Accelerating Changes in Oncology

Andre Goy, MD, MS

Editor-in-Chief Chief, Lymphoma Division, Professor and Chairman John Theurer Cancer Center at Hackensack University Medical Center

The current issue of Contemporary Oncology takes us through dramatic changes in the landscape of multiple myeloma (MM) that have occurred over the past decade and explores new developments in the context of stem cell transplantation in non-Hodgkin lymphoma (NHL), especially in the post-rituximab era.

In MM the most striking feature is the use of novel therapies such as proteasome inhibitors (bortezomib) and immunomodulatory drugs (IMiDs) (thalidomide, lenalidomide), that, together with autologous stem cell transplantation (ASCT), have transformed the management of MM and extended overall survival (OS). The impact of novel therapies has been most prominent in both the relapse and frontline settings. especially in combination of biologics or with chemotherapy regimens, as well as in the context of ASCT and as part of consolidation and maintenance strategies. The combination of so-called biologics with steroids has led to unprecedented complete response rates in MM patients, leading to practice-changing results and raising discussion on the role of ASCT consolidation.

Traditionally, ASCT in first response in MM was to reduce further residual tumor load after induction therapy while stem cells were often still “contaminated” with clonal plasma cells. With the current quality and depth of response seen in MM using novel biological triplets as induction, one could argue that ASCT consolidation might lead to an even greater benefit from high-dose therapy (HDT) and ASCT. On the other hand, some argue that ASCT as first consolidation became unnecessary and should be reserved for first relapse (ie, after the collection of stem cells postinduction at minimal disease burden). This important question of the role and timing of ASCT in MM remains unresolved pending ongoing clinical trials. However, elderly patients in whom HDT-ASCT is not appropriate might benefit more from these new biologic combinations, which offer very good cytoreduction with less toxicity.

New weekly schedules, as well as subcutaneous use of bortezomib, offer not only better convenience but also a better toxicity profile (eg, less neuropathy). In addition, the use of biologics as consolidation or maintenance therapy in both younger and older patients is becoming an asset in the management of MM. Meanwhile, in the relapse setting, many new therapies are making their way from second-generation proteasome inhibitors (carfilzomib) to new IMiDs (pomalidomide), targeted therapies (inhibitors of NF-κB, MAPK, and AKT), epigenetic agents (histone deacetylase inhibitors, vorinostat and panobinostat), and humanized monoclonal antibodies (elotuzumab and siltuximab). Interestingly, some of these new therapeutics appear to be able to overcome chemoresistance and conventional poor-risk features in MM. As the awareness of molecular heterogeneity of MM continues to grow (including its progression over time in a given patient), the next challenge will be to try to stratify patients in the clinic for conventional and biologic approaches.

When shifting to NHL, we can also see changes in the landscape of diffuse large B-cell lymphoma (DLBCL) over the past 2 decades. The introduction of rituximab with chemotherapy (ie, R-CHOP) was the first improvement in over 3 decades in the outcome of DLBCL. Shown initially in patients aged >60 years, the remarkable benefit of R-chemo has been confirmed across the board in all patients with DLBCL with an improvement in progression-free survival and OS confirmed with long-term follow-up and in all International Prognostic Index subgroups.

In the frontline setting, studies looking at intensification (ie, beyond R-CHOP) in poor-risk patients tend to show that in the era of rituximab there is no benefit of dose-dense CHOP-14, and that rituximab is likely to decrease potential differences between conventional and high-dose regimens. This was confirmed with several studies just presented at ASCO in June.

The use of rituximab has also altered the landscape in the relapse setting. In patients who fail prior R-chemo, the results of conventional strategy with salvage chemotherapy (ie, R-ICE) followed by HDT and ASCT have worsened, especially in patients who failed initial therapy within 1 year. The same is true in patients considered primary refractory to R-CHOP with very poor outcome, illustrating a need for improvement in the field of stem cell transplantation in DLBCL.

Several of these new approaches are reviewed by Scott D. Rowley, MD, in this issue (see page 9). In his commentary, Dr Rowley discusses the use of PET scans (trying to reach a PET-negative response to salvage therapy prior to HDT-ASCT), new agents (radioimmunotherapy consolidation prior to ASCT), new combinations (lenalidomide or other small molecules/monoclonal antibodies with R-ICE [rituximab, ifosfamide, carboplatin, etoposide]), and consolidation or maintenance strategies post-ASCT. Of note, a recent update of the CORAL trial at ASCO did not show a significant benefit with the use of rituximab maintenance post-ASCT, suggesting that other strategies are needed. Interventional immunotherapy post-ASCT is still early in its development, but extensive preclinical work, as well as known prognostic factors related to the immune system status and immune reconstitution post-ASCT (eg, impact of absolute lymphocyte count/absolute monocyte count ratio at day 15 post-ASCT) in DLBCL, provide a rationale for exploratory ongoing studies. Preliminary results looking at the use of MAb targeting PD-1 (CT-011) post-ASCT, as well as maintenance post-ASCT using the immunomodulator lenalidomide are encouraging.

The ultimate immunotherapy would be allogeneic stem cell transplant, which has strong limitations related to toxicity and/or graft versus host disease (GVHD), and the frequent need to use an unrelated donor (ie, due to the lack of a sibling donor); these factors are very relevant given the profile of the population of DLBCL patients. The development of nonmyeloablative approaches has certainly led to intriguing results—unfortunately, mostly in indolent diseases (follicular lymphoma and chronic lymphocytic leukemia) and, to a lesser degree, in mantle cell lymphoma. While data of allogeneic stem cell bone marrow transplant in DLBCL is limited, encouraging results are emerging with immunodepletion (using EPOCH with fludarabine and rituximab to deplete host CD4 cells before transplantation), as well as TH2 amplification of donor T cells. The goal is to skew the immunological repertoire in favor of graft-versus-solid-tumor as opposed to graft-versus-lymphoma effect, as shown in preclinical models. We at John Theurer Cancer Center have partnered with the National Cancer Institute to explore this strategy with very promising and potentially game-changing results, including in some patients with refractory/relapsed DLBCL. As in MM, a growing awareness of the molecular heterogeneity of DLBCL will hopefully lead to a better stratification of patients, both in the frontline and relapse settings where a variety of new agents are also being developed.

Finally, patients’ outcomes also rely on best supportive care, and there are new developments in that setting as well. Bisphosphonates introduced the concept of disease-modifying therapy by effectively reducing bone pain and skeletal-related events; they are now commonly used in patients with bone metastatic cancer or MM. In the past decade, the growing knowledge of bone biology and our understanding of the molecular mechanisms involved between cancer cells and the bone matrix led to the identification of new therapeutic targets for innovative “smart drugs.” The most investigated is the receptor activator of nuclear factor-Κb/(RANK)/RANK ligand/osteoprotegerin (RANK/RANKL/OPG) pathway, and denosumab is the first RANKL inhibitor approved by the FDA to reduce bone events (eg, pain control, fewer fractures, better functional outcome). Several other targeted agents in the field are being evaluated, illustrating the complexity of future therapies from targeting the tumor cells themselves to the microenvironment, including angiogenesis regulation, control of the dialogue between bone and tumor cells, and tumor cells with the immune system.

As I always tell residents on the floor, oncology is becoming more fascinating by the day and the dramatic changes seen over the past 2 decades will just continue exponentially, enabling us to move toward more rational therapeutics—a first step toward personalized medicine to further improve our patients’ outcomes.