NEW YORK—Advances in the molecular biology and treatment of both common and uncommon plasma-cell disorders have led to the development of proteasome-inhibitor therapy for Waldenström's macroglobulinemia (WM), siltuximab, the first-ever drug to be approved by the U.S. Food and Drug Administration for the treatment of multicentric Castleman's disease (a rare blood disorder similar to lymphoma) (OT 5/25/14 issue), and novel monoclonal antibodies and immunotherapy for multiple myeloma, topics that were discussed here at the Great Debates and Updates in Hematologic Malignancies meeting.
WM is an immunoglobulin M (IgM)-secreting disorder with a high rate of peripheral neuropathy. The clinical characteristics include bone marrow infiltration and hyperviscosity. “One-third of patients have MGUS [monoclonal gammopathy of undetermined significance] or smoldering myeloma, which separates them from multiple myeloma and more indolent disorders,” said Sagar Lonial, MD, Professor of Hematology and Medical Oncology at Emory University School of Medicine.
Symptom management guides the initiation of therapy in WM. Consensus panel recommendations for the criteria for initial treatment include hemoglobin levels less than 10 g/dL, platelet counts less than 100,000 mm3, symptomatic hyperviscosity, moderate to severe peripheral neuropathy, and other symptomatic autoimmune-related events.
Adverse prognostic factors that predict outcomes are age over 65, low hemoglobin levels and platelet counts, beta 2 microglobulin higher than 3 mg/L, and IgM over 7 g/dL.
In 2009, the consensus panel recommended that first-line therapy for WM patients include combination therapy, such as rituximab-cyclophosphamide-dexamethasone, rituximab as a single agent, nucleoside analogues, or alkylators. Salvage therapy should consist of re-using therapies, bortezomib, thalidomide plus steroids, alemtuzumab, and autologous hematopoietic stem cell transplant.
“Now we have changed to proteasome inhibitors as frontline therapy,” Lonial said. “Several trials of bortezomib-based upfront therapy—in particular, in combination with rituximab in untreated WM—have shown that some patients achieve complete responses. Complete responses are occurring more frequently with new drugs, which is significant. The depth of response correlates with increased outcomes.”
With bortezomib-based therapy in WM, peripheral neuropathy is an issue. Now clinicians use weekly subcutaneous doses of bortezomib in combination with rituximab in newly diagnosed or relapsed WM, he noted.
The proteasome inhibitor carfilzomib in combination with rituximab and dexamethasone, leads to favorable response rates, and “peripheral neuropathy becomes non-existent—This is further evidence of the value of proteasome inhibitors moving forward as frontline therapy.”
Use of another proteasome inhibitor, oprozomib, in once-daily, modified-release tablets has led to an 80 percent overall response rate in WM patients in a Phase 1/2 trial. “This oral proteasome inhibitor leads to limited peripheral neuropathy,” Lonial said. “We still have to work out the gastrointestinal toxicity issue, but the response is encouraging.”
Identification of Mutations
The big buzz in WM is identification of mutations, which has become a way to identify pathogenesis of the disease, he said. The MXD88 mutation is found in 70 to 80 percent of WM patients, and this will help identify agents that target pathways of this mutation.
“We have potential new therapeutic options using Btk inhibitors,” he said. “Btk is linked with early disease activity, and we have exciting, encouraging preclinical data with Btk inhibitors. A single-pill approach may be a game-changer in WM if we can identify a potential pathway that could be treated with Btk inhibitors.”
The treatment for WM is in evolution, Lonial continued. “The use of alkylators has dropped off. We know nucleoside analogues increase the risk of developing myelodysplastic syndromes. Because WM patients live so long, the risk of inducing a second malignancy is important to keep in mind.
“Clearly, proteasome inhibitors have significant activity and can be combined with rituximab. There is a future role for Btk inhibitors. When to use them is the new question. There is also a role for other targets in the BTK/TLR pathway for new treatments. We don't have enough data yet to identify how to maximize debulking WM patients.”
He then turned to Castleman's disease, a benign enlargement of lymph nodes that is driven by interleukin 6 (IL-6): “A good biopsy of lymph nodes is critically important to rule out other disorders that can give rise to similar pathology, including lymphoma, lupus, and rheumatoid arthritis,” he said.
The presentation of Castleman's disease is linked to overexpression of IL-6 in the blood. Other associated disorders including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome; amyloidosis; MGUS; myeloma; and lymphoma. “The management of Castleman's disease and POEMS can be a therapeutic dilemma. It's important to identify whether the patient has POEMS or Castleman's disease,” he said.
The newest treatment for Castleman's disease is siltuximab, which received FDA approval in late April. The anti-IL6 targeting agent has been studied in kidney cancer, solid tumors, and myeloma, and blocks the ability of IL-6 to associate with its receptor.”
He pointed to a Phase I trial at Emory University of siltuximab as a single agent, which showed 100 percent response in a 9 mg/kg dose and significant progression-free survival (PFS) of almost three years with a 12 mg/kg dose. “Responses like this have not been seen with rituximab or cytotoxic therapies,” he said.
