The year 2015 brought important advances in the treatment of multiple myeloma. Most impressive was the US Food and Drug Administration (FDA) approval of 4 novel agents—panobinostat (Farydak), daratumumab (Darzalex), elotuzumab (Empliciti), and ixazomib (Ninlaro)—as well as new indications for 3 drugs already on the market—lenalidomide (Revlimid), carfilzomib (Kyprolis), and pomalidomide (Pomalyst).
"This is an extraordinary moment in oncology," said Paul G. Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, during a session on new myeloma drugs at the 2015 American Society of Hematology (ASH) annual meeting.
"This is a revolutionary time in multiple myeloma. Daratuzumab, elotuzumab, and ixazomib promise to change the landscape of treatment and improve overall survival," agreed S. Vincent Rajkumar, MD, Professor of Medicine, Mayo Clinic, Rochester, MN, who spoke at the same session. "Largely because of the plethora of new agents," more than 80% of patients are alive 4 years or more after diagnosis. "We have to thank the FDA for approving these drugs so rapidly," Dr Rajkumar said.
"It is an exciting time for multiple myeloma patients, with more new therapeutic options available," echoed Sagar Lonial, MD, Professor and Chair, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, who spoke at an educational session at ASH 2015. "We have made significant progress, as evident by the improved survival over the past 15 years."
New Drugs and New Indications in 2015
On February 23, 2015, the FDA approved panobino-stat, the first histone deacetylase (HDAC) inhibitor for multiple myeloma. In November, the FDA approved the first 2 monoclonal antibodies, which harness the body's immune system to attack malignant cells, for multiple myeloma—daratumumab on November 16, followed on November 23 by the approval of elotuzumab, the second monoclonal antibody for this malignancy. On November 20, the FDA approved the next-generation proteasome inhibitor ixazomib, the first and only oral proteasome inhibitor approved in the United States.
In addition to these 4 novel therapies, on February 18, 2015, the FDA expanded the indication of lenalidomide, for use with low-dose dexamethasone, in newly diagnosed patients with multiple myeloma. This approval as first-line therapy for this immunomodulatory drug (IMiD) was based on data from the phase 3 FIRST clinical trial showing a 28% risk reduction for disease progression or death in newly diagnosed patients who received continuous lenalidomide plus dexamethasone versus melphalan plus prednisone and thalidomide (P<.001).1 Lenalidomide was previously approved for patients who have received at least 1 treatment.
"The approval of lenalidomide as an option for use in all patients with multiple myeloma represents a new paradigm in the management of this disease," Kenneth C. Anderson, MD, Program Director, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, said in an interview. "We now have clinical evidence demonstrating that starting and keeping newly diagnosed multiple myeloma patients on lenalidomide significantly improves progression-free survival."
On April 23, 2015, the FDA approved a new indication for pomalidomide for patients with relapsed or refractory multiple myeloma. The approval was for use in combination with low-dose dexamethasone for the treatment of patients with relapsed and/or refractory disease who have received at least 2 previous therapies, including lenalidomide and a proteasome inhibitor. This new indication was based on the final analysis of the MM-003 clinical trial, showing improved overall response and survival with pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in patients with multiple myeloma who had received at least 2 previous regimens.2
Finally, on July 24, 2015, the intravenous proteasome inhibitor carfilzomib (Kyprolis) received a new indication for use in combination with lenalidomide and dexamethasone for patients with relapsed and/or refractory multiple myeloma who have received 1 to 3 previous therapies. This approval was based on a significant 31% reduction in disease progression risk in the phase 3 ASPIRE clinical trial, and an unprecedented median progression-free survival (PFS) of 26.3 months.3
According to Dr Anderson, carfilzomib proved to be even more robust when combined with pomalidomide and dexamethasone. "The combination of a second-generation IMiD and a second-generation proteasome inhibitor seems to have additive benefit," Dr Anderson said at the 2015 National Comprehensive Cancer Network (NCCN) annual conference.
