Checkpoint inhibitor project
Targeting checkpoint inhibitors PD-1, PD-L1 and CTLA-4 for immune-based treatments has been shown to be effective for a variety of cancers but have shown significant toxicities when used to treat multiple myeloma patients. Thus, novel additional checkpoint receptors may be required to benefit myeloma patients with drugs that block the immune system.
B7H3 is an important modulator of immune responses that are capable of eliminating cancer cells. Thus, blocking expression of this immune checkpoint protein may result in a reduced ability of myeloma to grow and also enhance the anti-myeloma effects of immune T cells in the bone marrow microenvironment where myeloma grows. Our laboratory has found that B7H3 expression is increased in myeloma patients providing myeloma cells with protection from immune-mediated elimination. Notably, we have shown that treatment with a drug called ruxolitinib can block expression of B7H3 in myeloma patients, which allows the immune system to be restored so that it can eliminate the myeloma.
PVRIG and TIGIT
We are currently collaborating with Compugen Inc. to study Poliovirus receptor related immunoglobulin (PVRIG) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) in multiple myeloma. The regulation of natural killer cells and T cells by PVRIG and TIGIT, DNAM-1, TACTILE receptors are achieved as a result of complex interactions with their ligands by antibodies in tumor cells which is associated with paralysis of the immune system’s ability to knock out myeloma.
JAK inhibitor project
Multiple myeloma (MM) tumor cells evade host immunity through a variety of mechanisms, which may potentially include the PD-L1 and PD-1 axis (see above). This interaction contributes to the immunosuppressive bone marrow microenvironment, ultimately leading to reduced ability of immune cells to eliminate myeloma. We have demonstrated that an already available drug called ruxolitinib that is an inhibitor of JAK proteins reduces PD-L1 expression in the MM bone marrow; this restores immune-mediated elimination of myeloma.
In the clinic, we have demonstrated that this same drug when combined with steroids shows significant clinical benefit for heavily previously treated myeloma patients and this drug can also overcome resistance to a frequently used drug for treating myeloma called lenalidomide.
We are continuing to study a variety of JAK inhibitors alone and combined with other active anti-MM drugs to determine their effects on checkpoint proteins and immune mediated killing.
Tyrosine kinase inhibitor project
There is no preclinical or clinical data on the anti-MM effects of the tyrosine kinase inhibitor repotrectinib alone or in combination with anti-myeloma agents. This drug has shown benefit for treating patients with lung cancer. Importantly, it possesses JAK inhibitory features, so we are studying its anti-‑myeloma effects alone and in combination with a variety of other active anti‑MM drugs in vitro (in the test tube) and the anti-MM effects of this novel tyrosine kinase inhibitor alone using our human MM SCID mouse models in vivo.
COVID-19 and multiple myeloma
With the COVID-19 pandemic and its toll on immune compromised patients, we decided to embark on research related to the effectiveness of COVID-19 vaccines in our myeloma patients.
Response to first two vaccines
Our first study evaluated mRNA COVID-19 vaccine (Moderna and Pfizer) responses among patients with multiple myeloma compared with healthy controls. We found that myeloma patients had worse antibody responses to the first two doses with only a minority showing levels of antibody that were protective compared with 94% in the control group. We also identified several factors that help predict how well a patient may respond to vaccination, including age and the status of their myeloma; older patients and those whose disease was out of control had worse responses to vaccination. Another important factor was whether they received the Moderna or Pfizer vaccine. Patients who received Moderna responded better to vaccination than patients who received Pfizer.
New COVID-19 variant
While working on this study, a fully vaccinated patient developed COVID-19 after traveling to Mexico. Upon investigation, we found that this patient had contracted a previously unreported variant of the virus. We also found that while he had a normal antibody response to vaccination, his antibody levels had dropped much more rapidly after vaccination than had been observed in healthy individuals, likely contributing to his developing severe infection only 10 weeks after receiving the second vaccine dose. A rapid drop in antibody levels was also observed after the patient had recovered from COVID-19 as well.
Decay of antibody levels following vaccination
These findings prompted us to assess how fast antibody levels decrease following vaccination in myeloma patients compared to healthy individuals. As with the patient who developed COVID‑19 in Mexico, we found that antibody levels dropped significantly faster in myeloma patients, meaning they will likely need to get boosters more frequently.
Response to booster vaccine
Recently, we determined the effects of the COVID-19 booster dose on antibody levels among myeloma patients. We found that this third dose achieved much higher antibody levels than following the first two doses. We again found several factors (e.g., receiving Moderna was superior to Pfizer and those patients with increased antibody levels in response to the first two doses achieved higher levels) that help predict how well a patient may respond to this booster.
