Focus on Induction Regimens for Transplant-eligible Patients with Multiple Myeloma
Professor of Medicine
Weill Cornell Medical College
Chief Attending Physician
Adult Bone Marrow Transplant Service
Memorial Sloan Kettering Cancer Center
New York, New York
What are some barriers to the use of stem cell transplantation clinicians commonly experience when managing patients with MM?
Over the last decade, we have seen significant improvements in survival among patients with MM, largely because of increased use of stem cell transplantation and the introduction of novel therapies, such as the first generation of proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). Despite these encouraging trends, suboptimal utilization rates for stem cell transplantation have been observed in MM patients. Several factors may play a role in these low rates, including an insufficient number of transplant centers throughout the US to meet demand, and the fact that transplantation is largely referral-biased. Many community oncologists also believe that autologous hematopoietic cell transplantation (HCT) should be reserved only for younger patients. This is misguided because there is data showing that many older patients can benefit from autologous HCT to the same degree as their younger counterparts. In some cases, older adults may benefit more from the procedure because they achieve deeper remissions that last longer, which in turn decreases needs for further therapy over the disease course.
Lack of patient knowledge regarding stem cell transplantation is another key contributing factor to low utilization rates. The common perception among patients is that stem cell transplants are dangerous procedures associated with significant side effects. Clinicians can overcome this hurdle by educating patients on the differences between transplant types. Providing information on mortality rates and how quickly patients can return to work may be beneficial during patient consults. For autologous HCT, the mortality rate is less than 1%, and most patients can return to work within 3 months. For allogeneic HCT, efficacy has increased substantially; the non relapse mortality rate is 10-15%, and most patients can return to work in 9 to 12 months.
Autologous HCT is a vehicle used to deliver high-dose melphalan in a safe manner. High-dose melphalan is associated with the deepest depth of response, making it the single most effective agent for treating MM, but it can also result in bone marrow side effects. Frozen autologous or hematopoietic progenitor cells are used to overcome side effects. When used alone, high-dose melphalan can produce complete remission (CR) rates of 20-30%. For most malignancies, a cure typically occurs after using the most effective treatment upfront, and recent data from French investigators further supports this concept. A 2016 study found that elderly newly diagnosed MM patients receiving autologous HCT as first-line treatment had longer progression-free survival (PFS) and overall survival (OS) rates than those randomized to have their transplant delayed. After a median follow-up of 21 months, patients receiving autologous HCT as first-line treatment had a PFS of 76% and an OS of 88%.1 These results occurred in the context of best induction strategy, which involved a combination of bortezomib, lenalidomide, and dexamethasone. In addition, 75% of the delayed-transplant arm received autologous HCT within 2 years of being randomized to continued chemotherapy.
How can clinicians assess patient appropriateness for stem cell transplantation?
To optimize quality of care in MM, clinicians should have open communication with patients, community providers, and stem cell transplant centers. Patients should be seen early in the disease course to facilitate treatment plans, coordinate care, and identify potential barriers to stem cell transplantation. Clinicians should contact stem cell transplant centers to discuss patient eligibility with experts. If patient consultation is warranted, there should be a discussion about the timing of the consult.
When determining patient eligibility for stem cell transplantation, dialysis status and age should not be considered deciding factors. A 2017 study found that MM patients undergoing autologous HCT who were on dialysis achieved PFS and OS rates that were similar to those receiving autologous HCT with normal renal function.2 In 2014, a study by Merz, et al., showed that elderly MM patients receiving autologous stem cell transplantation achieved event-free survival and OS rates that were similar to their younger counterparts.3 Stem cell transplants should not be considered if patients specifically state that they do not wish to pursue it or if they have significantly uncontrolled comorbidities, such as severe congestive heart failure or COPD. Other factors should also be considered, including the possible need for special services and patients’ proximity to transplant centers in case they require a lengthy stay after the procedure.
What is the standard of care for induction therapy today, and how has this standard changed over time?