Panobinostat: First HDAC Inhibitor
Panobinostat was approved based on the phase 3 PANORAMA1 clinical trial, showing that the combination of panobinostat plus bortezomib and dexamethasone significantly increased the median PFS by approximately 4 months and reduced the risk for disease progression by approximately 37%.4
"The idea of getting panobinostat approved," Dr Anderson said at the 2015 NCCN conference, "is that we have a new class of drugs available in multiple myeloma, and it's the first step of what we hope will be an evolution toward more selective and better-tolerated HDAC inhibitors."
One of these HDAC inhibitors in the pipeline is rocilinostat (ACY-1215), which is a more selective inhibitor and may preserve the clinical efficacy of HDAC inhibitors while minimizing toxicity. Rocilinostat's oral formulation and preliminary potency and safety point to its potential in combination with proteasome inhibitors or IMiDs in a 3- or 4-drug regimen, according to Dr Lonial.5
A Paradigm Change: Monoclonal Antibodies
"The monoclonal antibodies recently approved in multiple myeloma are paradigm-changing agents," Dr Richardson said at the ASH 2015 drug approvals session. The use of daratumumab or elotuzumab as part of combination regimens boosts therapeutic aggressiveness, Dr Rajkumar said, noting that although they are indicated in the relapsed or refractory setting, their off-label use in newly diagnosed patients will be tempting.
Dr Richardson added, "Monoclonal antibodies may override the impact of mutations and provide entirely non—cross-resistant strategies, so we can add them to existing drugs."
Daratumumab is approved as monotherapy for patients who have received at least 3 previous treatments. Data presented at ASH 2015 showed high response rates with daratumumab as a single agent (31%),6 in combination with lenalidomide and dexamethasone (81%),7 and in combination with pomalidomide and dexamethasone (71%).8
"It's my personal opinion that daratumumab is the 'rituximab' of multiple myeloma," said study investigator Torben Plesner, MD, Vejle Hospital, University of Southern Denmark, at an ASH 2015 press briefing. "It is very effective when given with other core treatments, with no added toxicity." He discussed the updated data from the GEN503 trial of daratumumab, lenalidomide, and dexamethasone in 32 patients with relapsed or refractory disease.7
The overall response rate was 81%, with 34% of patients achieving a complete response or better and 63% achieving a very good partial response or better. The median response duration was not reached, and 91% of patients were free of progression at 12 months.7 The overall survival data are immature, but 90% of patients were alive and 72% were free of disease progression at 18 months.7
Daratumumab was also studied in combination with pomalidomide and dexamethasone in the MMY1001 trial of 98 patients with relapsed or refractory disease who received at least 2 previous treatments. Many patients were refractory to a proteasome inhibitor and an IMiD.8
Ajai Chari, MD, Director of Clinical Research, Multiple Myeloma Program, Mount Sinai School of Medicine, NY, reported that the response rate was 71% overall and 67% in patients with double-refractory disease.8
Finally, daratumumab was evaluated as a single agent in 148 patients in the GEN501 and SIRIUS trials. Saad Z. Usmani, MD, Director of Clinical Research in Hematologic Malignancies, Levine Cancer Institute, Charlotte, NC, said, “Daratumumab induced rapid, deep, and durable responses in a heavily pretreated/highly refractory population. A remarkable depth of response was observed in patients who were refractory to newer agents, including pomalidomide and carfilzomib.”6
Elotuzumab is indicated in combination with lenalidomide and dexamethasone after patients have received 1 to 3 previous therapies. Updates of the pivotal ELOQUENT-2 clinical trial, which led to the approval of elotuzumab, showed a persistence of benefit with further follow-up, including a 27% reduction in the risk for disease progression or death with elotuzumab plus lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone; the median overall survival was 43.7 months with the addition of elotuzumab versus 39.6 months without elotuzumab.9
"The elotuzumab combination demonstrated a durable and clinically relevant improvement in progression-free survival and response rate...and there is minimal incremental toxicity," said Dr Richardson at ASH 2015.