Development of assay to test antibodies to Omicron variants
We are now in the process of redesigning our antibody test to make it more specific to the newer Omicron variants, as these viral types make up nearly 90% of current COVID-19 cases in the United States. The goal is to better define how well multiple myeloma patients are protected from the current dominant variant of the virus.
Serum B-cell Maturation Antigen (sBCMA)
Standard myeloma biomarkers
Standard biomarkers for multiple myeloma include measuring blood and urine levels of the monoclonal immunoglobulin that is produced by the malignant plasma cell. These tests include serum protein electrophoresis, quantitative immunoglobulins, and the free light chain assay. Unfortunately, these tests are limited in their usefulness because they can be affected by kidney function and slowly respond to changes in the patient’s clinical status. Also, many patients have nonsecretory multiple myeloma in which these biomarkers are not measurable.
Our group has identified a new serum marker for following myeloma patients called serum B‑cell maturation antigen (sBCMA). The protein is present on the outside of myeloma cells and is shed into the blood. This protein is easy to measure in the blood using equipment that is currently available in clinical laboratories and is stable at room temperature for weeks making it a very convenient test.
sBCMA in myeloma
We have investigated the use of serum BCMA (sBCMA) for both predicting outcomes and monitoring of patients with multiple myeloma and related disorders. The average serum level among myeloma patients prior to starting treatment was more than 10 times higher than the amount found along healthy controls.
We have also investigated the use of sBCMA levels to track patients with myeloma who are receiving treatment. First, we showed that those with higher baseline sBCMA levels had worse outcomes. Second, changes in its levels correlated with changes in clinical status. Specifically, patients whose disease was worsening showed increasing amounts whereas those whose levels decreased showed improvements in their disease. We also showed that patients with levels in the normal range when they started new therapy had better outcomes. Furthermore, if patients started treatment with sBCMA levels that were above the normal range, they had better outcomes if their levels decreased to the normal range. Additionally, patients whose sBCMA increased by 25% or more from the start of their treatment during the first 12 weeks of treatment worsened faster. Importantly, while sBCMA levels correlated with changes in traditional blood markers for tracking myeloma, it identified changes in clinical status much more rapidly than those markers. Thus, worsening disease from a treatment could be found faster so patients could change therapies quickly. Lastly, for the growing numbers of patients with disease that is not measurable by the standard blood biomarkers, sBCMA can be used to monitor them effectively.
sBCMA in smoldering multiple myeloma and MGUS
Patients with a form of myeloma that does not initially require treatment is called smoldering multiple myeloma. These patients may progress to a point that they require treatment and we have shown that sBCMA levels predicted the likelihood of this occurring. Approximately 10 million Americans have a precursor form of myeloma called monoclonal gammopathy of undetermined significance (MGUS) with a higher risk of developing myeloma. We have shown that baseline sBCMA levels predicted the likelihood of that occurring and the survival of MGUS patients in general.
sBCMA in other diseases
We have also measured sBCMA in other related blood-based cancers including chronic lymphocytic leukemia (CLL), the most common type of leukemia. CLL patients showed elevated levels, and it predicted their outcomes and effectively monitored changes in their disease status similar to what we observed among patients with multiple myeloma. On the other hand, patients with primary immune deficient states that have reduced levels of immune cells show low levels of sBCMA and lower levels predict worse outcomes for these patients.
PEER-REVIEWED RESEARCH PAPERS- published since 2020
- Chen H, Li M, Sanchez E, Soof CM, Bujarski S, Ng N, Cao J, Hekmati T, Zahab B, Nosrati J, Wen M, Wang CS, Tang G, Xu N, and Berenson JR, “JAK1/2 Pathway Inhibition Suppresses M2 Polarization and Overcomes Resistance of Myeloma to Lenalidomide by Reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 Expression,” Brit J Haematol. 188(2):283-294 (2020).
- Moreau P, Stewart AKS, Dimopoulos M, Siegel D, Facon T, Berenson JR, Raje N, Berdeja JG, Orlowski RZ, Yang H, Ma H, Klippel Z, Zahlten-Kumeli A, Mezzi K, Iskander K, and Mateos VM, “Once-weekly (70 mg/m2) versus Twice-weekly (56 mg/m2) Dosing of Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma: A Post Hoc Analysis of the ENDEAVOR, A.R.R.O.W., and CHAMPION-1 Trials,” Cancer Medicine. 9:2989-2996 (2020).