A randomized Phase III trial of siltuximab versus best supportive care in 78 patients with Castleman's disease showed that one-third in the siltuximab group responded, compared with none in the control group. “This clearly demonstrates in a randomized setting that siltuximab targets IL-6 and has a major impact—It is a new, potent treatment option,” Lonial said.
After the presentation, a member of the audience asked whether if a WM patient has an IgM flare on rituximab, it is possible to give chemotherapy before rituximab. Lonial responded: “Clearly this happens. I would give the proteasome inhibitor for the first two weeks with corticosteroids, and then give rituximab at the end of two weeks. When you debulk the tumor first, flares decrease.”
Novel Antibodies and Immunotherapy
In a separate presentation, Paul G. Richardson, MD, Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center and Professor of Medicine at Harvard Medical School, spoke about advances in novel antibodies and immunotherapies for plasma-cell disorders.
“There are exciting developments in the immunotherapy area in myeloma,” he said. “Until recently, we were going down blind alleys. Now multiple agents have been approved based on Phase III clinical trials that target numerous pathways in myeloma. The monoclonal antibody space has become busy because these therapies target minimal residual disease.
“We need monoclonal antibodies and immunotherapy in multiple myeloma. Innovations to date, such as proteasome inhibitors and immune modulating drugs, have produced significant improvements in progression-free and overall survival. The next wave of therapies will likely be mutation-driven—not just related to plasma cell biology. Baseline immune function appears to be a barrier to cure. Arguably, this represents a timely mechanism and an opportunity to target new therapies.”
Richardson noted that monoclonal antibodies may have activity in high-risk disease, and represent true new mechanisms, as do vaccines, especially those that target minimal residual disease (MRD). He highlighted two agents—elotuzumab, an anti-CS1 monoclonal antibody; and daratumumab, an anti-CD38 monoclonal antibody.
Elotuzumab is believed to work primarily through natural killer cell-mediated ADCC (antibody-dependent cell-mediated cytotoxicity) against myeloma cells. “In combination with backbone agents—in particular, lenalidomide—it has shown true synergy in preclinical models,” he said.
He pointed to a Phase II trial of elotuzumab plus lenalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma that showed a high overall response rate of 82 percent. At a median follow-up of 14 months, the median progression-free survival (PFS) has not been reached, and the PFS rate was 65 to 75 percent. The combination was generally well-tolerated, he said.
“This is a dramatically enhanced response rate, and quite an impressive result. Elotuzumab shows great promise in the context of smoldering myeloma. It has excellent tolerability and good signals.”
He noted that the results of a Phase III trial of elotuzumab in patients with relapsed/refractory disease should be available soon.
The identification of CD38 in hematologic malignancies “is one of the most exciting developments in myeloma,” he said.
This multi-functional glycoprotein is found on the surface of many lymphoid and myeloid cells, and is expressed in many hematologic malignancies. Expression is correlated with disease progression.
Daratumumab is the first available CD38 monoclonal antibody with broad-spectrum killing activity. “Results from Phase II studies show that daratumumab has promise with once-weekly, single-agent activity,” he said, adding that results appear to be associated with its effects on the tumor environment.
Multiple myeloma patients have also responded to a combination of daratumumab plus lenalidomide and dexamethasone, with an encouraging safety profile. Another agent, SAR650984, also shows promise as a single agent with a similar signal as daratumumab in similar doses, he said.
In summary, Richardson said, “monoclonal antibodies present an attractive therapeutic strategy in multiple myeloma. Daratumumab has shown positive results as a single agent and in combination with lenalidomide and dexamethasone, and is now entering Phase II and III testing in relapsed/refractory multiple myeloma.”
Elotuzumab is the most advanced monoclonal antibody in development, and is currently in Phase III testing in both the upfront and relapsed/refractory multiple myeloma settings, primarily in combination, he said. Numerous other potential targets in multiple myeloma plasma cells have been identified, and a number of monoclonal antibodies are in development.
Monoclonal antibodies, vaccines, and other agents and modalities in multiple myeloma will play a key role in a tailored approach to therapy, he continued. “This will include the use of gene-expression profiling and proteomics to guide therapy, and risk adaptation and treatment combinations that will overcome resistance and target MRD.”
The moderator of the session that included both presentations, Robert Orlowski, MD, PhD, Professor in the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center, commented afterwards, “In general, we have made a lot of progress in myeloma. Survival has doubled in the past 10 years even before the introduction of new drugs such as pomalidomide and carfilzomib. Panobinostat is likely to be approved this year and monoclonal antibodies as well soon. There will be continued improvement, in particular in the relapsed/refractory setting.
“The general approach to multiple myeloma is combination therapy, especially in robust patients. For more fragile patients, a single or double transplant is a more appropriate approach,” he continued.
“Aggressive maintenance with cytotoxic therapy is possible in the right setting. But even with aggressive cytotoxic therapy, there is a role for stem cell transplant, which is still the standard of care. We are still not curing patients, but we can't throw away this bullet. We would like to push survival in good- or standard-risk patients, who make up 80 to 85 percent of patients. We have signs of hope that we can cure them with monoclonal antibodies.”