Prerna Mewawalla, MD, is a medical oncologist in Pittsburgh, Pennsylvania and is affiliated with multiple hospitals in the area, including Allegheny General Hospital and Western Pennsylvania Hospital.

Three New Drug Approvals in 14 Days: An Amazing Fortnight for Multiple Myeloma Treatment

Published: Tuesday, Dec 01, 2015

For decades multiple myeloma was treated with traditional chemotherapy regimens, such as VAD (vincristine, Adriamycin, dexamethasone). This changed in 2006 when thalidomide was approved.1 Shortly following this, bortezomib and lenalidomide gained approval. Then, in 2013, pomalidomide and carfilzomib were approved for multiple myeloma.2,3 Now, in a matter of 15 days, three new drugs were approved for myeloma, namely daratumumab, ixazomib, and elotuzumab.

The first agent, daratumumab, is a monoclonal antibody directed against CD38, which is present on most multiple myeloma cells. In the phase I/II GEN501 study, 72 patients received daratumumab at 16mg/kg or 8mg/kg. The objective response rate (ORR) was 36% for patients who received the 16mg/kg dose and were pretreated with a median of 4 prior regimens. The ORR was much higher in patients who had received just 2 to 3 prior treatments, at 56%.

Infusion reactions occurred in nearly half the patients, mostly grade 1/2, with grade grade 3/4 events in 4.7% of the patients. Other adverse events seen were fatigue (39%), anemia (33%), nausea (29%), and thrombocytopenia (25%). Interestingly the drug causes a positive indirect antiglobulin test and also interferes with ABO typing. It can also lead to a positive M spike as it is a IgG kappa antibody.

The FDA recommended that daratumumab should be used at 16 mg/kg weekly for 8 weeks followed by every 2 weeks for 16 weeks and then once every 4 weeks until disease progression.4

The second drug that was recently approved was the oral proteasome inhibitor ixazomib, which is to be used in combination with lenalidomide and dexamethasone for patients who have received at least 1 prior therapy. In a phase III study (TOURMALINE-MM1 trial), 722 patients were randomized to receive either lenalidomide with dexamethasone alone or ixazomib in addition to lenalidomide and dexamethasone.5 Overall, 77% of the patients had relapsed disease and had received a median of 1 prior treatment.

The median progression-free survival (PFS) was 20.6 months in the ixazomib arm versus 14.7 months with lenalidomide and dexamethasone alone. The ORR was 78.3% in ixazomib arm compared with 71.5% for lenalidomide and dexamethasone alone. Adverse events with or without ixazomib, respectively, were diarrhea (42% vs 36%), peripheral neuropathy (28% vs 21%), vomiting (22% vs 11%), and neutropenia (19% vs 16%).

Based on these findings, the FDA approved ixazomib with lenalidomide and dexamethasone. The dose to be used is 4 mg on day 1, day 8, and day 15 of a 28-day treatment cycle.

The third drug to be approved was elotuzumab, again in combination with lenalidomide and dexamethasone in patients who have failed at least 1 prior treatment. Elotuzumab is a humanized immunoglobulin G1 immunostimulatory monoclonal antibody targeted against CS1 (cell-surface glycoprotein CD2 subset 1), a glycoprotein that is expressed on myeloma and natural killer cells but not on normal tissues.6

In a phase III trial (ELOQUENT-2), 646 patients with relapsed/refractory myeloma were randomized to receive either elotuzumab in combination with lenalidomide and dexamethasone or lenalidomide with dexamethasone alone.7 Patients had received a median of 2 prior therapies. The PFS in the elotuzumab arm was 19.4 months versus 14.9 months (P <.001). The ORR in the elotuzumab arm was 79% vs 66% (P <.01).

The most common hematological all-grade adverse events in the elotuzumab arm versus the control arm, respectively, were lymphocytopenia (99% vs 98%) anemia (96% vs 95%), thrombocytopenia (84% vs 78%), and neutropenia (82% vs 89%). Other common adverse events seen were diarrhea (47% vs 36%), fatigue (47% vs 39%), and pyrexia (37% vs 25%).

These findings led to the approval of elotuzumab in combination with lenalidomide and dexamethasone. The recommended dose for elotuzumab is 10 mg/kg IV weekly for the first 2 cycles and then biweekly thereafter until disease progression.

With the advent of these 3 drugs, we now have a multitude of drugs that can be used in the relapsed refractory setting. The trick now is figuring out which one to use at which point. Studies are being done to answer these questions. Until then, treatment can be individualized based on patient comorbidities, disease risk, and prior treatments. This had definitely been a very gratifying fortnight for oncologists treating multiple myeloma.


References

  1. FDA Approves Thalomid (thalidomide) to Treat Multiple Myeloma [news release]. Silver Spring, MD: US Food and Drug Administration; May 26, 2006. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm095651.htm. Accessed November 30, 2015.
  2. FDA approves Pomalyst for advanced multiple myeloma [news release]. Silver Spring, MD: US Food and Drug Administration; February 8, 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm338895.htm. Accessed November 30, 2015.
  3. National Cancer Institute. FDA Approval for Carfilzomib. http://www.cancer.gov/about-cancer/treatment/drugs/fda-carfilzomib. Published July 2, 2013. Accessed November 30, 2015.
  4. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma [published online August 26, 2015]. N Engl J Med. doi: 10.1056/NEJMoa1506348
  5. Moreau P, Masszi T, Grzasko N, et al. Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (NCT01564537). 2015 ASH Annual Meeting; Orlando, FL; December 5-8, 2015. Abstract 727.
  6. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14:2775-2784
  7. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621-631.


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