Ola Landgren, MD, PhD, the inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, Miami Health System, discusses the clinical impact of the 4-drug combination of carfilzomib (Kyprolis), lenalidomide (Revlimid), dexamethasone, and daratumumab (Darzalex; KRd-D) in patients with multiple myeloma.

, which examined the quadruplet in patients with newly diagnosed multiple myeloma, yielded high rates of minimal residual disease (MRD) negativity and progression-free survival. Deep responses can be achieved through modern therapy in the absence of a bone marrow transplant, according to Landgren. Additionally, a once weekly administration of the quadruplet is reasonable for a defined period of time, he notes. However, going forward, it is not known whether every patient will need a full 8 cycles of therapy. When examining the median time to MRD negativity, patients enrolled on the trial achieved MRD negativity with 1 to 6 cycles of therapy. The median time to MRD negativity was 6 cycles, Landgren explains.

Compared with other available options, such as bone marrow transplant, which is associated with toxicities and sustained peripheral neuropathy, a once weekly infusion of the quadruplet is a positive prospective treatment, Landgren says. KRd-D is pushing the field forward and offers a new option for this patient population, Landgren concludes. 

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Ola Landgren, MD, PhD, discusses the clinical impact of the 4-drug combination of carfilzomib, lenalidomide, dexamethasone, and daratumumab in patients with multiple myeloma. 


Dr. Landgren on the Clinical Impact of KRd-D in Multiple Myeloma

Ola Landgren, MD, PhD, inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, Miami Health System, discusses the importance of understanding progressive vs stable multiple myeloma precursor conditions.

In a study that utilized whole exome sequencing to identify progressive and stable precursor conditions as separate entities, investigators focused on patients with low levels of disease, which made the research unique, Landgren says. If a large number patients with smoldering myeloma are studied, a number of them will inevitably develop multiple myeloma, Landgren explains.

However, if one has a large population of patients with monoclonal gammopathy of unknown significance, the proportion of those who develop multiple myeloma will be lower, Landgren says. For those who are going to progress, however, these considerations are equally important.

The study was difficult to perform because of technological limitations at the time, Landgren explains. Results from the study indicated that certain genomic signatures will activate in patients, including APOBEC, which is known to be associated with aggressive, solid, and metastatic cancers. APOBEC has been found to be present in multiple myeloma, as well as in patients with relapsed myeloma, Landgren concludes.

Ola Landgren, MD, PhD, discusses the importance of understanding progressive vs stable multiple myeloma precursor conditions.

Dr. Landgren on Examining Progressive vs Stable Myeloma Precursor Conditions

Chimeric antigen receptor (CAR) T-cell therapy has been developed as a novel strategy whereby the immune system functions as the "drug" against cancer—by taking out a patient’s own T cells from peripheral blood, inserting a so called "vector" in the T cells in the laboratory, and giving back the modified T cells to the patient. This has been found to work dramatically well in the setting of acute lymphoblastic leukemia and now reports of the initial patients treated with multiple myeloma are showing the immense potential in this disease.

The first study using CAR T-cell therapy in patients with myeloma was developed by James Kochenderfer, MD, and colleagues at the National Institutes of Health (NIH). Their results, based on small numbers, show impressive rapid clearance of large myeloma burden, resulting in complete response for a patient who failed most other therapies. It was first communicated as a plenary presentation at the 2015 ASH Annual Meeting.

The work by the NIH team serves as proof-of-concept for CAR T-cell therapy as a valid treatment approach in multiple myeloma. Also, based on small numbers, researchers at the University of Pennsylvania have been able to follow up on the NIH approach and show similar results using their CAR T cells. This further confirms the potential of this treatment strategy in myeloma.

At Memorial Sloan Kettering Cancer Center (MSK), patients with relapsed/refractory leukemias and lymphomas have been treated successfully with CAR T-cell therapy for several years. In parallel with ongoing work on leukemias and lymphomas, Eric Smith, MD, PhD, and Renier J. Brentjens, MD, PhD, have further developed myeloma-directed CAR T cells at MSK. Their work has focused on improving efficacy and limiting toxicity by introducing new features of the CAR T cells.

The MSK myeloma CAR T-cell therapy has several features which are different from other existing myeloma CAR T cells. Specifically, MSK’s newest version of the CAR T-cell therapy for myeloma has a built-in "off switch" which can be used to deactivate the CAR T cells. This will be used if there are severe toxicities. Also, the CAR T-cell receptor at MSK is human, which may avoid anti-CAR immune responses seen with CARs containing mouse-derived elements. Furthermore, this construct was selected out of many evaluated, and confers many favorable characteristics onto T cells that may increase efficacy.

The clinical lead principal investigator for the new myeloma CAR T-cell therapy study is Sham Mailankody, MBBS. He works closely with Drs. Smith and Brentjens on the new study. In March 2017, the first myeloma patients will be treated with CAR T cells at MSK.

Regarding study population, it is open for patients who have been diagnosed with multiple myeloma and have refractory, persistent, or progressive disease after receiving at least two prior lines of therapy, including treatment with an immunomodulatory drug and a proteasome inhibitor.

Regarding study design, this is an open-label, dose escalating, nonrandomized, single-center, phase I study of EGFRt/BCMA-41BBz CAR T cells.

On a practical note, patients will undergo leukapheresis of peripheral blood for further T cell enrichment; activation and genetic modification using a retroviral vector encoding a B-cell Maturation Antigen (BCMA)-targeted CAR, and the EGFRt safety system (EGFRt/BCMA-41BBz). These T cells will be expanded and after the appropriate number of cells are generated, the modified T cells may be infused fresh or frozen for later use, according to standard operation procedures.

These modified T cell infusions will be administered 2 days following a single day of conditioning chemotherapy. Serial sampling of blood and bone marrow will be performed following treatment to assess toxicity, therapeutic effects, and survival of the genetically modified T cells. For patients who have obtained clinical benefit from the initial T cell therapy and did not experience any non-hematologic grade 4 toxicities, additional modified T cells may be re-infused after 30 days at the treating physician’s discretion.

For physicians or patients who are interested in this study, please contact Analisa Wills, Cellular Therapeutics Center, MSK, for referrals to the protocol. Phone: 212-639-5317

Articles

Ola Landgren, MD, PhD, discusses a new clinical trial at Memorial Sloan Kettering examining a novel myeloma-directed CAR T-cell therapy developed by researchers at the cancer center.

Ola Landgren, MD, PhD

Articles

Dr. Landgren on the Clinical Impact of KRd-D in Multiple Myeloma

Dr. Landgren on Examining Progressive vs Stable Myeloma Precursor Conditions

Novel Study of Next-Generation BCMA-Targeted CAR-Modified T Cells for Multiple Myeloma Opens at MSK