Advances in myeloma treatments, diagnostics have specialists ‘talking about cure’
A decade ago, patients with newly diagnosed multiple myeloma typically survived 3 to 5 years.
However, the development of highly effective therapies — including proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies — has greatly improved outcomes.
In addition to extending survival, these newer agents are associated with considerably less toxicity.
“We not only have this expectation that we’re going to make the overwhelming majority of [patients with myeloma] live for a really long time ... but we also have the expectation that they are going to be functional for most of that time to work, to play and to enjoy being with their families,” David S. Siegel, MD, PhD, chief of the division of multiple myeloma at John Theurer Cancer Center at Hackensack University Medical Center, told HemOnc Today.
“I think most [clinicians] assume a patient who is diagnosed with myeloma today will live for a decade,” Siegel added. “That is a much different mindset.”
However, formidable challenges remain for the clinical and research communities.
Comparative data on novel agents from randomized controlled trials are lacking, leaving only results of systematic reviews or meta-analyses to guide how to sequence or combine them. Investigators also aim to improve their understanding of how minimal residual disease testing can guide patient care, as well as how cellular therapies may fit into the treatment paradigm.
“We have made a lot of progress, both with treatment and diagnostics, and things have changed dramatically for the better,” Noopur S. Raje, MD, director of the Center for Multiple Myeloma at Massachusetts General Hospital Cancer Center and professor of medicine at Harvard Medical School, told HemOnc Today. “The key now is to translate this progress into a curative platform for at least a subset of our patients.”
Incidence and outcomes
Multiple myeloma incidence increased by 126% worldwide from 1990 to 2016, according to a study by Cowan and colleagues published in September in JAMA Oncology.
Myeloma mortality increased by 94% during that same period.
Researchers attributed the increases primarily to the growth and aging of the global population.
High-income North America had the second-highest age-standardized incidence rate — 5.2 cases per 100,000 persons, or more than double the worldwide average of 2.1 per 100,000 persons — and the highest age-standardized death rate at 3 per 100,000 persons, twice the global average.
An estimated 30,770 new myeloma cases will be diagnosed in the United States this year, and approximately 12,770 individuals will die of the disease, according to SEER data. However, the mortality figure is greatly underestimated because it is rare that myeloma is listed as the cause of death for individuals with the disease, Siegel said.
Only half of patients treated for myeloma between 2008 and 2014 survived 5 years, but the development of highly effective agents for the induction, maintenance and relapsed/refractory settings have greatly improved outcomes.
These agents include proteasome inhibitors, such as bortezomib (Velcade, Takeda), carfilzomib (Kyprolis, Amgen) and ixazomib (Ninlaro, Takeda); immunomodulatory drugs, such as thalidomide (Thalomid, Celgene), lenalidomide (Revlimid, Celgene) and pomalidomide (Pomalyst, Celgene); monoclonal antibodies, including elotuzumab (Empliciti, Bristol-Myers Squibb) and daratumumab (Darzalex, Janssen); and histone deacetylase inhibitors, such as panobinostat (Farydak, Novartis) and vorinostat (Zolinza, Merck).
The expanded therapeutic armamentarium provides more choices for clinicians and their patients, but it also creates more questions.
“Previously, when patients developed resistance, their outcomes were quite dismal,” Saad Z. Usmani, MD, FACP, chief of plasma cell disorders and director of clinical research in hematologic malignancies at Levine Cancer Institute at Atrium Health, said in an interview. “We would be talking about median survival of 8 to 9 months.
“Now, the big debate is: We have all of these drugs, so how do we start sequencing them to give our patients the best outcomes?” added Usmani, a HemOnc Today Editorial Board member. “I still think this is a good problem to have considering, before all of these approvals, we were asking ourselves, ‘What do I do with my patients because I don’t have any effective options?’”
Comparative data lacking
Although comparative data from randomized controlled trials are lacking, several meta-analyses have been conducted to try to determine the most effective treatment approaches.
Sekine and colleagues performed a systematic review and meta-analysis to identify the best frontline induction therapy for patients eligible for autologous hematopoietic stem cell transplant. The analysis — published in August in Hematological Oncology — included data from 21 clinical trials (n = 6,474) that compared 11 different frontline regimens.
OS results showed induction treatment with cyclophosphamide, lenalidomide and dexamethasone was superior to thalidomide/dexamethasone-based regimens (HR = 0.76; 95% CI, 0.62-0.9); vincristine/doxorubicin/dexamethasone-based regimens (HR = 0.71; 95% CI, 0.52-0.9); and idarubicin/dexamethasone (HR = 0.37; 95% CI, 0.17-0.76).
