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EHA25 Virtual: Transition From Bortezomib to Ixazomib in Multiple Myeloma: Updated Real-World Data from the US MM-6 Community-Based Study

Authors: Robert M Rifkin, McKesson Specialty Health and the Rocky Mountain Cancer Centers/US Oncology Research, Denver, CO, US

Multiple myeloma is a plasma cell malignancy that accounts for about 10% of haematological malignancies.1 In recent years, its prognosis has improved dramatically thanks to the introduction of novel agents including proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies.2 Bortezomib, a first-in-class proteasome inhibitor, was approved by the US Food and Drug Administration (FDA) in 2003 and is considered one of the most effective drugs for the treatment of multiple myeloma currently in use.2 However, there are a number of challenges associated with its use. The TOURMALINE-MM1 trial (NCT01564537)3 demonstrated the efficacy and safety of a newer proteasome inhibitor, ixazomib, in conjunction with lenalidomide–dexamethasone in patients with relapsed/refractory disease.4

In an expert interview, Dr Robert M Rifkin from the McKesson Specialty Health and the Rocky Mountain Cancer Centers/US Oncology Research, Denver, CO, US, discusses the challenges of bortezomib therapy, the use of ixazomib and the US MM-6 study, which is investigating the use of ixazomib in conjunction with lenalidomide–dexamethasone in patients who have previously received a bortezomib-based induction regime.

Q. What are the challenges associated with the use of parenteral bortezomib among patients with multiple myeloma in US community settings?

The administration of parenteral bortezomib in the outpatient clinic setting provides several unique challenges. The original approval for parenteral bortezomib was for the intravenous route of administration. Over time, data emerged suggesting that subcutaneous bortezomib was much better tolerated. Bortezomib-based induction is now considered standard of care. In the US MM-6 study (NCT03173092),5 patients need only receive three cycles of bortezomib-based induction therapy prior to switching to an all oral regimen. The challenges prior to the in-class switch are largely those of scheduling. The exposure to subcutaneous bortezomib is relatively limited. Toxicity is therefore expected to be quite mild and manageable. On occasion, we do see some diarrhoea and fatigue. Neuropathy can also be an issue. All of these potential side effects are minimised with the subcutaneous route. Intravenous bortezomib is now rarely, if ever, utilised.

Q. What is the rationale for the use of oral ixazomib in this treatment setting?

The rationale for changing to oral ixazomib is to increase the convenience of utilising the ixazomib regimen in conjunction with lenalidomide and dexamethasone. This now becomes an all oral regimen. Once established on the regimen, the patient only needs a single monthly clinic visit. In previous studies the regimen employed in MM-6 has already been validated.6 The in-class transition employed here is also compliant with the FDA and labelled indication for ixazomib. As the study has continued, patient compliance has been excellent. In the area of the current coronavirus epidemic, this has become a relatively easily regimen to administer.

Q. What are the aims and design of the US MM-6 study?

The US MM-6 study is one of the first of its kind. The aim was to establish sensitivity of patients with newly-diagnosed multiple myeloma to bortezomib-based induction. Patients could then be transitioned if they were responding or stable to the all oral regimen referenced above. Not only is this more convenient, but the US MM-6 study also employs actigraphy. For 50% of each monthly cycle the patient wears a device that records activity and other metrics. This will allow us to analyse patient-reported outcomes compared to device-reported outcomes. Interestingly, and unexpectedly, patient compliance with actigraphy has been over 95%. This is testimonial to patients becoming more actively involved in their own clinical trial.

Q. What have been the major findings of the MM-6 study to date?

To date, major findings for the ongoing study, which are presented in abstract form at the Virtual Edition of the 25th European Hematology Association Annual Congress (EHA25 Virtual) (Abstract S332),7 have shown that the all oral regimen is quite tolerable. In addition, preliminary analysis demonstrates a continued deepening of the response to therapy. Toxicity has been minimal and quite manageable. The safety profile is that expected for the individual agents. A significant number of patients have been able to remain on the study for long periods of time. The actigraphy data is under preliminary analysis. The compliance rate is very exciting; this will provide a unique subset of data which will contribute to patient-reported outcomes.

Q. How will the findings of this study impact on future clinical practice?

The findings of the study are still a bit immature. However, it is clear that patients can tolerate the all oral triplet regimen quite well. Toxicities are as expected. Oftentimes, one of the goals of studies in multiple myeloma is to improve patient convenience. The MM-6 study is now demonstrating this using patient-reported outcomes and actigraphy. With fewer clinic visits, travel times and costs are minimised. In addition, it is our hope that a study design such as this will improve patient participation in clinical trials as the patients receive feedback on their actigraphy. Finally, the study was intentionally designed with over broad inclusion criteria. This more accurately reflects community practice and provides a rich source of real-world evidence. As drug development proceeds it is likely that other in-class transitions for other disease states will be evaluated as well. Overall, we are hoping that this unique study design will pave the way to accumulate more real-world evidence that will impact the design of future clinical trials.


Abstract S332, Long-Term Proteasome Inhibition in Multiple Myeloma (MM) Following an In-Class Transition From Bortezomib (Btz) to Ixazomib (Ixa): Updated Real-World (RW) Data from the US MM-6 Community-Based Study, was presented at EHA25 Virtual in June 2020 and is available here.



  1. Moreau P, San Miguel J, Sonneveld P, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28 (suppl_4): iv52–61.
  2. Iida S. EL30: Treatment of multiple myeloma: current status and a future perspective. Ann Oncol. 2019;30(Suppl_6):vi64.
  3. A Phase 3 Study Comparing Oral Ixazomib Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma. Identifier: NCT01564537. Available at: (accessed 20 July 2020).
  4. Moreau P, Masszi T, Grzasko N, et al. Oral iaxzomib, lenalidomide, and dexamethasone for multiple myeloma. NEJM 2016;374:1621–34.
  5. An Effectiveness and Safety Study of Ixazomib in Combination With Lenalidomide and Dexamethasone (IRD) in Participants With Multiple Myeloma (MM) Previously Receiving a Bortezomib-based Induction Regimen (US MM-6). Identifier: NCT03173092. Available at: (accessed 20 July 2020).
  6. Kumar SK, Berdeja JG, Niesvizky R, et al. Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance. Leukemia. 2019;33:1736–46.
  7. Manda S, Habte A. Yimer HA, Girnius SK, et al. Long-Term Proteasome Inhibition in Multiple Myeloma (MM) Following an In-Class Transition From Bortezomib (Btz) to Ixazomib (Ixa): Updated Real-World (RW) Data from the US MM-6 Community-Based Study. Presented at: Virtual Edition of the 25th European Hematology Association Annual Congress, 11–21 June 2020. Abstr S332.


Author profile: Dr Robert M Rifkin is a haematologist/oncologist with Rocky Mountain Cancer Centers in Denver, CO, US. Dr Rifkin is the associate chair of Hematology Research for The US Oncology Network and the disease lead for Multiple Myeloma. He also serves as the medical director of Biosimilars for McKesson. Dr Rifkin stresses access the importance of state-of-the-art care with emerging therapies and treatments. he has a passion for clinical research and the development of real-world evidence. He fundamentally believes it is essential to rapidly develop therapies and provide them to patients close to home.

Disclosure: Robert M Rifkin has served on the advisory boards for Amgen, Bristol-Myers Squibb, Celgene, Takeda and Karyopharm, and is a stockholder of the McKesson Corporation.

Support: Commissioned, edited and supported by Touch Medical Media, who commissioned the interview in liaison with W20 Group.

Published: 20 July 2020

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