Over the past decade, survival of patients with multiple myeloma has improved significantly, due in large part to development of new therapeutics that target intracellular signaling in malignant plasma cells. After many years of treatment failure in this disease setting, we are finally seeing clinically meaningful improvements in response duration with the development of myeloma-specific immune therapies. These strategies are well described by Luetkens and colleagues in this issue of ONCOLOGY.[1]

One of the challenges in reviewing this broad topic is to provide the information in a conceptual framework that clinicians can use to guide treatment decisions. To accomplish this task, two paths can be taken; the first involves dividing the large basket of “immune therapy” into three categories: passive immunity, adjuvant therapy, and active therapy (see Figure).[2] The second path is to identify the appropriate clinical setting for use of a given agent.

Passive immunization is currently the most clinically relevant immunotherapy used in the treatment of patients with multiple myeloma. In this approach, monoclonal antibodies directly target specific receptors on myeloma cells. Two antibodies are approved for this purpose by the US Food and Drug Administration: daratumumab, which targets CD38, and elotuzumab, which targets SLAMF7 (signaling lymphocyte activation molecule F7); both agents have recently been reviewed in the medical literature.[3] Monoclonal antibodies not only target the myeloma cell itself, but they can also coordinate the immune response via upregulation of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.[4] Chemoimmunoconjugates that target receptors such as CD38, SLAMF7, or BCMA (B-cell maturation antigen) are also in development. The activity of these agents may not require antibody-dependent cellular cytotoxicity mechanisms, a feature that could be critically important given that multiple myeloma is often associated with underlying immune dysfunction. New monoclonal antibodies targeting the programmed death 1/programmed death ligand 1 axis have also been studied in myeloma, and while ineffective as single agents, in combination with immunomodulatory drugs (lenalidomide and pomalidomide) they have demonstrated significant activity, validating this target in myeloma. Additionally, “off-the-shelf” novel dual targeting antibody strategies are being developed that engage both the myeloma cell and effector T cells. These include bispecific antibody technology targeting BCMA, CD38, or SLAMF7 on the tumor cell, in addition to treatments targeting CD3 on host T cells.

Adjuvant therapy uses a vaccine-based approach to enhance innate immune responses, but clinical outcomes following monotherapy with this type of treatment may not be sufficient to be effective in the short term. Multiple platforms have been evaluated and are under investigation, including peptide-based vaccines and cellular vaccination strategies using dendritic cells. Preliminary results of studies of both approaches confirm that they induce antitumor immune responses, but the question of whether these treatments translate into significant clinical benefit cannot be answered without further study.

Active cellular therapy represents an additional means by which we can manage multiple myeloma by engaging the patient’s own immune system. Allogeneic transplant was the first modality to use active cellular therapy in the treatment of multiple myeloma. It has yielded mixed clinical outcomes in patients with multiple myeloma across a large number of studies, due in large part to high rates of graft-vs-host disease and relapse. As outlined by Luetkens and colleagues, engineered cellular therapy has shown initial promise in multiple myeloma, but the duration of response is often limited. Therapy using chimeric antigen receptor T cells and T-cell receptor–transduced T cells are the two major strategies now under investigation. The issues of identifying the optimal target(s), developing therapies with costimulatory mechanisms of action, and employing strategies that minimize the toxicity of treatment will need to be addressed in carefully designed clinical trials.

As previously noted, the second path of critical importance in providing a conceptual framework for the management of multiple myeloma is to describe the clinical setting in which the specific immune therapy would be most useful. Current treatment for myeloma includes therapies for four different disease states, and the goals of treatment for each of these are different.

In the presymptomatic phase of either monoclonal gammopathy of unknown significance or asymptomatic myeloma, immune strategies could be used to prevent the progression to symptomatic myeloma or the development of a myeloma-defining event. This would be of particular interest if the immune-based treatment was targeting not only the tumor, but also the relationship between tumor cells and the bone marrow microenvironment, since doing so might further disrupt critical molecular survival signals.

In the patient with newly diagnosed symptomatic multiple myeloma, the goal of therapy would be maximal disease control by targeting multiple clones, with the net achievement of minimal residual disease negativity, a particular challenge among high-risk patients.