PFS analysis showed treatment with bortezomib, thalidomide and dexamethasone was superior to thalidomide/dexamethasone-based regimens (HR = 0.66; 95% CI, 0.51-0.84); vincristine/doxorubicin/dexamethasone-based regimens (HR = 0.61; 95% CI, 0.46-0.82); idarubicin/dexamethasone (HR = 0.42; 95% CI, 0.22-0.78); and high-dose dexamethasone alone (HR = 0.62; 95% CI, 0.410.9).
“Our study endorses current recommendations on combined immunomodulatory drugs and proteasome inhibitors [as] frontline regimens (in triplets) in transplant-eligible [patients with multiple myeloma], but also formally demonstrates the favorable performance of lenalidomide in overall and progression-free survival when compared with bortezomib/thalidomide protocols,” researchers wrote.
Gay and colleagues conducted a meta-analysis of 11 phase 3 trials (n = 5,073) to compare the effectiveness of different maintenance regimens for newly diagnosed myeloma.
The results, published in October in JAMA Oncology, showed lenalidomide/prednisone (HR = 0.39; 95% CI, 0.28-0.53) and lenalidomide alone (HR = 0.47; 95% CI, 0.39-0.55) conferred better PFS than no maintenance/placebo, interferon, thalidomide alone, thalidomide/bortezomib, thalidomide/interferon, lenalidomide/prednisone and bortezomib/prednisone.
OS analyses showed lenalidomide alone (HR = 0.76; 95% CI, 0.51-1.16) was the most effective option, followed by bortezomib/thalidomide and bortezomib/prednisone.
Luo and colleagues conducted a meta-analysis of 24 randomized controlled trials to assess treatment options for relapsed/refractory myeloma. They determined the combination of daratumumab, lenalidomide and dexamethasone likely is the most efficacious.
Although these analyses were designed to inform treatment decisions, conclusions are impossible to draw because the patient populations are so different, Usmani said.
Until definitive comparative data are available, treatment choices must be personalized, he added.
“Physicians have to look at the patient populations that were included in each of those clinical trials and determine if that scenario fits with their patient,” Usmani said. “We must look at patient factors, disease factors and treatment factors before we decide the next best course of action.”
Factors such as performance status, symptoms, age, comorbidities, risk factors and prior treatments — along with patients’ social support and distance from an infusion center — should be considered.
“The No. 1 factor is: What are the goals of therapy? Is it prolonged life, or do you want the most aggressive treatment to try to get them into complete remission while, at the same time, preserve their quality of life?” Henry Chi Hang Fung, MD, FACP, FRCPE, vice chair of the department of hematology/oncology and chief of the section of hematologic malignancies at Fox Chase Cancer Center, as well as director of the Fox Chase-Temple University Hospital bone marrow transplant program, told HemOnc Today.
Role of transplant
Standard treatment for myeloma consists of induction followed by autologous HSCT for eligible patients.
Due to the success of novel agents, debate has intensified about transplant’s role moving forward.
“There is this instinctive need to find something that gets rid of stem cell transplant, but the reality is no one has ever demonstrated that undergoing stem cell transplant doesn’t lead to better outcomes,” Siegel said. “Stem cell transplants put patients into a lottery to do really well for a really long period of time.”
“As of right now, transplant is here to stay,” she said. “Even the most recent data, in the context of new drugs, show transplant does better.”
Dhakal and colleagues conducted a systematic review and meta-analysis of randomized phase 3 trials to evaluate the role of high-dose therapy with melphalan followed by autologous stem cell transplant. A conventional meta-analysis included four trials (n = 2,421) and a network meta-analysis included five trials (n = 3,171).
Results, published in March in JAMA Oncology, showed combined HRs of 0.55 (95% CI, 0.41-0.74) for PFS and 0.76 (95% CI, 0.42-1.36) for OS in favor of high-dose melphalan and transplant compared with standard-dose therapy using novel agents.
“About 10% of patients will stay in remission for about a decade and, of those, about half will stay in remission for 2 decades,” Siegel said.
A study by Jain and colleagues, presented in February at BMT Tandem Meetings, showed upfront high-dose chemotherapy plus autologous HSCT prolonged PFS compared with standard-dose chemotherapy or delayed transplantation among patients with newly diagnosed myeloma (HR = 0.73; 95% CI, 0.56-0.94).
