Emerging Approaches to the Treatment of Newly Diagnosed Multiple Myeloma
Professor of Cancer Research
Director, Center for Individualized Medicine
What recent progress has been made regarding the management of patients with newly diagnosed multiple myeloma?
Prior to autologous stem cell transplant (SCT), patients with newly diagnosed multiple myeloma (NDMM) commonly require therapy with three-drug combinations that include a proteasome inhibitor, an immune modulator, and dexamethasone. For several years now, the combination of bortezomib, lenalidomide, and dexamethasone (VRd) has been the de facto standard of care for younger NDMM patients. VRd is now increasingly being used as frontline therapy for older individuals, albeit with dose attenuation.
Recently, ongoing clinical trials have investigated the efficacy of carfilzomib, lenalidomide, and dexamethasone (KRd) as an emerging treatment approach to NDMM. KRd has an advantage in that it causes very little neuropathy. However, experts have suggested that, for now, KRd be reserved for more physically fit patients because carfilzomib has been linked to an increased incidence of cardiovascular events.1 Ongoing clinical trials comparing VRd with KRd are focused on correlating each regimen with patient outcomes and toxicities, and we are awaiting results from these studies.
The FDA’s recent approval of daratumumab, a monoclonal antibody, highlights a significant advance in the frontline treatment landscape for NDMM. Incorporating this therapy and other emerging and novel agents in combination regimens may soon be available to treat NDMM patients. The ALCYONE study demonstrated that the four-drug combination of daratumumab plus bortezomib, melphalan, and prednisone (VMP) yielded positive results when compared with VMP alone.2 Other smaller phase 2 studies have assessed the addition of daratumumab to VRd or KRd, with positive results being observed for each of these regimens.3-4 As ongoing studies reach maturity, the potential may exist to tailor four-drug therapies to patients with specific disease characteristics or risk factors. Finally, numerous other three- and four-drug combinations (e.g., those that incorporate elotuzumab or ixazomib) are being investigated in clinical trials to determine if different regimens can improve efficacy and/or reduce toxicity.
What efficacy and safety data are being reported from recent clinical trials of emerging therapeutic strategies for NDMM?
Multiple randomized clinical trials are continuing to explore emerging therapeutic agents as potential treatments for NDMM, including daratumumab, carfilzomib, ixazomib, and elotuzumab. Preliminary results suggest that each of these agents has important benefits and risks that must be considered as clinicians prepare to incorporate them into treatment. Daratumumab has been approved for use in the frontline setting when used with the VMP regimen, and ongoing trials are exploring different combinations and dosing regimens and schedules. In the relapse setting, phase 3 trials examining the combination of daratumumab with lenalidomide- or bortezomib-based regimens resulted in a significant improvement in objective response rate (ORR), depth of response, and progression-free survival (PFS).3-4 Daratumumab can require an infusion time of
Emerging Agents in Clinical Trials
When compared with bortezomib, research has shown that carfilzomib, a second-generation proteasome inhibitor approved for use in relapsed/refractory myeloma, has demonstrated promising efficacy when used in the NDMM setting. In clinical trials, carfilzomib-based treatment regimens have achieved high complete response rates as frontline treatment for NDMM patients. In relapsed/refractory myeloma trials, carfilzomib has been shown to result in deep responses and improved PFS and overall survival (OS) when compared with lenalidomide- or bortezomib-based treatment controls.8 However, carfilzomib may be inconvenient for patients due to a dosing schedule that requires treatment on 6 days over the course of one month. Recently, however, the use of weekly carfilzomib demonstrated equivalent efficacy and improved PFS when compared with twice-weekly delivery.9 An advantage of carfilzomib is that it is not associated with peripheral neuropathy. However, 3%-7% of patients have reported developing cardiovascular events, such as hypertension, shortness of breath, and heart failure.8 As such, clinicians must perform a detailed clinical history of prior cardiac disease and assess future risk of cardiac issues prior to prescribing carfilzomib.
