1. Fuerst, Mark L.

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NEW YORK CITY-The best initial therapy for younger, fit multiple myeloma patients is a triple combination of a proteasome inhibitor plus immunomodulatory drugs (IMiDs), but a select group of other patients may do well with induction therapy with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) or clarithromycin [Biaxin], lenalidomide, and dexamethasone (BiRD) combination therapy, according to experts at Lymphoma & Myeloma 2017: An International Congress on Hematologic Malignancies.

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Best Initial Therapy

In this debate, Ajai Chari, MD, Associate Professor of Medicine, Hematology, and Medical Oncology at Icahn School of Medicine at Mount Sinai in New York, took the position of lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone (RVD) or carfilzomib, lenalidomide, and dexamethasone (KRd) as the best initial therapy.


He began by describing the factors needed to select multiple myeloma therapy, which include the patient, disease, and treatment. "If the patient was previously treated, what was the depth and duration of response? Did the patient relapse after 60 days, or is this progression? We need to think about regimens, routes of administration, and costs," said Chari.


The goal of induction therapy is to optimize the risk-versus-benefit ratio. For newly diagnosed patients eligible for stem cell transplantation, complete response (CR) rates are low, from 5 percent to 15 percent, with doublet therapy including dexamethasone. Triplet therapy with RVD is the most widely used therapy in the U.S., even though there are more adverse events, including grade 3 neurologic, pain, and sensory symptoms, as compared to lenalidomide and low-dose dexamethasone.


"Response rates are superior and deeper with RVD. But can we do better?" asked Chari. "More is not always better." High-dose dexamethasone leads to inferior overall survival (OS) as compared to low-dose dexamethasone. Four-drug therapy, adding cyclophosphamide to RVD, did not lead to a significant difference in CR, and increased neutropenia by fourfold, he said.


In newly diagnosed, transplant-eligible patients, deeper responses can be achieved by adding transplantation to RVD. The IFM/DFCI 2009 study showed 4-year OS of more than 80 percent with this combination.


Induction with KRd along with autologous stem cell transplantation (ASCT) can lead to "impressive" very good partial response (VGPR) rates, he said. "Clearly this regimen has shown to be outstanding," said Chari.


He noted that minimal residual disease (MRD) status has an effect on post-ASCT CR and patient OS. "We need to use the best regimen pre-transplant to minimize MRD," he said.


Studies show RVD leads to good progression-free survival (PFS) and OS, which supports triple therapy with an IMiD combination. In a comparison of KRd versus carfilzomid, cyclophosphamide, and dexamethasone (KCd), adverse events were comparable, but efficacy as measured by VGPR was superior with KRd (74%) over KCd (61%).


Chari stated that "young fit patients are less likely to have treatment-related toxicity. Lenalidomide-dexamethasone is associated with longer PFS than thalidomide-dexamethasone. Phase III studies show that RVD is better than RD, even with intravenous bortezomib, in terms of overall response rate, PFS, and OS. Proteasome inhibitors plus IMiDs and dexamethasone yield deeper responses than proteasome inhibitors plus cyclophosphamide and dexamethasone."


"If you believe in evidence-based medicine, there is only one answer in this debate," Chari concluded.


CyBorD & BiRD

Although RVD or KRd may be the first regimen chosen today, to be pragmatic many patients can receive a modified regimen with CyBorD and BiRD, said Joseph Mikhael, MD, Professor of Medicine at the Mayo Clinic Arizona. "Do we always need two novel agents, a proteasome inhibitor and an IMiD together? I suggest we do not need that for everyone," he said. "One size does not fit all. We need to appreciate the additional toxicity that accompanies more novel agents and recognize there are subpopulations in which CyBorD and BiRd may be preferred regimens."


Mikhael cited reasons why three drugs may not be better than two. Using a military analogy, he noted that all five branches of the military may not be necessary to win a battle, just as two drugs may be enough in multiple myeloma.


"More will always be better in terms of response and PFS if there is little or no overlapping toxicity leading to discontinuation. But clinical trial results are not predictive of individual patient results," he said.


Every drug comes with short-term and long-term toxicity. "Long-term risks are not always known. The current trend to treat longer could lead to more toxicity. This may not be necessary if the desired response is obtained with lesser amounts of drug," said Mikhael.


Cost is an important issue, and myeloma costs are among the highest in cancers. Clinicians need to factor in adding in monoclonal antibodies and large co-payments for oral medications. Often the benefit is marginal and may not be necessary, he said.


Long-term survival is difficult to prove in multiple myeloma. "Could we be reducing options later in the disease course? Is a combination of drug A and B really better than drug A followed by drug B?" he asked, noting this is especially important in low-risk disease.


Quality of life is finally gaining recognition in multiple myeloma now that it is more measureable and reproducible. "We treat people, not disease. We must assess the impact of quality of life in all patients, especially the elderly. We need more quality-of-life data directly from large trials and patient-reported outcomes," he said.


Mikhael noted that very few clinical trials assess sequential therapies. "In the clinic, we can start with one agent and then add another if the desired response is not achieved," he said. This strategy is hard to assess prospectively, but anecdotally is highly effective. Some patients remain on long-term singlet or doublet therapy with outstanding results, he said.


In the Mayo Clinic database, 15-20 percent of long-term survivors never achieve CR. Most of these patients have low-risk genetics, especially hyperdiploidy. "Not all patients require multi-drug combination therapy. This is similar to treating low-grade lymphoma. We need to respect the biology," said Mikhael.


CR is not always the goal of therapy. Response may be a surrogate marker for survival, but this is clearly not the case in all patients, including those who are genotypically and phenotypically indolent, as well as the elderly, he said.


In support of BiRD, he said it was a highly active regimen with long-term efficacy and safety, with minimal toxicity and cost added by including clarithromycin. "We are seeing similar results in amyloidosis. This is an attractive regimen when a proteasome inhibitor is not available or tolerated. An all-oral regimen is feasible for most patients," said Mikhael.


CyBorD is also a highly active regimen with long-term evidence. Neuropathy is manageable, and this regimen is dramatically less expensive than lenalidomide-based regimens. It is attractive for patients with renal dysfunction, cytopenias, and dexamethasone intolerance, he said.


In conclusion, Mikhael said "currently, when available, feasible, and affordable, VRD remains the first treatment of choice. However, both BiRD and CyBorD should be considered in multiple subpopulations, including those with lack of access, when cost is prohibitive, with renal failure, dexamethasone intolerance, and cytopenias. Sequential approaches are also feasible."


Before the debate, the vast majority (88%) of the audience believed that KRd and VRD were the best initial treatments for these patients. However, after hearing Mikhael's convincing argument, only 67 percent felt that way afterward.


Mark L. Fuerst is a contributing writer.