Multiple myeloma (MM) is a heterogeneous disorder which accounts for 10% of hematological cancers (1). Incidence of MM was found to be 2.1 (per 100,000 of people) in Ukraine, which is much lesser than in the United States (4.3) and Europe (4.1) (2) and almost on par with incidence in India, i.e., 1.2–1.8 per 100,000 of people (3).

There has been a remarkable improvement in the survival of MM patients in the last decades. This clinical progress was attributed to the availability of novel and target specific approach to treatment – proteasome inhibitors and immunomodulators (iMiDs), such as thalidomide, lenalidomide, and bortezomib and autologous stem cell transplantation (ASCT) (2).

Multiple myeloma poses a significant health-care challenge from both cost and quality of care perspective. In the US, the cost of MM is attributed to almost 9–10% of total cancer care costs. The rapidly increasing trend in costs is due to the development of novel agents, new diagnostic and treatment modalities, aging, and expanding populations, and increasing health-care costs (4).

Bortezomib, a first in class protease inhibitor (PI) was approved in 2003 for the treatment of progressive MM in patients who had received at least two prior therapies. In combination with melphalan and prednisone, it is also indicated for the treatment of adult patients with previously untreated MM who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation. Currently, it has been recommended for primary induction therapy and also for consolidation and salvage therapy post relapse (5).

Since its development, bortezomib has come a long way in treating MM patients. Its wider therapeutic spectrum ranging from frontline induction to maintenance therapy has been increasingly explored in studies with the goal of achieving deeper responses, longer progression free survival (PFS), and possibly overall survival (OS). Bortezomib, in combination with other drugs, can also be reused in relapse setting (6).

Novel drugs, such as carfilzomib, Ixazomib, and pomalidomide, have also been introduced lately, leading to the bright future of MM patients. A few more drugs with novel mechanisms of action are under testing phase in clinical trials.

These drugs are used either alone or as a part of combination regimen to demonstrate substantial activity in terms of higher complete response (CR) rates than previous standard regimens.

There are several aspects, which need to be considered in the management of MM. A common treatment algorithm to standardize treatment worldwide, cost reduction for emerging treatment strategies, uniform adaptation of treatment guidelines, country-wide variations in outcome of MM, need for better care, and improved communication among treatment providers are some of these aspects. The concept of clonal diversity among patients needs attention while deciding the MM therapies. Moreover, there is an unmet medical need for more treatment options in relapsed or refractory disease, extramedullary disease, and those with high-risk cytogenetic profiles (4).

To address such issues, there is a need for collaborative effort. In this regard, a joint panel meet of international experts was held in New Delhi on May 19, 2016. Various experts in hematology and oncology were invited from India and Ukraine to share experiences from their respective countries in the management of MM, with special emphasis on the role of bortezomib in MM.

This paper reflects the management in MM patients, ushering toward the role of bortezomib alone or in combination with other drugs. The paper also focusses on analysis from various trials and discussing their implications in clinical practice. It briefs about the challenges, unmet medical needs discussed in the experts meeting, and finally discusses the management strategies followed in Ukraine, the differences from practices in India, with the current challenges faced by the physicians and patients in these developing countries.

The management of MM patients and the choice of therapy (category 1 or category 2A drugs) as per the National Comprehensive Cancer Network (NCCN) guidelines (7) (Table 1) was an important point of discussion in the meeting. There was also a brief discussion on the key trials conducted on bortezomib (Table 2).

The treatment strategy is based on NCCN guidelines in India. For the diagnosis and treatment of MM in Ukraine, system of international guidelines [British Committee for Standards in Hematology (BCSH) (8), European Society for Medical Oncology (ESMO) (9), and NCCN guidelines (7)] was incorporated into Ukrainian National Guideline at the end of year 2015 (10). The treatment algorithm for the management of MM according to national requirements is as depicted in the Figure 1A.

Currently routine MM management in Ukraine could vary and differ from guideline due to limitations in health-care resources.

Management of MM in developing economies was another point of interest in the meeting.

As MM has evolved from acute to chronic disease, there is a continuous increase in treatment costs due to longer OS and continual care required during remissions and relapses. Novel agents, such as immune modulators (iMiDs) and PIs, have improved the response rates and survival, but they are given in addition to standard treatments. Additional costs of routine diagnostics, stem cell transplants, and supportive care further pose a tremendous economic burden to the patients and the health-care system. These are important aspects to be considered, especially in emerging economies where there are lack of proper resources and funds (23).

On the basis of most recent published estimates of the average prices in the US, cost of one 21-day cycle of bortezomib was estimated to be $6,450 (3.5 mg vial, quantity 4) or $70,950 per patient (11 cycles) (24). These costs vary as per regimen and further across countries due to variation in pricing agreements and availability of generics (24).