In a 2015 update of the first randomized study of elotuzumab given with bortezomib and dexamethasone, a 24% reduction in risk for progression or death was observed with the regimen. The median overall survival was not reached with the triple therapy compared with 34.7 months in the control arm.10
Thierry Facon, MD, Lille University Hospital, France, said in an interview that the PFS benefit is "impressive," noting that the signals of activity with lenalidomide and with bortezomib indicate that physicians will be able to pair elotuzumab with either agent.
Ixazomib: First Oral Proteasome Inhibitor
The approval of the oral proteasome inhibitor ixazomib brings a convenient new option to a treatment model that has relied on the intravenous delivery of most drugs.
In the phase 3 TOURMALINE-MM1 clinical trial, the median PFS was 20.6 months with ixazomib plus lenalidomide and dexamethasone versus 14.7 months with lenalidomide plus dexamethasone alone.11 Other studies reported in 2015 demonstrated high response rates for ixazomib in combination with pomalidomide and dexamethasone in patients with relapsed and/or refractory disease, including a 100% response rate in standard-risk patients,12 as well as in combination with cyclophosphamide and dexamethasone in newly diagnosed patients who are not eligible for transplant.13
Ixazomib "fits very well" in the relapsed or refractory space, Dr Richardson said at ASH 2015, thanks to its strong tolerability and convenient once-weekly dosing. According to Dr Richardson, ixazomib should be especially beneficial in combination with lenalidomide and dexamethasone in high-risk patients, who need a proteasome inhibitor.
"What strikes me is this is a very simple regimen, as you take just 3 drugs a month, and the side-effect profile is outstanding," agreed Dr Rajkumar at ASH 2015.
Dr Rajkumar said that ixazomib can be viewed as an effective alternative to bortezomib in standard-risk patients who are frail or elderly (≥75 years), and in other patients who cannot take bortezomib.
Triplet Therapies Now Standard of Care
Three-drug regimens should be the standard of care in most newly diagnosed patients with multiple myeloma, according to a study that validated a practice that has become common in the United States.14 The use of 3 drugs followed by continuous maintenance led to a significant 29% reduction in risk for disease progression and death in the phase 3 SWOG S0777 trial.14
SWOG S0777 is the first and only randomized clinical trial comparing initial treatment with a 2-drug regimen (lenalidomide and dexamethasone) versus a 3-drug regimen (bortezomib plus lenalidomide and low-dose dexamethasone).14
Induction with bortezomib plus lenalidomide and low-dose dexamethasone followed by continuous maintenance with lenalidomide and dexamethasone can therefore be considered the standard of care in newly diagnosed patients, the experts agreed at ASH 2015.
"In my view, we have established in the induction therapy setting that 3 drugs are better than 2 for most patients, and an IMiD plus proteasome inhibitor combination is likely the best regimen to use," Dr Lonial said.
Drug combinations will virtually always top the sequential use of agents in multiple myeloma, he said. They lead to deeper and more durable responses, and they potentially suppress resistant clones in patients at standard risk and in those at high risk of progression. "The best shot of eliminating or suppressing the disease is at the very beginning," he said.
Although the 3-drug regimen of cyclophosphamide, bortezomib, and dexamethasone, which many clinicians now use, is less expensive than the regimen of bortezomib, lenalidomide, and low-dose dexamethasone, it is not the most effective and, Dr Lonial noted, is not his first treatment choice.
The approval of 4 new agents from 2 new drug classes in 1 year has greatly expanded the treatment armamentarium in this disease. Immunotherapy has become a focus of treatment and research in oncology, and the pipeline includes agents that will further harness the immune system to attack this blood cancer and improve outcomes.15 With a better understanding of the biology of multiple myeloma, these treatments will be tailored to the individual patient. According to Dr Lonial, "The availability of future technologies for personalized immune approaches, identifying actionable mutations, and establishing biomarkers for treatment responsiveness opens the doors for personalized medicine in the management of relapsed multiple myeloma in the future."5
"Multiple myeloma has become a chronic illness in many patients," Dr Anderson said in an interview. "As we have more classes of novel agents, especially immunotherapies, it will become a chronic illness with curative potential."
