The past year has seen remarkable advances in the treatment of leukemia, lymphoma, and multiple myeloma, which combined account for 9.9% of the estimated 1,806,590 new cases of cancer diagnosed in the United States and an estimated 56,840 cancer-related deaths.1 Novel therapies are providing innovative options for patients with incurable blood cancers, including multiple myeloma, a disease that is diagnosed in more than 32,000 people each year and causes about 13,000 deaths annually.2
Up until 2020, the major classes of drugs used to treat myeloma included the immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. However, despite the efficacy of these drugs, nearly all patients will become refractory to these therapies, and therefore new treatments are urgently needed. Thus, there has been intense interest in the development of novel therapies targeting B-cell maturation antigen (BCMA).
Sarah A. Holstein, MD, PhD
BCMA: Novel Target in Multiple Myeloma
BCMA is widely expressed on the surface of myeloma cells, and currently there are three categories of therapies being developed that target BCMA: antibody-drug conjugates, bispecific T-cell engagers/bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapy.
The first anti-BCMA therapy to receive U.S. Food and Drug Administration (FDA) approval is belantamab mafodotin-blmf. This agent is an antibody-drug conjugate, and it received accelerated FDA approval in August 2020 as a single agent. The approval was based on the primary results from the phase II, two-arm DREAMM-2 trial, which showed an overall response rate of 31% in patients receiving the recommended dose of 2.5 mg/kg, and an overall response rate of 34% in patients receiving a dose of 3.4 mg/kg.3 Belantamab mafodotin is approved for use in patients with relapsed or refractory myeloma who have received four or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Ongoing studies are evaluating belantamab mafodotin in combination with a variety of other antimyeloma drugs.
As noted, CAR T cells targeting BCMA are also being developed. One such CAR T-cell product is idecabtagene vicleucel (bb2121), which has been evaluated in patients who have received at least three prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. In September 2020, the FDA accepted the biologics license application for the therapy, and FDA approval of idecabtagene vicleucel is anticipated by March 2021.
More targeted therapies and less chemotherapy in difficult-to-treat lymphomas made headlines this year, including two combination immunotherapy regimens in the treatment of non-Hodgkin lymphomas featured in ASCO’s Clinical Care Advances 2020 report. One is rituximab plus lenalidomide for the treatment of two common indolent types of non-Hodgkin lymphoma, follicular and marginal zone, which the FDA approved in 2019. Notably, this is the first combination the FDA has approved for these lymphomas that does not include chemotherapy.
The second important clinical research advance cited by ASCO is a combination of rituximab plus an investigational drug known as 5F9 (short for Hu5F9-G4) in the treatment of relapsed or resistant diffuse large B-cell and follicular lymphomas. 5F9 is a monoclonal antibody that targets the macrophage immune checkpoint CD47, blocking the “don’t eat me” signal on cancer cells. The results from a phase IB study of the combination therapy are showing promising preliminary efficacy, warranting larger and longer studies.4
Most recently, in October 2020, the FDA extended the approval of pembrolizumab for adult patients with relapsed or refractory classical Hodgkin lymphoma and for pediatric patients with refractory classical Hodgkin lymphoma or classical Hodgkin lymphoma that has relapsed after two or more lines of therapy. The approval was based on the findings from the KEYNOTE-204 phase III study, which demonstrated pembrolizumab was superior to brentuximab in treating relapsed or refractory classical Hodgkin lymphoma.5
Still, chemotherapy remains a crucial component in the treatment of lymphoma, and clinical trials incorporating immunotherapy with chemotherapy for late-stage Hodgkin lymphoma are showing encouraging results. In a phase II study of nivolumab plus AVD (doxorubicin, vinblastine, dacarbazine) in newly diagnosed patients with advanced-stage classical Hodgkin lymphoma, there was a 9-month progression-free survival rate of 92% and an overall survival rate of 98%, with most patients achieving complete remission by the end of therapy.6