Outcomes for MM have significantly improved with the introduction of new drug regimens, including IMiDs and PIs, but many patients still relapse or become refractory to first-line treatments. Several years ago, induction therapy use was heterogeneous, varying between doublet and triplet regimens. Since that time, there has been a paradigm shift as data from meta-analyses and randomized trials supported use of triplet therapy for MM.4,5 Bortezomib, lenalidomide and dexamethasone (RVD), and cyclophosphamide, bortezomib and dexamethasone (CyBorD) are standard of care triplet regimens for MM, but studies comparing RVD and CyBorD are needed to determine if one approach is superior to another. In addition, clinical trials are exploring the efficacy of a quadruple therapy combination of daratumumab, bortezomib, lenalidomide, and dexamethasone for MM patients.
What is the overall safety and efficacy of stem cell transplantation procedures?
Overall, research indicates that stem cell transplantation is safe. The US mortality rate associated with these procedures is less than 1%.6 In recent years, there has been a shifting trend toward performing stem cell transplants as outpatient procedures, making it more accessible and convenient for patients. However, there is still significant symptom burden to consider. About one-third of patients with MM have fatigue at 1 month post-transplantation, and about 10% report significant nausea, vomiting, and gastrointestinal toxicity.7 Recognizing that interleukin-6 is a key mediator of transplant related fatigue, researchers are exploring the effect of blocking this glycoprotein to improve fatigue.8 A 2017 study found that acupuncture appears to improve appetite and sleep in MM patients who receive stem cell transplants, but larger studies are required.9 Research is also needed to determine effective strategies for reconstituting the immune system more quickly so patients can resume their normal lifestyle.
With regard to efficacy, data demonstrate that 40-50% of patients receiving modern induction treatment achieve CR.10 When used with maintenance lenalidomide, stem cell transplants are associated with an average remission duration of more than 4 years.11 Approximately 30% of patients who undergo stem cell transplantation and achieve CR remain in remission for more than 10 years after the procedure.12
Are there any disease- or treatment-related factors that preclude eligibility for transplant in the relapsed MM setting?
When considering autologous HCT, relapsed MM patients are precluded from transplant eligibility if they do not have enough available stem cells. All MM patients should be encouraged to have their stem cells collected early in the disease course, even if they decide to delay their transplant. This ensures that a sufficient number of healthy stem cells (which have not been exposed to chemotherapy) will be available if there is progression to an autologous HCT as salvage treatment. For both allogeneic and/or autologous transplant candidates, relapsed MM patients are precluded from transplantation if they have severe comorbidities (eg, cardiomyopathy), which may occur after receipt of carfilzomib therapy. These individuals are also precluded if they have any severe infections, which may occur after multiple treatments have been used. As part of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), trials are exploring the role of allogeneic transplantation in high-risk MM patients in the upfront setting.
What clinical trials should clinicians be aware of regarding transplantation in high-risk MM?
The StaMINA and European Myeloma Network (EMN) trials are two recent investigations that explored the role of tandem stem cell transplantation in MM. On the surface, results from these analyses appear to contradict each other, but the reality is they should not be comparable because the study populations were very different. In StaMINA, a key finding was that tandem autologous HCT was not superior to a single autologous HCT followed by lenalidomide maintenance in the upfront treatment of MM with regard to PFS or OS rates.13 StaMINA participants could receive induction therapy for up to 1 year prior to being registered for the trial, and about 70% of those randomized to tandem transplantation actually received it. The EMN trial concluded that upfront tandem autologous stem cell transplantation after bortezomib-based induction therapy for newly diagnosed MM was superior to a single autologous stem cell transplantation in terms of prolonged PFS.14 For EMN, the selection criteria was rigorous, with all participants receiving 4 cycles of RVD, then a transplant, and then a second transplant within 3 to 6 months. About 80% of patients randomized to tandem transplantation actually received it. In short, patients enrolled in StaMINA differed significantly from those participating in EMN.
Despite their differences, the StaMINA and EMN trials did provide helpful insights. The StaMINA findings suggest there may not be a role for tandem transplantation among MM patients with more than 6 months of induction treatment. The EMN results indicate there may be a role for tandem transplantation among patients receiving 4 cycles of chemotherapy in the outpatient setting. Research is ongoing to reconcile differences from the StaMINA and EMN trials in the outpatient setting.
In addition to these studies, other research is exploring the role of allogeneic transplantation in high-risk MM patients whose remission lasted less than 18 months after first receiving an autologous stem cell transplant. The hope is that these studies will inform us on strategies to extend survival, improve quality of life, and reduce treatment burden.
What key takeaways should community oncologists remember when considering stem cell transplantation as an option for their patients?
