Q. How are the drugs approved in 2015 used in treatment?
A. In approving Farydak® (panobinostat), Darzalex® (daratumumab), Ninlaro® (ixazomib), and Empliciti® (elotuzumab) in 2015, the US Food and Drug Administration (FDA) broke with precedent and approved three of four new drugs to treat myeloma based not on their improved efficacy over older drugs, but on their novel mechanisms of action. Of the four new therapies, only Darzalex has single-agent activity and was approved based on its superiority to existing treatments for myeloma.
With a new HDAC inhibitor, two monoclonal antibodies, and an oral proteasome inhibitor added to the existing armamentarium of anti-myeloma agents, doctors find themselves with a wealth of anti-myeloma weapons and, as yet, limited approved indications for their deployment. Until further clinical trials better define the optimal use of the new drugs and determine how they fit in with the older drugs, treatment decisions must be based on the new agents’ strictly limited FDA-approved indications.
Adding to the drugs’ limited indications for use are the hard realities of financial constraints. Although doctors can legally write prescriptions for drugs once they are approved by the FDA, neither Medicare nor most commercial insurers will pay for drugs when they are prescribed “off label,” that is, for treatment outside of the indication that is specifically described in the FDA approval language. For example, if a drug is indicated for the treatment of patients who have had one to three prior therapies, insurance will not cover its use in a previously untreated patient. Moreover, in this new era of limits on medical costs, some health plans refuse to authorize single or combination therapies even when prescribed for their approved indications because they are deemed too expensive. And in a new twist on cost-cutting, some healthcare organizations are financially penalizing physicians who prescribe expensive therapies, effectively quashing their use. A well-publicized protest by oncologists and pharmacists at Memorial Sloan-Kettering Cancer Center last year is certain to become more widespread in the coming years as doctors and hospital pharmacists refuse to supply expensive new drugs unless they have been proven better or safer than existing, less expensive agents of the same class.
Farydak was approved by the FDA in February 2015, and is indicated “in combination with bortezomib (Velcade®) and dexamethasone (dex) for the treatment of adult patients with relapsed and/or refractory myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory drug (IMiD®). Patients in the PANORAMA-1 registration trial (the trial from which data was presented to the FDA to support Farydak’s approval) were randomized to Farydak + Velcade + dex (FVD) or to placebo + Velcade + dex, and could not be refractory to Velcade. Patients in the trial could be refractory to an IMiD.
The subset of patients in the PANORAMA-1 study who benefited most from FVD in terms of depth of response and median progression-free survival (PFS) were heavily pretreated and had received both Velcade and an IMiD. Therefore, it was the data only from this subset of patients that was submitted to the FDA for approval of Farydak.
Materials provided to prescribing oncologists from Novartis, the manufacturer of Farydak, indicate that a patient who may be treated with FVD should have had at least a partial response (PR) to prior Velcade treatment with manageable toxicity, and then relapsed after a fixed number of Velcade cycles or after another therapy, such as an IMiD-based therapy. The patient should have had progressive disease on, or be refractory to, an IMiD-based regimen with Revlimid® (lenalidomide), Thalomid® (thalidomide), or Pomalyst® (pomalidomide).
Advice for patients contemplating FVD: Patients in the PANORAMA-1 study who received Velcade as a subcutaneous (SQ) injection rather than via an intravenous (IV) infusion tolerated FVD better. Therefore, we encourage patients to ask their doctors about receiving SQ injections of Velcade with this regimen. Side effects must be carefully managed with FVD, and doses of the drugs may be modified to make the regimen safer and improve quality of life.
Darzalex is the first monoclonal antibody approved to treat myeloma, and the first of the three new myeloma drugs to be approved last November. Of the four new agents approved last year, only daratumumab was approved as a single agent rather than a part of a combination therapy.
The two registration trials for Darzalex enrolled a total of 148 patients with relapsed/refractory myeloma who had received at least three prior lines of therapy, including an IMiD and a proteasome inhibitor. Nearly 30% of the 106 patients in the larger trial, and 36% of the 42 patients in the smaller trial, had a complete or partial reduction of their disease burden. Based on these data, daratumumab was approved by the FDA “in patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.”
The FDA granted “breakthrough” status for daratumumab when it was in clinical trials and gave it priority review based on clinical evidence suggesting that, if approved, it would offer a “substantial improvement over available therapies.” None of the other drugs approved in 2015 received breakthrough status or demonstrated that it was “a substantial improvement over available therapies.”
Until clinical trial results broaden the indications for this effective new drug to include additional disease settings and combinations with additional agents, its current use outside of trials is as a single agent for patients who have had at least three prior therapies including an IMiD and a proteasome inhibitor, or who are refractory to both of these drug classes. Prescribing Darzalex in combination with another agent is not an approved indication, and therefore would likely pose a problem with insurance coverage.
Advice for patients contemplating Darzalex: Darzalex can cause low blood cell counts, which can be a problem for patients who have been heavily pretreated and already have low levels of white and red blood cells and low platelets. Your doctor should monitor your blood tests carefully and hold or adjust doses accordingly. Darzalex can also interfere with blood typing for transfusions and with some of the tests used to assess response to treatment.
Ninlaro is the first oral proteasome inhibitor – the class of drugs that includes Velcade and Kyprolis® (carfilzomib) – a welcome convenience for patients. Another advantage of Ninlaro is the lower incidence and decreased severity of peripheral neuropathy (PN) in clinical trials with Ninlaro-treated patients as compared to historical data for those treated with Velcade. Despite these advantages, however, the two drugs cannot, at this time, be used interchangeably: Velcade is approved for use throughout the myeloma disease course, while Ninlaro is currently approved only in combination with Revlimid and dexamethasone for the treatment of patients who have received at least one prior therapy.
The registration trial for Ninlaro was the TOURMALINE study, in which patients were randomized to receive either the all-oral triplet regimen Ninlaro (ixazomib) + Revlimid + dex (IRD) or placebo + Revlimid + dex. IRD is a second-line therapy, and may benefit patients who have already had Velcade and/or Revlimid and who may need to boost a waning or suboptimal response to Revlimid + dexamethasone.
Advice to patients contemplating IRD: According to the package insert, patients taking IRD should receive preventive treatment with both an anti-viral medication and a blood thinner.
Empliciti, a monoclonal antibody that binds to a myeloma cell surface antigen called SLAMF7, was approved based on the ELOQUENT-2 registration trial in which patients with relapsed/refractory myeloma were randomized to either Empliciti + Rev + dex (ERD) or to placebo + Rev + dex. The addition of Empliciti resulted in a 30% reduction in the risk of disease progression, and an increase in remission duration of 4.5 months. On November 30, Empliciti was approved in combination with Revlimid and dexamethasone for the treatment of patients with myeloma who have received one to three prior therapies.
Nine clinical trials investigating Empliciti’s safety and efficacy in combination with other drugs and across disease states are currently recruiting patients, and another trial will begin accrual in the near future; the results of these trials will undoubtedly better define and expand its use. Currently it is often used outside the clinical trial setting for patients who have plateaued with a partial response to Revlimid + dexamethasone in an attempt to deepen their responses.
Advice to patients contemplating ERD: Low white blood cell counts are common with ERD, leading to an increased risk of infection. Your blood counts should be monitored carefully on this regimen, and patients who experience any signs of infection – fever, sore throat, mouth sores – should contact their healthcare providers immediately.