The Year in Hematologic Malignancies: Novel Agents, New Combinations

Kate M. O'Rourke

Disclosures

December 11, 2014

In This Article

With 2014 winding down, Medscape asked several experts in hematologic malignancies to weigh in on the big news of the year. Following are highlights in multiple myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma.

Multiple Myeloma

According to Shaji Kumar, MD, from Mayo Clinic in Rochester, Minnesota, the updated definition of multiple myeloma by the International Myeloma Working Group[1] will have a big impact on practice. Now, in addition to existing requirements of attributable CRAB features (hypercalcemia, renal failure, anemia, and bone lesions), the definition includes validated biomarkers that predict for early development of CRAB features.

"The way we used to define myeloma is that patients had to have the CRAB symptoms before we would start treatment. The problem is that some of those changes, such as renal insufficiency and bone disease, can be debilitating once they occur," said Dr Kumar. "The new guidelines move the bar for treating a little lower. Now, if clinicians see bone marrow plasma cells of 60% or greater, a serum free light chain ratio of 100 or greater, or an MRI scan showing two or more lesions, they can start treatment."

At the recent annual meeting of the American Society of Hematology (ASH), researchers presented data from the phase 3 ASPIRE trial[2] showing that adding carfilzomib (Kyprolis®) to lenalidomide (Revlimid®) and dexamethasone improved median progression-free survival (PFS) by 6 months in patients with relapsed multiple myeloma.

"Carfilzomib was approved a couple of years ago on an accelerated strategy in bortezomib-refractory patients. The ASPIRE trial is the confirmatory trial," said Noopur Raje, MD, director of the Multiple Myeloma Program at Massachusetts General Hospital in Boston.

Positive news for several investigational agents also continued throughout 2014. Phase 1/2 data support phase 3 testing of the all-oral triple therapy of ixazomib (Takeda), dexamethasone, and lenalidomide in treatment-naive patients with multiple myeloma.[3,4] At the annual meeting of the American Society of Clinical Oncology (ASCO), investigators reported promising results from phase 2 trials of daratumumab (Genmab) and SAR650984 (Sanofi).[5,6]

"Both of these drugs showed good single-agent activity," said Dr Raje. "Phase 2 data with daratumumab in combination with lenalidomide and dexamethasone in relapsed or relapsed/refractory multiple myeloma were presented at ASH, and the response rates are in excess of 80%."[7]

Daratumumab is now on an accelerated approval pathway. At the ASH meeting, investigators presented data that SAR650984 in combination with lenalidomide and dexamethasone results in a response rate of roughly 65% in relapsed/refractory multiple myeloma.[8]

On the downside, the investigational histone deacetylase inhibitor (HDAC) panobinostat (Novartis) seems to have been stopped in its tracks. At the annual ASCO meeting, the phase 3 PANORAMA-1 trial[9] demonstrated that adding panobinostat to bortezomib (Velcade®) and dexamethasone improved PFS by 4 months in patients with relapsed or refractory myeloma.

"Everybody thought that this was going to be the next drug that the FDA would approve, but unfortunately the FDA Oncologic Drugs Advisory Committee voted against panobinostat, largely because of the toxicities," said Dr Raje. "There was a fair amount of gastrointestinal toxicity and thrombocytopenia noted with this combination. The question is, now what happens to the development of HDAC inhibitors? Should we be looking at other partner compounds that do not have overlapping toxicities?"

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