In the patient with early relapse (failure of one to three prior lines of therapy), the goals are to target the tumor and restore immune function, allowing patients to eventually gain host antitumor immunity and long-term disease control.

Finally, for patients with refractory disease, the sole focus is on symptom burden and disease control, since few other treatment options are available. Based on this framework, different immune strategies will be needed that will likely be partnered with existing agents, and may involve sequencing of immune-based treatments based on where a particular patient is in the trajectory of his or her treatment.

The development of novel therapies has brightened the clinical outlook for patients with multiple myeloma. Unfortunately, while survival outcomes have improved, the fraction of patients with multiple myeloma who are cured of their disease remains low. Immune therapies offer the hope for further improvement in outcomes and higher rates of cure. Disseminating new information about immunotherapies for multiple myeloma in a way that provides a roadmap to approach treatment in the context of disease- and patient-related factors is essential to improving our patients’ quality of life and clinical outcomes.

Dr. Kaufman is a consultant to Celgene, Seattle Genetics, and Sutro Pharmaceuticals; serves on the data safety monitoring boards of Incyte, Pharmacyclics, and TG Therapeutics; and receives research funding from Merck, Novartis, and Onyx. Dr. Lonial serves as a consultant to Bristol Myers-Squibb, Celgene, Janssen, Merck, Novartis, Onyx, and Takeda

 Luetkens T, Yousef S, Radhakrishnan SV, Atanackovic D. Current strategies for the immunotherapy of multiple myeloma. Oncology (Williston Park). 2017;31:55-63.

 Neri P, Bahlis NJ, Lonial S. New strategies in multiple myeloma: immunotherapy as a novel approach to treat patients with multiple myeloma. Clin Cancer Res. 2016 Oct 19. [Epub ahead of print]

 Hofmeister C, Lonial S. How to integrate elotuzumab and daratumumab into therapy for multiple myeloma. J Clin Oncol. 2016 Oct 31. [Epub ahead of print]

 Tai YT, Anderson KC. Antibody-based therapies in multiple myeloma. Bone Marrow Res. 2011;2011:924058.

Articles

Unfortunately, while survival outcomes with novel therapies have improved, the fraction of patients with multiple myeloma who are cured of their disease remains low. Immune therapies offer the hope for further improvement in outcomes and higher rates of cure. 

 Insights Into the Appropriate Use of New Antimyeloma Therapies

Despite consensus on the diagnosis and staging of cancer anorexia/cachexia syndrome, there is currently no accepted standard of care, and affected patients remain widely undertreated. There is general agreement that, because of the complex pathophysiology involved, management should be multimodal and offered earlier in the course of anticancer treatment.[1] However, clarification is needed regarding how to deliver the appropriate anticachexia and antianorexia therapies. In this issue of ONCOLOGY, Dev et al provide an important step forward, offering a model for the multimodal management of cachexia that includes core treatments, as well as evidence-based and investigational approaches, and that details how these target different aspects of the syndrome.[2] Acknowledging the limited data available on some of the treatments discussed, the authors also provide valuable clinical practice points to guide the delivery of cancer care. We wish to draw further attention to the role of physical activity and exercise, which they propose as core treatments.

Physical activity can be defined as “any bodily movement, produced by skeletal muscles, that increases energy expenditure above resting levels,” and includes domestic, occupational, leisure, or other activities.[3] Exercise is a subset of physical activity in that it meets the previously described definition, but it involves “structured, repetitive, and planned movement undertaken to improve or maintain one or more components of physical fitness.”[3] The terms are often used interchangeably; however, for purposes of research, treatments should be correctly defined and described. In the clinical setting, the language used to describe treatments can influence health professional and patient engagement; thus, it can at times be helpful to refer to an exercise program as “physical activity” or by a description of its content, such as a “walking group.”