Fung emphasized the importance of early transplant for eligible patients, noting they may not be candidates when they are older or after they undergo a few years of other therapies. In contrast, upfront HSCT does not make a patient ineligible for treatment with novel agents.
Despite the benefits of HSCT, studies have shown the procedure is underused among transplant-eligible patients with newly diagnosed myeloma.
Rosenberg and colleagues used the California Cancer Registry to identify 13,494 patients diagnosed with myeloma between 1998 and 2012. They published their findings in June in Journal of the National Cancer Institute.
Approximately one in five (20.8%) patients analyzed underwent autologous HSCT (median time to transplant, 9.4 months).
Median OS for those who underwent autologous HSCT was 72.9 months (95% CI, 68-78).
Researchers observed improved OS with autologous HSCT at any time (adjusted HR = 0.83; 95% CI, 0.75-0.92). However, patients who underwent autologous HSCT more than 1 year after diagnosis achieved shorter OS (adjusted HR = 1.33; 95% CI, 1.16-1.51).
A study by Ailawadhi and colleagues showed racial and geographic disparities persist in transplant for myeloma.
They used the National Cancer Database to identify 15,021 patients who underwent HSCT as part of initial therapy for myeloma between 2004 and 2013. The majority (77.5%) were non-Hispanic white, whereas 15.1% were non-Hispanic black, 5.2% were Hispanic and 2% were non-Hispanic Asian.
Higher median income appeared associated with increased likelihood of HSCT among non-Hispanic whites and Hispanics, and higher education appeared associated with HSCT receipt among non-Hispanic whites and non-Hispanic blacks.
The trend is a matter of education, according to Raje, a co-author of upcoming ASCO guidelines for myeloma treatment.
“It’s really important for the community oncologist to understand patients should be evaluated by a physician whose expertise is in the disease stage or a transplant center before anyone is labeled as a nontransplant candidate,” Raje said. “In our consensus guidelines, we recommend that all patients be referred to or be evaluated by people with that expertise.”
Misconceptions also play a role, Siegel said.
“If you say ‘transplant’ to someone, even someone who doesn’t know anything about it, it sounds like a horrible thing,” Siegel said. “The word has a lot of negative connotations. I think that instinct is there for oncologists as well as patients, and I don’t think it’s justified.”
Clinicians can help by reminding patients that autologous HSCT is safe, Fung said. Treatment-related mortality is less than 1%.
“I need to remind patients not to Google,” Fung said. “Less than 1% is probably safer than any major surgery. It’s safer than a drive on the freeway.”
CAR T-cell therapy
The potential of chimeric antigen receptor (CAR) T-cell therapy has generated tremendous excitement in the myeloma community.
As of late November, the FDA had approved two CD19-directed CAR T-cell therapies for hematologic malignancies.
Tisagenlecleucel T-suspension (Kymriah, Novartis) is approved for the treatment of certain children and young adults with ALL or large B-cell lymphoma. Axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead) is approved for treatment of certain adults with relapsed or refractory large B-cell lymphoma.
Given the success of this modality in other blood cancers, research has intensified into its use for myeloma treatment. Although most investigations are still early, the data are encouraging.
Raje presented data at this year’s ASCO Annual Meeting on bb2121 (Bluebird Bio), a second-generation CAR T-cell therapy that targets B-cell maturation antigen (BCMA), which is found on essentially all myeloma tumor cells.
A dose-escalation trial included 22 patients (median age, 65 years) who previously received daratumumab and were refractory to their last line of therapy.
“These were patients who really had no other treatment options,” Raje said.
Data from 18 evaluable patients showed a 94% overall response rate, with 56% of patients achieving complete remission or unconfirmed complete remission.
Median PFS was 11.8 months among the entire cohort and 17.7 months for those who tested negative for minimal residual disease (MRD). Eighty-one percent of patients remained progression free at 6 months, and 71% were progression free at 9 months.
Researchers observed no dose-limiting toxicities, and no grade 3 or higher neurotoxicities.
Grade 1/grade 2 cytokine release syndrome occurred among 71% of the cohort, and two patients experienced grade 3 or higher cytokine release syndrome that resolved in 1 day.
P-BCMA-101 (Poseida Therapeutics) is another BCMA-targeting CAR T-cell product under investigation. Early data showed this therapy appeared safe for the treatment of patients with relapsed/refractory myeloma.
