions. Such remissions have been shown in other contexts to be associated with better long-term outcomes. Though there have been some patient deaths associated with the drug, these incidents are unlikely to represent a barrier to the drug’s progress. However, because this T-cell engager will have to compete with CAR-T cell therapies, it would be beneficial for Bristol Myers Squibb if they could show response rates of at least 10 months. It would be perhaps surprising if the response rates were on this order and the safety signals also favorable.

Though Regeneron’s pipeline BCMA x CD3 BiTE is in the early stages, interesting data are coming out of the trial, including what appears to be a complete lack of associated neurotoxicity. However, given the small sample sizes thus far, it is simply soon to predict what will happen with this drug or to fairly compare the data associated with this drug with, for instance, Bristol Myers Squibb’s CC-93269.

Innovation in multiple myeloma therapy continues

The results we see from current clinical trials serve not only to help us evaluate new therapies but also to provide insights into future research and development.  For example, based on our growing understanding of the efficacy of CAR-T cell therapies, a group at University College London has begun looking at the feasibility of targeting more than one antigen on malignant myeloma cells as a way to continue to target these cells if they lose one of the antigens.

At the same time, researchers at the Fred Hutchinson Cancer Research Center in Seattle are looking at utilizing a gamma secretase inhibitor to stabilize BCMA and increase its functional expression. They plan to investigate whether this approach allows for more robust CAR-T cell responses.

We need more data to determine the clinical value of new multiple myeloma drugs

There is a lot for physicians to consider when approaching multiple myeloma therapy, and we need more data to determine how innovations in this space will impact the way that we tackle the disease. More data will help us determine, for instance, if it is reasonable to give CAR-T cell therapies upfront, and if so, to which patients.

Given the multiple trips to academic centers that are required for these therapies, we need more information on their therapeutic value to assess whether the inconveniences they pose – particularly to patients in rural settings –  are worth pursuing these interventions upfront rather than, for instance, less laborious autologous stem cell transplants.

If multiple CAR-T cell therapies become available simultaneously, physicians are likely to prefer the one that is associated with the longest progression-free survival. Toxicity will be the next important feature of these drugs, as how well drugs are utilized often depends on day-to-day toxicity.

The realities of toxicity may not be apparent until drugs are used clinically, as the information on toxicity that we receive from drug companies is not always accurate. For instance, Celegene claims that in the case of severe renal failure, adjusting the dose of Revlimid is an adequate way to ensure patient safety, but we find clinically that this is not the case. In addition to toxicity and the duration progression-free survival, physicians will also factor in ease of administration, including manufacturing time, when evaluating CAR-T cell therapies.

Which (if any) of these multiple myeloma therapies will become standards of care? Time – and data – will tell.

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About Dr. Syed Abbas Ali

Dr. Syed Abbas Ali is an Assistant Professor of Oncology at Johns Hopkins University Hospital, where he focuses his research on BCMA-targeted CAR T-cell therapies for the treatment of multiple myeloma. Prior to joining the faculty at JHU, Dr. Ali conducted research at the National Cancer Institute under Dr. James Kochenderfer and was an author on the first BCMA-targeted CAR-T clinical trial in humans for multiple myeloma. Dr. Ali also served as Director of Infusion Services at the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences. In his practice at Johns Hopkins, Dr. Ali is involved in the direct care of patients with multiple myeloma, conducts autologous and allogeneic transplants, and also pursues research regarding the use of vaccines in multiple myeloma.

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This article is adapted from the GLG teleconference “Targeting BCMA in Multiple Myeloma.” If you would like access to this teleconference or would like to speak with Dr. Ali or any of our more than 700,000 experts, contact us.