Ixazomib, an FDA-approved oral delivery proteasome inhibitor for myeloma, has resulted in deep and durable responses in phase 2 clinical trials when added to lenalidomide and dexamethasone in NDMM patients who did not undergo SCT.10,11 Benefits of ixazomib include an oral route of delivery, a relatively limited toxicity profile, and a slightly lower incidence and severity of neuropathy (when compared with bortezomib). Responses to ixazomib appear to emerge more slowly than those seen with other protease inhibitors, although the frequency and depth of responses accumulate over time. Ongoing studies are investigating ixazomib in the frontline setting. Once approved in the NDMM setting, this agent may be beneficial for patients who prefer oral medications.
Clinical trials are also examining the combination of elotuzumab, a monoclonal antibody, with lenalidomide and dexamethasone in NDMM patients. A phase 2 trial demonstrated that this regimen achieved a good ORR with an acceptable safety profile. Elotuzumab may also be infused at a higher rate to reduce infusion time. This approach offers convenience without inducing additional infusion reactions.12 In addition, elotuzumab has a dosing schedule of once every two weeks.
With numerous therapeutic options currently available or under investigation for patients with NDMM, community oncologists must carefully balance the benefits and risks of each new agent or combination regimen prior to initiating treatment. As a result, clinicians must remain up-to-date on results of clinical trials exploring these agents to ensure that the most appropriate patients are receiving optimized therapeutic strategies at the right time.
What common concerns do NDMM patients have when treatment is initiated, and when should referral to a clinical trial be considered?
When patients are diagnosed with multiple myeloma, their concerns must be discussed and addressed before initiating treatment. Patients should be informed that they have the potential to live for multiple years with this disease, even if they are at high risk, due to recent advances in treatment. With appropriate long-term therapy, survival in myeloma has tripled over the past decade, with the average OS currently at approximately 8-10 years.13 Patients must also be counseled on the importance of undergoing genetic assessments, as these will determine prognosis and guide treatment planning. In addition, NDMM patients should receive education on emerging agents and regimens in late-phase clinical trials, including those with potential to receive FDA approval in the next 18 months. The goal of educational and counseling strategies is to ensure that each patient understands that prognoses and survival rates have improved dramatically in recent years, and that, as additional new agents and combinations are approved, these rates will only continue to increase.
Three Strategies for Alleviating Concerns in NDMM Patients
In addition, community oncologists should discuss what treatment will be like for NDMM patients and provide education on how therapy will impact daily life. Patients should understand risks for toxicity and side effects associated with the therapies they receive. They must also be reassured that the treatments of today are vastly improved from what had been previously available. Current non-transplant treatments for NDMM do not result in incapacitation, cause hair loss, or result in persistent nausea or vomiting. In addition, targeted drugs currently available or being explored in clinical trials for NDMM have a favorable toxicity profile. For some patients, these therapies may be compatible with maintaining a normal lifestyle throughout treatment.
Some myeloma patients may go into remission and will not require treatment. These patients should be counseled that they may relapse and their disease may return. All NDMM patients are at risk of becoming refractory to treatment over time. Patients must be aware of this information so that they will work closely with their treatment team to optimize disease management and to ensure realistic expectations of treatment.
Per recommendations from national guidelines, NDMM patients should be encouraged to participate in clinical trials.14 These studies are essential to fostering progress in treating the disease. Numerous trials are continuing to enroll patients with newly diagnosed disease, although access to these studies can be challenging. Community oncologists should collaborate and partner with specialized centers that have access to a diverse number of trials and seek out these studies early in the disease course. Delays in clinical trial referral can limit available options, as patients may develop compounding problems, such as low blood counts and other complications. These events may potentially exclude patients from participating in studies.
- Dimopoulos MA, Roussou M, Gavriatopoulou M, et al. Cardiac and renal complications of carfilzomib in patients with multiple myeloma. Blood Adv. 2017;1:449-454. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738981/. Accessed September 13, 2018.