- Henning C, Wang J, Swift R, Eades B, Spektor TM, and Berenson JR, “Removal of A Silicone Gel Breast Implant in a Multiple Myeloma Patient Improved Disease Status: A Case Report,” Case Reports in Oncology. 13(3):1103-1110 (2020).
- Berenson JR, To J, Spektor T, Turner C, Sanchez A, Ghermezi M, Eades BR, Swift RA, Schwartz G, Eshaghian S, Stampleman L, Moss R, Lim S, and Vescio R, “A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide for Patients with Relapsed/Refractory Multiple Myeloma (RRMM),” Clinical Cancer Res. 26(10): 2346-2353 (2020).
- Henning C, Meyers S, Eades B, Swift B, Bussell L, Spektor TM and Berenson JR, “The Efficacy of Topical Use Crisaborole 2% Ointment for Skin Lesions from Necrobiotic Xanthogranuloma Associated with Multiple Myeloma,” Clinical Lymphoma, Myeloma and Leukemia. 20(8): e492-e495 (2020).
- Meyers S, Henning C, Swift R, Eades B, Spektor TM, and Berenson JR, “Treatment with Elotuzumab in Combination with Dexamethasone Achieves a Complete Remission in a Previously Treated Multiple Myeloma Patient: A Case Report,” Clinical Lymphoma, Myeloma and Leukemia. 20(11):e801-e804 (2020).
- Regidor B, Swift R, Eades B, Emamy-Sadr M, Tarhini F, Spektor TM, and Berenson JR, “Frequent Occurrence of Hypophosphatemia among Multiple Myeloma Patients Treated with Elotuzumab: A Single Clinic Retrospective Study,” Annals of Hematol. 100(4):1079-1085 (2020).
- Jew S, Chang T, Bujarski S, Spektor TM, Soof C, Chen H, Safaie T, Li M, Sanchez E, Wang C, Emamy‑Sadr M, Swift R, Rahbari A, Patil S, Souther E, and Berenson JR, “Normalization of Serum B‑cell Maturation Antigen Levels Predicts Overall Survival in Multiple Myeloma Patients Starting Treatment,” Brit J Haematol. 192:272-280 (2021).
- Chen H, Li M, Sanchez E, Ng N, Yu E, Bujarski S, Yin Z, Wen M, Hekmati T, Field D, Wang J, Nassir I, Yu J, Huang J, Daniely D, Wang CS, Xu N, Spektor TMS, and Berenson JR, “Ruxolitinib Reverses Checkpoint Inhibition by Reducing PD-L1 Expression and Increases Anti-tumor Effects of T‑cells in Multiple Myeloma,” Brit J Haematol. 192:568-576 (2021).
- Jew S, Bujarski S, Soof C, Chen H, Safaie T, Li M, Sanchez E, Wang C, Emamy-Sadr M, Swift R, Rahbari A, Patil S, Souther E, Spektor T, and Berenson JR, “Estimating a Normal Reference Range for Serum B-cell Maturation Antigen Levels for Multiple Myeloma Patients,” Brit J Haematol. 192(6):1064-1067 (2021).
- Regidor B, Goldwater M-S, Wang J, Swift R, Eades B, Emamy-Sadr M, Eshagian S, Spektor TM, and Berenson JR, “Low Dose Venetoclax in Combination with Bortezomib, Daratumumab and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma Patients—A Single Center Retrospective Study,” Annals of Hematol. 100:2061-2070 (2021).
- Bujarski S, Goldwater M, Regidor BS, Jew S, Swift RA, Eades BR, Emamy-Sadr M, Souther E, Li M, Wang C, Xu N, Chen H, Spektor TM, and Berenson JR, “Baseline Serum B-cell Maturation Levels Predict Time to Disease Progression for Patients with Smoldering Multiple Myeloma,” Eur J Haematol. 107:318-323 (2021).
- Bujarski S, Udd K, Soof C, Chen H, Spektor T, Safaie T, Li M, Sanchez E, Stern J, Wang C, Xu N, Emamy-Sadr M, Swift R, Rahbari A, Patil S, Souther E, and Berenson JR, “Baseline and Increases in Serum B-Cell Maturation Antigen Levels Rapidly Indicate Changes in Clinical Status among Relapsed/Refractory Multiple Myeloma Patients undergoing New Treatments,” Targeted Oncology. 16:503-515 (2021).