1. Benboubker L, Dimopoulos MA, Dispenzieri A, et al; for the FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906-917.
2. Celgene. Pomalyst (pomalidomide) label update including progression-free and overall survival benefits approved by U.S. FDA. Press release. April 23, 2015. http://ir.celgene.com/releasedetail.cfm?releaseid=908418. Accessed January 27, 2016.
3. Stewart AK, Rajkumar SV, Dimopoulos MA, et al; for the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152.
4. San-Miguel JF, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15:1195-1206. Erratum in: Lancet Oncol. 2015;16:e6.
5. Lonial S, Nooka AK. Novel combination approaches for myeloma. Hematology Am Soc Hematol Educ Program. 2015;2015:286-293.
6. Usmani S, Weiss B, Bahlis NJ, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Presented at the 57th American Society of Hematology Annual Meeting. Orlando, FL; December 5-8, 2015. Abstract 29.
7. Plesner T, Arkenau H-T, Gimsing P, et al. Daratumumab in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: updated results of a phase 1/2 study (GEN503). Presented at the 57th American Society of Hematology Annual Meeting. Orlando, FL; December 5-8, 2015. Abstract 507.
8. Chari A, Lonial S, Suvannasankha A, et al. Open-label, multicenter, phase 1b study of daratumumab in combination with pomalidomide and dexamethasone in patients with at least 2 lines of prior therapy and relapsed or relapsed and refractory multiple myeloma. Presented at the 57th American Society of Hematology Annual Meeting. Orlando, FL; December 5-8, 2015. Abstract 508.
9. Dimopoulos MA, Lonial S, White D, et al. Eloquent-2 update: a phase 3, randomized, open-label study of elotuzumab in combination with lenalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma—3-year safety and efficacy follow-up. Presented at the 57th American Society of Hematology Annual Meeting. Orlando, FL; December 5-8, 2015. Abstract 28.
10. Palumbo A, Offidani M, Pégourie B, et al. Elotuzumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma: 2-year follow-up. Presented at the 57th American Society of Hematology Annual Meeting. Orlando, FL; December 5-8, 2015. Abstract 510.
11. Moreau P, Masszi T, Grzasko N, et al. Ixazomib, an investigational oral proteasome inhibitor (PI), in combination with lenalidomide and dexamethasone (IRd), significantly extends progression-free survival (PFS) for patients (Pts) with relapsed and/or refractory multiple myeloma (RRMM): the phase 3 Tourmaline-MM1 study (NCT01564537). Presented at the 57th American Society of Hematology Annual Meeting. Orlando, FL; December 5-8, 2015. Abstract 727.
12. Voorhees PM, Mulkey F, Hassoun H, et al. Alliance A061202. a phase I/II study of pomalidomide, dexamethasone and ixazomib versus pomalidomide and dexamethasone for patients with multiple myeloma refractory to lenalidomide and proteasome inhibitor based therapy: phase I results. Presented at the 57th American Society of Hematology Annual Meeting. Orlando, FL; December 5-8, 2015. Abstract 375.
13. Dimopoulos MA, Grosicki S, Jedrzejczak WW, et al. Randomized phase 2 study of the all-oral combination of investigational proteasome inhibitor (PI) ixazomib plus cyclophosphamide and low-dose dexamethasone (ICd) in patients (Pts) with newly diagnosed multiple myeloma (NDMM) who are transplant-ineligible (NCT02046070). Presented at the 57th American Society of Hematology Annual Meeting. Orlando, FL; December 5-8, 2015. Abstract 26.
14. Durie B, Hoering A, Rajkumar SV, et al. Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT): results of the randomized phase III trial SWOG S0777. Presented at the 57th American Society of Hematology Annual Meeting. Orlando, FL; December 5-8, 2015. Abstract 25.
15. Ali SA, Shi V, Wang M, et al. Remissions of multiple myeloma during a first-in-humans clinical trial of T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor. Presented at the 57th American Society of Hematology Annual Meeting. Orlando, FL; December 5-8, 2015. Abstract LBA-1.