The addition of the monoclonal antibody rituximab to standard chemotherapy is also proving to be beneficial in the treatment of children with high-risk, mature B-cell non-Hodgkin lymphoma. In a European Intergroup for Childhood Non-Hodgkin Lymphoma/Children’s Oncology Group phase III trial, the combination therapy was found to significantly improve event-free and overall survival in these patients. However, rituximab/chemotherapy was associated with higher rates of severe febrile neutropenia and infection and a significantly higher rate of low immunoglobulin G levels.7
Accelerating Progress in the Treatment of CLL
Over the past year, the results of several clinical trials using chemotherapy-free treatments are providing promising news for patients with chronic lymphocytic leukemia (CLL). This rare hematologic cancer is diagnosed in more than 21,000 people each year in the United States and results in more than 4,000 deaths.8
Findings from the phase III MURANO trial investigating venetoclax plus rituximab vs bendamustine plus rituximab in patients with relapsed or refractory CLL showed that 4-year progression-free survival and overall survival were significantly better in the patients receiving venetoclax plus rituximab, especially in those with undetectable minimal residual disease (MRD). Progression-free survival rates at 18 months after the end of treatment were 90.3% in those with MRD negativity, 64.4% in those with low MRD positivity, and 8.3% in those with high MRD positivity.9
The final results from another phase III study, the ASCEND trial, are also showing prolonged progression-free survival achieved by a noncytotoxic regimen in patients with CLL. This study investigated the Bruton’s tyrosine kinase inhibitor acalabrutinib as monotherapy compared with idelalisib plus rituximab or bendamustine plus rituximab in adults with relapsed or refractory CLL who had received at least one prior line of treatment. At a median follow-up of 22 months, patients receiving acalabrutinib achieved significantly prolonged investigator-assessed progression-free survival vs the standard arm of the study, which was consistent across prespecified high-risk genomic subgroups, including those with unmutated IGHV and del(17p)/TP53 mutation.10
These and other developments in clinical research that are changing the treatment paradigm for patients with hematologic malignancies are discussed further in this almanac.
DISCLOSURE: Dr. Holstein has served as a consultant for or received honoraria from Celgene, Genentech, GSK, Oncopeptides, Sanofi, and Takeda; and has received research funding from Oncopeptides.
1. Leukemia & Lymphoma Society: Facts and Statistics. Available at https://www.lls.org/facts-and-statistics/facts-and-statistics-overview/facts-and-statistics. Accessed October 22, 2020.
2. American Cancer Society: Key Statistics About Multiple Myeloma. Available at www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html. Accessed October 22, 2020.
3. Lonial S, Lee HC, Badros A, et al: Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): A two-arm, randomised, open-label, phase 2 study. Lancet Oncol 21:207-221, 2020.
4. Markham MJ, Wachter K, Agarwal N, et al: Clinical Cancer Advances 2020: Annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 38:1081, 2020.
5. Kuruvilla J, Ramchandren R, Santoro A, et al: KEYNOTE-204: Randomized, open-label, phase III study of pembrolizumab versus brentuximab vedotin in relapsed or refractory classic Hodgkin lymphoma. ASCO20 Virtual Scientific Program. Abstract 8005.
6. Ramchandren R, Domingo-Domènech E, Rueda A, et al: Nivolumab for newly diagnosed advanced-stage classic Hodgkin lymphoma. J Clin Oncol 37:1997-2007, 2019.
7. Minard-Colin V, Aupérin A, Pillon M, et al: Rituximab for high-risk, mature B-cell non-Hodgkin’s lymphoma in children. N Engl J Med 382:2207-2219, 2020.
8. American Cancer Society: Key Statistics for Chronic Lymphocytic Leukemia. Available at www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/key-statistics.html. Accessed October 22, 2020.
9. Kater AP, Wu JQ, Kipps T, et al: Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia. J Clin Oncol. September 28, 2020 (early release online).
10. Ghia P, Pluta A, Wach M, et al: ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 38:2849-2861, 2020.