- Visram A, Soof C, Rajkumar SV, Kumar SK, Bujarski S, Spektor TM, Kyle RA, Berenson JR, and Dispenzieri A, “Serum BCMA Levels Predict Outcomes in MGUS and Smoldering Myeloma Patients,” Blood Cancer J. 11:120-126 (2021).
- Stampfer SD, Goldwater M, Jew S, Bujarski S, Daniely D, Regidor B, Chen H, Xu N, Li M, Green T, Fung E, Aquino E, Swift R, Eshaghian S, Feinstein A, Spektor TM, and Berenson JR, “Response to mRNA Vaccination for COVID-19 among Patients with Multiple Myeloma,” Leukemia 35:3534-3541 (2021).
- Bujarski S, Sutanto C, Spektor TM, To J, Swift RA, Green T, Eades BR, Emamy-Sadr M, Souther E, and Berenson JR, “Use of Serum B-cell Maturation Antigen (sBCMA) Levels to Predict Outcomes for Myeloma Patients Treated with Ruxolitinib, Lenalidomide and Methylprednisolone,” Hematological Oncology. 40(2):243-248 (2022).
- Yashar D, Spektor TM, Martinez D, Sanchez AJ, Ghermezi M, Swift RA, Eades B, Schwartz G, Eshaghian S, Lim S, and Vescio R, and Berenson JR, “A Phase 2 Trial of the Efficacy and Safety of Elotuzumab in Combination with Pomalidomide, Carfilzomib and Dexamethasone for High-Risk Relapsed/Refractory Multiple Myeloma,” Leukemia and Lymphoma (published online).
- Stampfer SD, Goldwater M-S, Bujarski S, Regidor B, Zhang W, Feinstein AJ, Jew S, Chen H, Xing N, Li M, Fung E, Aquino E, Swift R, Eshaghian S, Vail E, and Berenson JR, “Severe Breakthrough COVID-19 with a Heavily Mutated Variant in a Multiple Myeloma Patient 10 Weeks after Vaccination,” Clinical Infection in Practice (published online).
- Zeidan, AM, Cook RJ, Bordoni R, Berenson JR, Edenfield WJ, Zhou G, Asatiani E, and Savona MR, “A Phase 1/2 Study of the Oral Novel JAK1 Inhibitor INCB052793 and Itacitinib Alone or in Combination with Standard Therapies for Advanced Hematologic Malignancies,” Clinical Lymphoma, Myeloma and Leukemia (published online on January 20, 2022).
- Daniely D, Forouzan E, Spektor TM, Cohen A, Bitran JD, Chen G, Moezi MM, Bessudo A, Coleman T, Hrom J, Eshaghian S, Swift RA, Eades BR, Lim S, and Berenson JR, “A Phase 1/2 Study of Ixazomib as a Replacement for Bortezomib or Carfilzomib for Multiple Myeloma Patients Recently Relapsed or Refractory to Their Last Combination Regimen Containing Either Bortezomib or Carfilzomib,” Experimental Hematol. (published online on April 10, 2022).
- Soof CM, Spektor TM, Parikh SA, Slager SL, Rabe KG, Call TG, Kednerian SS, Ding W, Muchtar E, Ghermezi M, Kay NE, and Berenson JR, “Serum B-Cell Maturation Antigen as a Prognostic Marker for Untreated Chronic Lymphocytic Leukemia,” Experimental Hematol. (in press).
RESEARCH PAPERS – Submitted for publication
- Freytes CO, Stewart K, Vescio R, Schiller G, Ballester O, Noga S, Rugo H, Stadtmauer E, Sahebi F, Tarantolo S, Stiff P, Meharchard J, Schlossman R, Brown R, Tully H, Jacobs C, DiPersio J, Anderson K, Berenson JR, and Sing A, “CD34 Selection of Autologous Peripheral Blood Progenitor Cells Does Not Delay Immune Reconstitution or Increases the Incidence of Infections in Patients Transplanted for Multiple Myeloma,” (submitted).
- Menke D, Chadburn A, Green E, Berenson JR, Said J, and Thome S, “Pathogenic Implications of Differences in Detection of HHV-8 Genome and HHV-8 vIL-6 Production in Castleman’s Disease: Implications for Pathogenesis,” (submitted).
- Hortobagyi GN, Theriault RL, Berenson JR, Lipton A, Kowalski MO, and Seaman JJ, “Skeletal‑Related Events Associated with Metastatic Breast Cancer and Multiple Myeloma: A Comparative Analysis of Three Multicenter, Randomized Trials of Pamidronate Therapy,” (submitted).