There is warranted excitement surrounding the emergence of novel therapies for MM, but clinicians should be cognizant of the important role of stem cell transplantation when managing these patients. To date, randomized trials have shown that MM patients who undergo stem cell transplantation early have longer PFS. Clinicians should collect healthy stem cells early so that they may be used as salvage therapy in the event of relapsing MM. Patients achieving a complete response with other therapies may also derive benefit from a stem cell transplant. A deep response with stem cell transplantation is important to improving patient outcomes.
Ultimately, stem cell transplantation is a treatment choice, meaning it is critical to adequately inform patients and consult with experts to make informed decisions. Autologous stem cell transplants should not be viewed as a last resort treatment; instead, they should be viewed as effective treatment options worthy of consideration. For younger patients with relapsed MM and/or high-risk features, allogeneic stem cell transplantation has the potential to be curative, and trials are still exploring its role in the upfront setting and after relapses. These trials will inform us on ways to ensure that patients live longer and with the best quality of life possible.
- Garderet L, Beohou E, Caillot D, et al. Upfront autologous stem cell transplantation for newly diagnosed elderly multiple myeloma patients: A prospective multicenter study. Haematologica. 2016;101(11):1390-1397. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394878/
- Mahindra A, Hari P, Fraser R, et al. Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: A Center for International Blood Marrow and Transplant Research analysis. Bone Marrow Transplant. 2017;52(12):1616-1622. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859934/.
- Merz M, Neben K, Raab MS, et al. Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents. Ann Oncol. 2014;25(1):189-195. https://academic.oup.com/annonc/article/25/1/189/166016
- Sun Z, Zheng F, Wu S, et al. Triplet versus doublet combination regimens for the treatment of relapsed or refractory multiple myeloma: A meta-analysis of phase III randomized controlled trials. Crit Rev Oncol Hematol. 2017;113:249-255. https://www.croh-online.com/article/S1040-8428(16)30312-2/pdf
- Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG ;S0777): A randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546834/
- Gertz MA, Buadi FK, Hayman SR, et al. Safety outcomes for autologous stem cell transplant in multiple myeloma. Mayo Clin Proceed. 2018;19(1):56-58. https://www.sciencedirect.com/science/article/pii/S0025619617306961
- Campagnaro E, Saliba R, Giralt S. Symptom burden after autologous stem cell transplantation for multiple myeloma. Cancer. 2008;112(7):1617-1624. https://onlinelibrary.wiley.com/doi/epdf/10.1002/cncr.23299
- Burger R. Impact of interleukin-6 in hematological malignancies. Transfus Med Hemother. 2013;40(5):336-343. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822278/
- Deng G, Giralt S, Chung DJ, et al. Acupuncture for reduction of symptom burden in multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation: A randomized sham-controlled trial. Support Care Cancer. 2018;26(2):657-665. https://link.springer.com/article/10.1007%2Fs00520-017-3881-7
- Cornell RF, D’Souza A, Kassim AA, et al. Maintenance versus induction therapy choice on outcomes after autologous transplantation for multiple myeloma. Biol Blood Marrow Transplant. 2017;23(2):269-277. https://www.sciencedirect.com/science/article/pii/S108387911630489X
- Mian I, Milton DR, Shah N, et al. Prolonged survival with a longer duration of maintenance lenalidomide after autologous hematopoietic stem cell transplantation for multiple myeloma. Cancer. 2016;122(24):3831-3837. https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.30366
- Lehners N, Becker N, Benner A, et al. Analysis of long-term survival in multiple myeloma after first-line autologous stem cell transplantation: Impact of clinical risk factors and sustained response. Cancer Med. 2018;7(2):307-316. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806105/
- Stadtmauer EA, Pasquini MC, Blackwell B, et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide (len) and dexamethasone (RVD) consolidation with len maintenance (ACM), tandem autoHCT with len maintenance (TAM) and autoHCT with len maintenance (AM) for up-front treatment of patients with multiple myeloma (MM): Primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 – StaMINA Trial). Blood. 2016 128:LBA-1. http://www.bloodjournal.org/content/128/22/LBA-1
- Cavo M, Petrucci MT, Raimondo FD, et al. Upfront single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma: An intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO95 MM trial). Blood. 2016;128:991. http://www.bloodjournal.org/content/128/22/991