The availability of generic drugs at a comparatively lower cost without compromising quality would be an affordable option.

For example, the steep decline in imatinib costs per patient treatment for chronic myeloid leukemia (CML) per month occurred after its patent expiry and entry of generic version in the market in various countries (Figure 1B) (25). Similarly, the appearance of the generic atorvastatin boosted lipid-lowering treatment economic availability in the US after atorvastatin patent expiry (Figure 1C) (26).

Costs can be reduced further by the use of guideline based therapy, targeted therapies, and therapies that offer lower toxicity, higher survival, and better quality of life. Appropriate supportive care strategies, minimizing hospitalization, and department (ED) visits, decreasing the use of medical care at the end of life are the other ways of cost containment.

Cost containment is an important goal to reduce this burden; however, it should not be the only consideration for treatment choice. Quality of care and an optimal outcome should be the priority for both the managed care organizations and patients.

A few pharmacoeconomic models and studies have been done to study the cost-effectiveness.

Garrison et al. conducted a pharmacoeconomic analysis for transplant ineligible patients comparing MP with novel regimens, such as VMP, melphalan/prednisone/thalidomide (MPT), melphalan/prednisone/lenalidomide (MPR), and MPR-R. The study concluded that VMP is likely to be more cost-effective and cost saving as compared to other regimens (27).

In case of RRMM, bortezomib is comparatively a more cost-effective treatment (in terms of cost/life year gained) as compared to other available options. It provides an additional life year at a cost of $45,356. Also its incremental cost-effectiveness ratio (ICER) remains favorable (28).

In two studies done by the investigators in Ukraine, bortezomib was found to be the most economically significant treatment. A retrospecive analysis of the pilot study was performed in Ukraine at Kiev center. The average annual total cost of pharmacotherapy in MM patients in 2012 was equivalent to 2,297,984 EUR of which bortezomib had taken the major part of total costs (29, 30).

Evaluations of newer, advanced therapies are lacking despite their significant contribution in improving quality of life and survival of patients and therefore warranted in future.

With the rapidly evolving treatment landscape and forthcoming options and guidelines, a lot of flexibility is allowed in prescribing, as described under NCCN guidelines. Formulating clinical pathways using an evidence-based approach in line with guidelines might be a good option. This might also reduce local, regional, and national variations in practice.

A tremendous effort is required to improve the health-care access to the MM patients. Quality cancer care systems should be implemented with more defined networking amongst the health-care providers, medical oncologists, hematologists, surgeons, etc. and strong decision-support strategies. More transplant or transfusion centers need to be established, and a larger number of oncologists and surgeons are required to be added to the current pool.

Furthermore, an improved collaboration between all the stakeholders, health-care professionals, pharmaceutical industry, regulatory agencies, and managed care organizations is the need of hour to fill the current gaps in the management of MM in emerging or developing nations.

Cost reduction, improved healthcare access, enhanced collaboration, and common treatment strategies are few issues, which need immediate attention in the management of MM.

The recent advancements in the management of MM and possible addition of second- or third-generation PIs and iMiDs in the near future will increase the economic burden. Whether this increased burden is justified by the health gain produced is the question, which needs further investigation through more pharmacoeconomic studies and head-to-head trials between various agents for determining their cost-effectiveness and overall benefit.

India and Ukraine Haemato-oncology Group (DC, DB, IK, IKK, OT, RN, and VK) – equal contribution by all authors, listed in alphabetical order. AG developed the structure and arguments for the paper; SA contributed in providing graphs; NG drafted the manuscript; all the authors made critical revisions and approved the manuscript.

Dharma Choudhary, BLK Super Specialty Hospital, New Delhi, India, dharmabmt@yahoo.in. Dinesh Bhurani, Heamato-Oncology Services & Bone Marrow Transplant Unit, Rajiv Gandhi Cancer Institute & Research Centre, Delhi, India, bhurani@gmail.com. Iryna Kryachok, National Cancer Institute, Kiev, Ukraine, irina.kryachok@gmail.com. Iryna Koren’kova, Kiev Center for Bone Marrow Transplantation, Kiev, Ukraine, irina_br@mail.ru. Orest Tsyapka, Institute of Blood Pathology and Transfusion Medicine, Lviv, Ukraine, tsyapka@yahoo.com. Rahul Naithani, Hematology & Bone Marrow Transplantation, Max Hospitals, New Delhi, India, dr_rahul6@hotmail.com. Viktor Kozlov, Odessa Regional Clinical Hospital, Odessa, Ukraine, v_kozlov@ukr.net.

AG, MM, YB, NG, and SA are employees of Dr. Reddy’s Laboratories Ltd., India. The reviewer SG and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.