A strong theoretical rationale and consistent laboratory data reported in the medical literature underscore the role of physical activity and exercise in cachexia management. These behavioral modifications should be applied soon after the diagnosis of cancer, not only by people at risk for cachexia but also those with any sign of metabolic disturbance. Early on in the disease process, patients are generally likely to be less symptomatic, have less impairment, and retain an ability to increase muscle mass (ie, have “anabolic potential.”)[4] In patients with early-stage cancer, the cumulative effect of cachexia, comorbidities, and physical inactivity is also less likely to have precipitated a refractory state, in which treatment options are limited.[5]

Exercise is probably superior to physical activity for addressing weakness and exercise intolerance caused by cancer cachexia, since it provides a greater stimulus, better able to provoke a training response in the muscular, cardiovascular, and respiratory systems. Resistance training, with fixed or free weights, should be selected primarily to facilitate muscular improvements, whereas endurance training-for example, using stationary cycling-should be selected to enhance aerobic fitness.[5,6] One challenge of cachexia is that it can be difficult to identify the primary target for training, given that patients commonly present with both muscle weakness and exercise intolerance. Thus, patient preference may help guide the type of exercise offered. For example, patients with exertional breathlessness often express a preference for resistance training because of its low cardiorespiratory demand.[7]

While a strong evidence base supports exercise training in people with early-stage cancer,[8] relatively few studies have examined its use in advanced disease,[9] and there are no controlled trials including patients with any degree of confirmed cachexia.[10] Exercise programs can also be physically demanding, as reflected in the low rates of uptake and completion reported in clinical studies.[11] Even when “light” programs are offered, patients and health professionals frequently report that patients are “too busy” to engage in treatments they may perceive to be “unnecessary” or “burdensome.”[12,13]

A focus on physical activity has the advantage of directly targeting the patient’s lived experience of cachexia, which is often typified by a reduced ability to perform daily tasks and activities, as well as reduced participation in work, social life, and society.[14] Supporting continued or renewed participation may bring meaningful outcomes as patients prioritize their independence in self-care, domestic, and leisure activities.[15] This may also be achieved in the short term, with improvements in task performance sometimes occurring before changes in body composition.

However, it is important to recognize that, for most people, engaging in physical activity and exercise treatments demands a change in behavior. Tools such as the “capability, opportunity, motivation, and behavior” (COM-B) model from the Behaviour Change Wheel created by Michie et al, provide a framework for supporting people in undertaking physical activity and/or exercise.[16] The first step in a behavior change approach is to inform patients, families, and other health professionals of the possible benefits of having patients maintain or increase their levels of physical activity; where possible, patients should be directly encouraged to participate in an activity of particular interest to them. Any concerns that could limit patient engagement, such as fear of exertional symptoms, or the restricting of domestic tasks by a family member to “protect the patient,” should be identified, explored, and challenged in a sensitive manner by the healthcare provider. Patients’ positive health beliefs and behaviors should also be reinforced and augmented. Techniques may include goal setting, action planning, or graded activity, each tailored to the individual patient’s circumstances but with the common aim of maximizing participation in daily life.[17] Plans should be in place to help patients continue positive behaviors when faced with obstacles. For example, if inclement weather prevents outdoor walking, then indoor exercises can be completed; such workaround strategies can also help patients adjust to the challenges presented by cancer and its treatment.[18]

Behavior change approaches are unlikely to reverse cachexia-related impairments, but they should elevate the patient’s activity and participation levels, and contribute to an improved quality of life as part of a multimodal treatment strategy.[19] In a recent trial, behavior change techniques were used to implement exercise and lifestyle-modification programs for patients with head and neck cancer who were undergoing radiotherapy.[20] Despite declining total body lean and fat mass, suggesting progressive cachexia, some patients were able to improve their physical activity levels and build functional capacity both during and after cancer treatment. The skills required to deliver physical activity and exercise treatments are already present in settings where rehabilitation professionals are integrated within clinical service teams.[21] When such expertise is not readily available, techniques that focus on behavior change may offer a useful starting point to help patients to live fully in the face of cancer cachexia.

The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article

 Aapro M, Arends J, Bozzetti F, et al. Early recognition of malnutrition and cachexia in the cancer patient: a position paper of a European School of Oncology Task Force. Ann Oncol. 2014;25:1492-9.

