- Personalizing Therapy for Patients with Multiple Myeloma
- Targeting BCL2 with Venetoclax in Patients with Relapsed CLL
BACKGROUND: Multiple myeloma is no different from other cancers that have wide variations in their genetic and mutation profiles. Many subsets of patients with multiple myeloma exist, with different biologic drivers and patient-specific characteristics that impact therapeutic efficacy. Understanding the patient’s genetic and functional status can therefore help in tailoring patient-specific treatment regimens.
METHODS: As part of a review article, investigators discuss the role of functional status and genetics to help guide therapeutic decisions for patients with multiple myeloma and improve patient outcomes.
RESULTS: The genetic landscape of this disease is complicated—involving from 5 to 20 different genotypes—therefore, assessing each patient carefully for functional and genetic status may help improve outcomes. Functional assessment in a patient with multiple myeloma is an important early driver, because it determines the intensity of therapy. Traditionally, functional status was used to determine if a patient should undergo autologous stem cell transplant (SCT) as part of the initial therapy. The authors argue that this may not be necessary, because evidence shows that patients aged ≥70 years can undergo transplant as long as they receive a lower dose of melphalan chemotherapy during the transplant process.
A patient’s frailty may be more important when deciding on an initial treatment regimen that includes either an intensive triplet therapy or less intensive with only doublet therapy. For patients fit enough for a transplant, the authors recommend initial triplet therapy with lenalidomide (Revlimid), bortezomib (Velcade), and the corticosteroid dexamethasone, followed by transplant. By contrast, for older patients who are frail, they note that evidence from recent clinical trials suggests that a 2-drug regimen is better tolerated in this patient population and has equivalent outcomes to triplet therapy. Genomic profile can also be used to tailor therapy to the individual patient with multiple myeloma. Evolving molecular diagnostic tests, such as targeted gene sequencing, RNA sequencing, or copy number arrays, can facilitate a more accurate stratification of patients. In transplant-eligible newly diagnosed patients with multiple myeloma, Dr Lonial and Dr Nooka recommend intensive induction triplet therapy with lenalidomide, bortezomib, and dexamethasone, and continued triplet maintenance therapy for patients with high-risk disease at diagnosis; for standard-risk patients, they recommend lenalidomide-only maintenance therapy. Patients with newly diagnosed disease who are too frail to undergo an SCT and have standard-risk disease, can receive doublet therapy with lenalidomide and dexamethasone or with bortezomib and dexamethasone. However, newly diagnosed patients with high-risk disease should receive a modified dose of lenalidomide, bortezomib, and dexamethasone triplet therapy.
“The use of an optimal induction regimen followed by high-dose therapy does not limit the ability to tailor therapy to patients,” the experts note. “Once the initial induction and consolidation (with a transplant) are complete, there are likely to be opportunities to tailor therapy in the maintenance phase on the basis of genetics.”
As for future directions on how to tailor treatments for multiple myeloma, they conclude, “The current literature suggests that the use of biology-driven treatments, taking into account functional status and genetics, is likely the first and most important step. The incorporation of these agents with biology-based approaches will likely yield the best and most effective treatments as we continue to learn how best to target the many mutations found in patients with myeloma.”
Source: Lonial S, Nooka AK. Myeloma is not a single disease.
J Oncol Pract. 2016;12:287-292.
|COMMENTARY BY ROBERT J. IGNOFFO|
This clinical review highlights important considerations when making decisions about primary, induction, and maintenance therapy. Improvement in overall and progression-free survival has been shown with SCT, and the use of a 3-drug induction regimen. Furthermore, an immunomodulatory drug plus a proteasome inhibitor combined with dexamethasone is the preferred 3-drug induction regimen because it has a greater likelihood of inducing a complete remission and leading to a curative transplant. However, whether a patient can receive an SCT or a 3-drug induction regimen often depends on a patient’s functional, cytogenetic, and mutational status.
Myeloma presents with a wide variety of mutations, leading to variable survival and response characteristics. The use of patient functional status and cytogenetics should be considered when making therapeutic decisions about induction and maintenance therapy, especially in frail patients. The authors stress that functional performance status is more important than chronologic age, and recommend the use of measurement tools, such as the Frailty Index, to guide the clinician in selecting appropriate therapy.
BACKGROUND: Targeted therapies have improved the outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but achieving complete remission remains uncommon. Venetoclax is an investigational inhibitor of B-cell lymphoma-2 receptor (BCL2), which is a protein that is central to the survival of CLL cells.
METHODS: A total of 116 patients were enrolled in the study; 56 patients in the dose-escalation cohort received active treatment in 1 of 8 dose groups that ranged from 150 mg to 1200 mg daily; in an expansion cohort, 60 patients were treated with venetoclax in a weekly stepwise ramp-up dosing of up to 400 mg daily.
RESULTS: The majority of patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Patients receiving venetoclax had an overall response rate of 79% and a complete response rate in 20% of patients, including 5% who had no minimal residual disease by flow cytometry. Venetoclax was active at all dose levels, and no maximum tolerated dose was identified. Among patients with an adverse prognosis, the response rates ranged from 71% to 79% depending on the subgroup, including those with resistance to fludarabine (79%), chromosome 17p deletions (71%), and those with unmutated IGHV (76%). The researchers also estimated the 15-month progression-free survival rate to be 69% with the expansion dose. In terms of safety, tumor lysis syndrome occurred in 10 patients in the dose-escalation group, but clinically important sequelae occurred in only 3 of those patients, 2 of whom had severe sequelae. After adjustments were made to the dosing schedule, no incidences of tumor lysis syndrome occurred in the expansion cohort. Other adverse events included mild diarrhea, upper respiratory tract infection, nausea, and grade 3 or 4 neutropenia, which occurred in 41% to 52% of patients. This first trial of venetoclax demonstrates the potential of BCL2 antagonism as an additional therapy for patients with relapsed CLL, including those with poor prognostic features. Furthermore, the overall response rate in patients provides support for investigating venetoclax as a treatment option for patients with heavily pretreated relapsed or refractory small lymphocytic lymphoma, concluded the researchers.
Source: Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311-322.
|COMMENTARY BY ROBERT J. IGNOFFO|
CLL is a chronic disease that primarily occurs in elderly patients. It is well known that treating elderly patients with cytotoxic agents is difficult because of the high frequency of life-threatening toxicities, especially febrile neutropenia. According to the National Comprehensive Cancer Network (NCCN) guidelines, ibrutinib and idelalisib in combination with rituximab are the standard of care for patients with refractory CLL. Venetoclax was developed to effectively inhibit the BCL2 receptor while having little effect on platelets. However, it has been associated with several adverse events, including diarrhea, upper respiratory infection, and neutropenia in 40% to 50% of patients. Grade 4 neutropenia also occurred in half of patients, but was controlled with a granulocyte colony-stimulating factor. Fortunately, febrile neutropenia occurred in <20% of patients. This phase 1 study produced approximately 80% partial and complete responses at all dose levels in patients with refractory CLL—even those with poor prognostic features, and aged ≤86 years. These impressive results have led the NCCN to update its latest guideline to include venetoclax as a first-line agent for the treatment of patients with refractory CLL.