Sarah Holstein, MD, PhD, associate professor of medicine, University of Nebraska Medical Center, discusses the emergence of bispecific T-cell engagers (BiTEs) in multiple myeloma.

There is much excitement surrounding AMG 420, which is the first BiTE candidate in multiple myeloma, says Holstein. In a phase I study evaluating AMG 420, 7 of 10 patients with heavily pretreated multiple myeloma who were administered a 400-µg/day dose responded to the therapy; 4 patients achieved a complete response (CR). Moreover, the 4 patients with CRs and 1 patient who achieved a partial response had no minimal residual disease. The BiTE candidate binds to the antigen BCMA that is expressed on multiple myeloma cells, which makes it a viable candidate worth pursuing in the space.

The idea behind these engagers is to take the antigen recognition part of an antibody that identifies BCMA on the surface of myeloma cells and an antibody recognizing CD3 on a T cell. Through this recognition, the 2 antibodies hook together, which allows the T cell to be brought to the myeloma cell. As a result, cytotoxic T cells are brought directly to the target cancer cell, explains Holstein.

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Dr. Holstein on BiTEs in Multiple Myeloma

Sarah Holstein, MD, PhD, associate professor of medicine, University of Nebraska Medical Center, discusses recent data with venetoclax (Venclexta) in the treatment of patients with relapsed/refractory myeloma.

The interest with using the BCL2 inhibitor in this patient population is inspired by recent data suggesting that it has a signal in patients with t(11;14) disease. There were also encouraging data seen with venetoclax in combination with bortezomib (Velcade) and it appears that patients do not need to have t(11;14) disease in order to respond to that regimen, Holstein says.

Most recently, there were early data presented at the 2018 ASH Annual Meeting of venetoclax in combination with the proteasome inhibitor carfilzomib (Kyprolis). Although this was a relatively small study, there were interesting response rates observed, Holstein adds. Notably, it appeared that patients were responding to this combination at the same level—irrespective of having high- or standard-risk cytogenetics. There was a small number of patients who had t(11;14) and all of them responded, so clearly there is a signal there, she concludes.

Sarah Holstein, MD, PhD, associate professor of medicine, University of Nebraska Medical Center, discusses recent data with venetoclax in the treatment of patients with myeloma.

Dr. Holstein on Recent Data With Venetoclax in Myeloma

Sarah Holstein, MD, PhD, associate professor of medicine, University of Nebraska Medical Center, discusses the role of melflufen in the treatment of patients with myeloma.

At its heart, melflufen is related to melphalan, a traditional drug that oncologists have used in the myeloma space for the last 50-plus years. In the United States, although the low-dose form of melphalan is rarely used anymore, it is often used in a high-dose form in the context of stem cell transplant. Melflufen is essentially a pro-drug version of melphalan which takes advantage of the biology of malignant plasma cells, Holstein explains.

Melflufen has a lipophilic component to it. The drug gets readily taken up into the cells, but for it to become active, it needs to first be cleaved by enzymes called aminopeptidases. Myeloma cells express many aminopeptidases, Holstein notes, because it is part of a plasma cell that needs protein and then be able to degrade protein, so that more proteins can be produced. As a result of myeloma cells having high levels of aminopeptidases, they then cleave the melflufen into the active alkylating moiety, which essentially gets trapped inside the cell where it can act as an alkylating agent.

Melflufen is an interesting way to more effectively deliver high concentrations of an active alkylator agent more selectively to myeloma cells, and, therefore, avoid some of the toxicity that is often seen with higher doses of melphalan, she concludes.

Dr. Holstein Discusses Role of Melflufen in Myeloma

Sarah Holstein, MD, PhD, associate professor, University of Nebraska Medical Center, discusses the mechanism of action for bb21217 in the treatment of patients with myeloma.

The community has only seen early data with this new BCMA-directed chimeric antigen receptor (CAR) T-cell product, but the results have been promising. Holstein says that bb21217 is taking the construct from bb2121 and enhancing it, taking the T cells and developing them in the company of a drug that alters their phenotype and makes them more memory-like. The hypothesis is that this will improve the persistence of the T cells when they are administered into the patient and create a more durable response.

In the CRB-402 trial presented at the 2018 ASH Annual Meeting, bb21217 was found to be safe and tolerable. The objective response rate was 83.3%, with a very good partial response or better rate of 75%. Complete remissions were still achieved as far as 10 months from infusion time. In terms of safety, 67% of the cohort developed cytokine release syndrome, but only 1 patient demonstrated a grade 3 event.