- Chen T, Ma P, Ravera C, Deckert F, Berenson JR, Goodin S, LoRusso P, Schran H, and Seaman J, “Plasma and Urine Pharmacokinetics of Zoledronic Acid in Cancer Patients with Bone Metastases by Noncompartmental and Compartmental Analyses,” (submitted).
- Berenson JR, “Constitutively Active Nuclear Transcription Factor NF-B has Recently Emerged as a Major Underlying Factor in the Development,” (submitted).
- Yeh H and Berenson J, “New Directions in the Treatment of Multiple Myeloma,” Medscape (submitted).
- Baritaki S, Suzuki E, Umesawa K, Spandidos D, Berenson JR, Daniels TR, Penichet ML, Palladino M, and Bonavida B, “Reversal of Tumor Cell Resistance to TRAIL-Mediated Apoptosis by the Novel Proteasome Inhibitor, NPI-0052, via Inhibition of the Yin Yang 1 and Up-Regulation of DR5,” (submitted).
- Bashey A, Pérez WS, Zhang M-J, Anderson KC, Ballen K, Berenson JR, Fonesca R, Fréytes CO, Gale RP, Gibson J, Giralt SA, Kyle RA, Lazarus HM, Maharaj D, McCarthy PL, Milone GA, Nimer S, Pavlovsky S, Reece DE, Schiller G, and Vesole DH, and Parameswaran H, “Syngenic Hematopoietic Stem Cell Transplantation for Multiple Myeloma: A Comparison to Autologous Transplantation,” (submitted).
- Cueto J, Waterman G, and Berenson J, “Achievement of Long-term Durable Remission with Single-Agent Zoledronic Acid for a Patient Active Multiple Myeloma,” (submitted).
- Papanastassiou J, Anderson G, Berenson J, Chung G, Van Meirhaeghe J, Phillips F, Scott M, Small B, and Vrionis F, “Which Patients May Not Benefit from Vertebral Augmentation? Treatment Algorithm for Vertebral Compression Fractures,” (submitted).
- Chen H, Zhang Y, Mao H, Zhao A, Du F, Gian J, Yang J, Wei J, Liu X, Sha Z Han Y, Situ W, Li C, Sheng L, Xu Y, Shou Z Vardanyan S, Bonavida B, and Berenson J, “Serum Autoantibodies Directed Against Moesin N1-297/C471-577 is Elevated in Immune Thrombocytopenia,” (submitted).
- Halleluyan R, Keilty D, and Berenson JR, “Extramedullary Multiple Myeloma Involving the Pancreas: A Case Report,” (submitted).
- Xu N, Yu E, Ng N, Li M, BS, Bujarski S, Yin Z, Hekmati T, Yu J, Daniely D, Wang CS, Chen H, and Berenson JR, “The JAK1/2 Inhibitor Ruxolitinib Downregulates the Immune Checkpoint Protein B7-H3 in Multiple Myeloma,” (submitted).
- Stampfer SS, Bujarski S, Goldwater M-S, Jew S, Regidor B, Chen H, Xu N, Li M, Fung E, Swift R, Beatty B, Eshaghian S, and Berenson JR, “Loss of Anti-Spike Antibodies Following mRNA Vaccination for COVID-19 among Patients with Multiple Myeloma,” (submitted).
- Afari J, Spektor TM, Turner C, Cohen A, Mackintosh R, Bessudo A, Jhangiani H, Gabrail N, Kubba S, Neidhart J, Swift RA, Eades BR, Kim C, Kim S, Vescio R, and Berenson JR, “Efficacy and Safety of Pomalidomide as a Replacement Therapy for Multiple Myeloma Patients Who are Refractory to Lenalidomide-Containing Combination Regimens,” (submitted).
- Yashar D, Regidor B, Goldwater M-S, Fung E, Kim C, and Berenson JR, “Targeting B-Cell Maturation Antigen for Treatment and Monitoring of Multiple Myeloma: Current Clinical Data and Its Future Potential,” (submitted).
- Berenson JR, Kim C, Bujarski S, To J, Spektor TM, Martinez D, Turner C, Matthew Ghermezi, Eades BR, Swift RA, Schwartz G, Eshaghian S, Stampleman L, Moss RA, Lim S, MD, and Vescio R, “A Phase 1 Trial of Ruxolitinib, Steroids and Lenalidomide for Relapsed/Refractory Multiple Myeloma Patients,” (submitted).