- Mateos MV, Dimopoulos MA, Cavo M, et al; ALCYONE Study Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378:518-528. Available at: https://www.nejm.org/doi/10.1056/NEJMoa1714678/. Accessed September 13, 2018.
- Voorhees, PM, Costa, LJ, Reeves, B, et al. Interim safety analysis of a phase 2 randomized study of daratumumab (dara), lenalidomide (r), bortezomib (v), and dexamethasone (d; dara-RVd) vs. RVd in patients (pts) with newly diagnosed multiple myeloma (mm) eligible for high‐dose therapy (HDT) and autologous stem cell transplantation (ASCT). Blood. 2017;130:1879. Available at: http://www.bloodjournal.org/content/130/Suppl_1/1879. Accessed September 13, 2018.
- Chari A, Usmani SZ, Krishnan A, et al. Daratumumab (dara) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with newly diagnosed multiple myeloma (MMY1001): updated results from an open-label, phase 1b study. Blood. 2017;130:3110. Available at: http://www.bloodjournal.org/content/130/Suppl_1/3110. Accessed September 13, 2018.
- Nooka AK, Gleason C, Sargeant MO, et al. Managing infusion to new monoclonal antibodies in multiple myeloma: daratumumab and elotuzumab. J Oncol Pract. 2018;14:414-422. Available at: http://ascopubs.org/doi/10.1200/JOP.18.00143. Accessed October 16, 2018.
- Barr H, Dempsey J, Waller A, et al. Ninety-minute daratumumab infusion is safe in multiple myeloma. Leukemia. 2018 Mar 31 [Epub ahead of print]. Available at: https://www.nature.com/articles/s41375-018-0120-2. Accessed October 16, 2018.
- Usmani SZ, Jakubowiak A, Chari A, et al. Split dosing of daratumumab (D) in a phase 1b study of D plus carfilzomib (K)-based regimens in patients (pts) with multiple myeloma (MM). Ann Oncol. 2017;28(suppl 5):997PD. Available at: https://academic.oup.com/annonc/article/28/suppl_5/mdx373.003/4109082. Accessed October 16, 2018.
- Mushtaqa A, Kapoora V, Latifa A, et al. Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: a systematic review. Crit Rev Oncol Hematol. 2018;125:1-11. Available at: https://www.croh-online.com/article/S1040-8428(17)30393-1/pdf. Accessed September 13, 2018.
- Moreau P, Mateos MV, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018;19:953-964. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29866475. Accessed October 16, 2018.
- Kumar S, Berdeja J, Niesvizky R, et al. Deep and durable responses with weekly ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM): long-term follow-up of patients not undergoing stem cell transplantation (SCT). Clin Lymphoma Myeloma Leukemia. 2017;17:S335-S336. Available at: https://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(17)31157-6/abstract. Accessed September 13, 2018.
- Richardson P, Hofmeister C, Rosenbaum C, et al. Twice-weekly ixazomib plus lenalidomide-dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM): long-term follow-up data for patients not undergoing stem cell transplantation (SCT). Clin Lymphoma Myeloma Leukemia. 2017;17: S337. Available at: https://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(17)31158-8/abstract. Accessed September 13, 2018.
- Takezako N, Ohta K, Handa H, et al. Elotuzumab plus lenalidomide/dexamethasone (ELd) Vs Ld in patients with newly diagnosed multiple myeloma: phase 2, randomized, open-label study in Japan. Blood. 2017;130:434. Available at: http://www.bloodjournal.org/content/130/Suppl_1/434. Accessed September 13, 2018.
- Fonseca R, Abouzaid S, Bonafede M, et al. Trends in overall survival and costs of multiple myeloma, 2000–2014. Leukemia. 2017;31:1915-1921. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596206/. Accessed September 13, 2018.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 1.2019. July 20, 2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed September 13, 2018.