 Dev R, Wong A, Hui D, Bruera E. The evolving approach to management of cancer cachexia. Oncology (Williston Park). 2017;31:23-32.

 Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Rep. 1985;100:126-31.

 Prado CM, Sawyer MB, Ghosh S, et al. Central tenet of cancer cachexia therapy: do patients with advanced cancer have exploitable anabolic potential? Am J Clin Nutr. 2013;98:1012-9.

 Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol. 2013;10:90-9.

 den Kamp CO, Langen R, Minnaard R, et al. Pre-cachexia in patients with stages I–III non-small cell lung cancer: systemic inflammation and functional impairment without activation of skeletal muscle ubiquitin proteasome system. Lung Cancer. 2012;76:112-7.

 Maddocks M, Armstrong S, Wilcock A. Exercise as a supportive therapy in incurable cancer: exploring patient preferences. Psychooncology. 2011;20:173-8.

 Mishra SI, Schrerer RW, Geigle PM, et al. Exercise interventions on health-related quality of life for cancer survivors. Cochrane Database Syst Rev. 2012;8:CD007566.

 Oldervoll LM, Loge JH, Lydersen S, et al. Physical exercise for cancer patients with advanced disease: a randomized controlled trial. Oncologist. 2011;16:1649-57.

 Grande AJ, Silva V, Riera R, et al. Exercise for cancer cachexia in adults. Cochrane Database Syst Rev. 2014;11:CD010804.

 Maddocks M, Mockett S, Wilcock A. Is exercise an acceptable and practical therapy for people with or cured of cancer? A systematic review. Cancer Treat Rev. 2009;35:383-90.

 Cheville AL, Rhudy L, Basford JR, et al. How receptive are patients with late stage cancer to rehabilitation services and what are the sources of their resistance? Arch Phys Med Rehabil. 2016 Aug 31. [Epub ahead of print]

 Granger CL, Denehy L, Remedios L, et al. Barriers to translation of physical activity into the lung cancer model of care: a qualitative study of clinicians’ perspectives. Ann Am Thorac Soc. 2016 Sep 30. [Epub ahead of print]

 Wheelwright S, Darlington AS, Hopkinson JB, et al. A systematic review of health-related quality of life instruments in patients with cancer cachexia. Support Care Cancer. 2013;21:2625-36.

 Eva G, Wee B. Rehabilitation in end-of-life management. Curr Opin Support Palliat Care. 2010;4:158-62.

 Michie S, Ashford S, Sniehotta FF, et al. A refined taxonomy of behaviour change techniques to help people change their physical activity and healthy eating behaviours: the CALO-RE taxonomy. Psychol Health. 2011;26:1479-98.

 Buffart LM, GalvÃ£o DA, Brug J, et al. Evidence-based physical activity guidelines for cancer survivors: current guidelines, knowledge gaps and future research directions. Cancer Treat Rev. 2014;40:327-40.

 Rebar AL, Dimmock JA, Jackson B, et al. A systematic review of the effects of non-conscious regulatory processes in physical activity. Health Psychol Rev. 2016;10:395-407.

 Maddocks M, Hopkinson J, Conibear J, et al. Practical multimodal care for cancer cachexia. Curr Opin Support Palliat Care. 2016;10:298-305.

 Capozzi LC, McNeely ML, Lau HY, et al. Patient-reported outcomes, body composition, and nutrition status in patients with head and neck cancer: results from an exploratory randomized controlled exercise trial. Cancer. 2016;122:1185-200.

 Stout NL, Silver JK, Raj VS, et al. Toward a national initiative in cancer rehabilitation: recommendations from a subject matter expert group. Arch Phys Med Rehabil. 2016;97:2006-15.

Despite consensus on the diagnosis and staging of cancer anorexia/cachexia syndrome, there is currently no accepted standard of care, and affected patients remain widely undertreated. 

Oncology Vol 31 No 1

Insights Into the Appropriate Use of New Antimyeloma Therapies

Early Engagement in Physical Activity and Exercise Is Key in Managing Cancer Cachexia