Dr. Holstein Discusses Mechanism of bb21217 in Myeloma

Sarah Holstein, MD, PhD, associate professor of medicine, University of Nebraska, discusses considerations for determining an optimal treatment sequence for patients with myeloma.

In the relapsed/refractory setting, there are several classes of drugs with multiple FDA-approved agents in each class—naturally, sequencing is a challenge. However, Holstein says there are many factors to consider that will help refine this paradigm. For example, there are patient factors like whether or not they have high-risk cytogenetics. In that instance, Holstein would consider treatment with an immunomodulatory agent plus a proteasome inhibitor. Other important clinical factors that would drive sequencing are underlying comorbidities, she adds.

Physicians have to envision future lines of therapy before determining the current one, Holstein says. If a patient relapsed 5 or 6 years after receiving an autologous stem cell transplant, the best option might be to try a second transplant or another therapeutic strategy that would have an aggressive, immediate impact. This approach would differ from a patient who you would like to have remain on a certain therapy for an extended period of time, she explains.

There are also logistical factors to consider, like if a patient works full-time or lives a significant distance from the clinic. In those situations, physicians would probably want to avoid a therapy that requires infusions multiple times per week.

Sarah Holstein, MD, PhD, associate professor of medicine, University of Nebraska, discusses considerations for determining on optimal treatment sequence for patients with myeloma.

Dr. Holstein on Sequencing Strategies in Myeloma

Sarah Holstein, MD, PhD, associate professor, University of Nebraska Medical Center, discusses the use of triplets and quadruplets in the treatment of patients with multiple myeloma.

For triplet therapy, Holstein says that there is a lot of excitement around carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd). There has also been some interest with lenalidomide, ixazomib (Ninlaro), and dexamethasone in older patients, as this is an all-oral triplet. Currently, the standard of care for newly diagnosed patients is the triplet of lenalidomide plus bortezomib (Velcade) and dexamethasone (RVd).

Most quadruplets being currently tested center around adding antibodies such as daratumumab (Darzalex) to the backbone of a proteasome inhibitor plus an immunomodulatory agent, says Holstein. Some of these quadruplets include daratumumab plus RVd and daratumumab plus KRd. Initial studies are showing high response rates, Holstein says.

Sarah Holstein, MD, PhD, associate professor, University of Nebraska Medical Center, discusses the use of triplets and quadruplets in the treatment of patients with multiple myeloma.
 

Dr. Holstein Discusses Triplets and Quadruplets in Myeloma

Sarah Holstein, MD, PhD, associate professor, University of Nebraska Medical Center, discusses induction therapy for the treatment of patients with multiple myeloma.

Patients with high-risk disease initially do well on induction therapy, but have a much higher rate of relapse and live a shorter time progression-free, says Holstein. The current standard of care induction therapy for patients with myeloma is lenalidomide (Revlimid) plus bortezomib (Velcade) and dexamethasone (RVd). Although, Holstein says that there are ongoing studies investigating the addition of carfilzomib (Kyprolis) as a replacement for bortezomib.

There is a lot of excitement surrounding the triplet of carfilzomib, lenalidomide, and dexamethasone (KRd), but there is also interest in the triplet of lenalidomide, ixazomib (Ninlaro), and dexamethasone in the older patient population. This is an all-oral regimen, which might be well tolerated in this population, Holstein says.

Most of the interest with quadruplets has been with adding antibodies such as daratumumab to the backbone of a proteasome inhibitor plus an immunomodulatory agent. This includes daratumumab plus RVd and daratumumab plus KRd.

Sarah Holstein, MD, PhD, associate professor, University of Nebraska Medical Center, discusses induction therapy for the treatment of patients with multiple myeloma.
 

Dr. Holstein Discusses Induction Therapy for Multiple Myeloma

Sarah Holstein, MD, PhD, Assistant Professor of Oncology, Lymphoma/Myeloma Service Department of Medicine, Roswell Park Cancer Institute, discusses an updated of analysis CALGB/ECOG/BMT CTN 100104, which investigated lenalidomide maintenance therapy after single autologous stem cell transplant (ASCT) for multiple myeloma.

The updated analysis followed-up with patients after a medium of 65 months, compared to a medium of 34 months in the original study. After the extended follow-up, lenalidomide continued to show benefit, says Holstein. Time to progression in the lenalidomide arm was twice as long after extended follow-up compared to the original study results. .

There was also a continued significant improvement in overall survival (OS) in the lenalidomide arm after longer follow-up. Median OS has not yet been reached in that arm. Benefit after longer follow-up was seen in both patients who previously received lenalidomide or thalidomide as induction therapy. .