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ABSTRACTDespite considerable advances in treatment approaches in the past two decades, multiple myeloma remains an incurable disease. Treatments for myeloma continue to evolve with many emerging immunotherapies. The first immunotherapy used to treat hematologic cancers, including multiple myeloma, was an allogeneic stem cell transplant. In the mid-2000s, immunomodulatory drugs thalidomide, lenalidomide, and subsequently pomalidomide were proven to be effective in multiple myeloma and substantially improved survival. The next wave of immunotherapies for multiple myeloma included the monoclonal antibodies daratumumab and elotuzumab, which were approved by the Food and Drug Administration in 2015. Subsequently, a variety of immunotherapies have been developed for multiple myeloma, including chimeric antigen receptor T cells, bispecific antibodies, antibody drug conjugates, and checkpoint inhibitors. Many of these emerging treatments target the B cell maturation antigen, which is expressed on plasma cells, although several other novel receptors are also being studied. This review summarizes the evidence of these various immunotherapies, their mechanism of action, and data from clinical trials regarding the treatments’ safety and efficacy.

B-cell maturation antigen (BCMA) was identified as a prognostic marker in multiple myeloma more than two decades ago. Starting in 2014, the first use of BCMA as a treatment target was evaluated in patients with multiple myeloma who received chimeric antigen receptor (CAR) T cells. 1,2 Today, a range of myeloma treatments target BCMA, including CAR T cells, along with antibody drug conjugates and bispecific antibodies; some agents are in development, and some have been approved by the Food and Drug Administration (FDA). 3 The rapid translation from preclinical studies to several FDA-approved treatments is a new chapter in the remarkable success . . .

The costs of both newly approved, and established anticancer drugs have risen dramatically in the past decade, to the point where the costs of such treatments are becoming unsustainable. In this perspective, the authors outline the extent of this problem, and how it is likely to continue, while also suggesting measures that could be taken in future to address these rising costs. Globally, annual spending on anticancer drugs is around US$100 billion, and is predicted to rise to $150 billion by 2020. In the USA, a novel anticancer drug routinely costs more than $100,000 per year of treatment. When adjusted for per capita spending power, however, drugs are most unaffordable in economically developing nations, such as India and China. Not only are launch prices high and rising, but individual drug prices are often escalated during exclusivity periods. High drug prices harm patients — often directly through increased out-of-pocket expenses, which reduce levels of patient compliance and lead to unfavourable outcomes — and harms society — by imposing cumulative price burdens that are unsustainable. Moreover, high drug prices are not readily explained by rational factors, including the extent of benefit patients are likely to derive, the novelty of the agents, or spending on research and development. Herein, we summarize the available empirical evidence on the costs of anticancer drugs, probe the origins and implications of these high costs, and discuss proposed solutions.

Resistance mechanisms are being defined for CAR T cells. Tumor cells emerging after GPRC5D CAR T-cell therapy could have decreased or lost expression of the GPRC5D target through biallelic gene loss or transcriptional down-regulation.

In an early-phase study involving 17 patients with highly refractory multiple myeloma, CAR T-cell therapy with specificity for a G protein–coupled receptor that is expressed on myeloma cells produced a response in 71% of the patients.

High prices for cancer drugs preclude independent comparative effectiveness trials that would seek to establish equally effective but cheaper alternatives — thereby protecting the market share of expensive drugs. How can we make progress toward conducting such trials? The high cost of cancer drugs has been criticized by leading academics 1 and lamented in the popular press. 2 The average price of 1 year of treatment with a new cancer drug now exceeds $100,000, 1 and the benefits of many of these therapies — often improvement in median survival on the order of weeks to months — do not appear commensurate with their prices. 2 Expensive cancer drugs cost society in two ways. First, high prices are borne by payers each time these drugs are prescribed. And second, high prices preclude independent comparative effectiveness trials that would seek to establish equally effective . . .

Drug regulators’ acceptance of any statistically significant improvement shown in a single randomized trial and lofty drug prices has created a situation where it is now, hypothetically, profitable for a company to run a clinical trials portfolio of chemically inert compounds. While the current cancer drug pipeline is certainly superior to inert drugs, we must rethink market incentives to encourage transformational drug development.

Malignant T-cell transformation after chimeric antigen receptor (CAR) T-cell therapy has been described, but the contribution of CAR integration to oncogenesis is not clear. Here we report a case of a T-cell lymphoma harboring a lentiviral integration in a known tumor suppressor, TP53 , which developed in a patient with multiple myeloma after B-cell maturation antigen (BCMA) CAR T-cell therapy. A woman with multiply relapsed multiple myeloma had complete remission with cilta-cel, but a low-grade T-cell lymphoma soon developed in the GI tract that contained an insertion of the CAR construct disrupting expression of p53.

AbstractObjectiveTo determine the differences between recommendations by the National Comprehensive Cancer Network (NCNN) guidelines and Food and Drug Administration approvals of anticancer drugs, and the evidence cited by the NCCN to justify recommendations where differences exist.DesignRetrospective observational study.SettingNational Comprehensive Cancer Network and FDA.Participants47 new molecular entities approved by the FDA between 2011 and 2015.Main outcome measuresComparison of all FDA approved indications (new and supplemental) with all NCCN recommendations as of 25 March 2016. When the NCCN made recommendations beyond the FDA’s approvals, the recommendation was classified and the cited evidence noted.Results47 drugs initially approved by the FDA between 2011 and 2015 for adult hematologic or solid cancers were examined. These 47 drugs were authorized for 69 FDA approved indications, whereas the NCCN recommended these drugs for 113 indications, of which 69 (62%) overlapped with the 69 FDA approved indications and 44 (39%) were additional recommendations. The average number of recommendations beyond the FDA approved indications was 0.92. 23% (n=10) of the additional recommendations were based on evidence from randomized controlled trials, and 16% (n=7) were based on evidence from phase III studies. During 21 months of follow-up, the FDA granted approval to 14% (n=6) of the additional recommendations.ConclusionThe NCCN frequently recommends beyond the FDA approved indications even for newer, branded drugs. The strength of the evidence cited by the NCCN supporting such recommendations is weak. Our findings raise concern that the NCCN justifies the coverage of costly, toxic cancer drugs based on weak evidence.

In hindsight, we realize that we could have been more precise when using the terms ‘profit’ and ‘revenue’ in our article ‘Low-value approvals and high prices might incentivize ineffective drug development’. Total revenue is defined as the receipts from sales1. Profit is defined as the excess of the receipts from sales over the spending of a business during any period1. Hence, profit is the total revenue minus the costs of a business, over a given period. Profit calculations include credit transactions and asset revaluations as well as cash transactions and changes in the value of real assets1.