Poseida Therapeutics released data in September from 11 patients (median age, 60 years) in an ongoing phase 1 trial. The analysis included patients who underwent a median six prior therapies, and 73% were considered high risk.
Overall, the agent appeared safe, with one instance (9%) of suspected cytokine release syndrome that appeared minimal and short-lived.
Researchers observed no patients with neurotoxicity and no ICU admissions. No patients required treatment with tocilizumab (Actemra, Genentech) or steroids.
At the time of reporting, all 11 patients remained in the study, with seven of 10 having achieved at least a partial response using International Myeloma Working Group criteria.
“There are many other targets other than BCMA,” Siegel said. “We are going to see multitarget CAR T cells. We’re going to see all kinds of technical strategies in order to improve the ease with which we do these trials. There will be off-the-shelf CAR T-cell studies.
“It is going to be a breakthrough,” Siegel added. “Whether it will be a breakthrough like what we see in lymphoma and leukemia, we will have to wait and see, but I do think we should be very excited.”
One of the biggest concerns about CAR T-cell therapy is its cost, and clinicians are still uncertain about how these therapies will be reimbursed.
The list price for axicabtagene ciloleucel in the United States is $373,000, and tisagenlecleucel T-suspension is priced at $475,000.
The price of one-time CAR T-cell infusions should be put into context, Raje said.
“Myeloma therapies are not inexpensive, and we use continuous therapies,” she said.
For example, the cost for 1 year of therapy with lenalidomide, bortezomib and dexamethasone is $200,000, and this therapy can be administered for multiple years.
“Cost is always high when you are developing a new drug,” Raje said. “There are a bunch of different CAR T-cell therapies that will be developed, so competition will bring the cost down.
“Ultimately, it is unclear how CAR T-cell therapy will be covered,” she added. “That is an evolving issue, and I do not think we need to worry about that so much at this stage.”
Access may be a more urgent concern, as very few centers are able to administer CAR T-cell therapy.
“If a patient cannot access the treatment, whatever you have doesn’t really matter,” Fung said.
Pharmaceutical companies are taking steps to open more centers that can administer approved therapies, Raje said.
“Now the question is: Can something like cellular therapy replace transplant?” Raje said. “We don’t know the answer to that, and that would rely on us having to do clinical trials in the early stage.”
Beyond the excitement surrounding CAR T-cell therapy, researchers also are intrigued by BCMA-targeting off-the-shelf products, which may help address the issues of cost and accessibility.
BCMA is a “lucrative target” for myeloma treatment, Usmani said.
“It is very important in the biology of plasma cells, but it’s also very important because it is largely expressed on plasma cells and very few other cells,” Siegel added. “When you target BCMA, you’re not targeting a lot of other stuff that is important in terms of limiting toxicities.”
GlaxoSmithKline developed GSK2857916, an anti-BCMA monoclonal antibody-drug conjugate that is being assessed in the DREAMM-1 trial.
One cohort included 35 patients (median age, 60 years; range, 46-75) with relapsed/refractory myeloma who underwent stem cell transplant if eligible and had at least three prior lines of therapy, including alkylators, proteasome inhibitors and an immunomodulatory drug.
Data presented at last year’s ASH Annual Meeting and Exposition showed an overall response rate of 60% (95% CI, 42.1-76.1), including two complete responses, one stringent complete response, 15 very good partial responses and three partial responses.
Media PFS was 7.9 months (95% CI, 3.1-not estimable).
The FDA granted GSK2857916 breakthrough therapy and orphan drug designations.
“I have not a seen a monoclonal antibody perform as well as this one,” Raje said. “It’s much better than even single-agent daratumumab, with a PFS of close to 8 months.”
Eighty percent of patients experienced grade 3 or grade 4 adverse events, and 14% experienced serious adverse events. Twenty-three percent of patients developed infusion-related reactions.
Two-thirds of patients required dose modification. The most common grade 3 or grade 4 events were thrombocytopenia (34%) and anemia (14%).
Another key research area is bispecific T-cell engager antibodies, also known as BITEs.
“BITEs target a specific protein on the tumor cells. They engage and activate the T cells and bring them close to the tumor to do their job,” Raje said. “It’s an immune-based approach, and we have several BITEs that are in clinical trials against BCMA.”
In September, Amgen reported initial data from its ongoing phase 1 trial assessing AMG 420, a BCMA-targeting BITE, for the treatment of patients with relapsed/refractory myeloma.
Five patients achieved a stringent complete response, with four having negative minimal residual disease for more than 10 months.
“BITEs are really early in development,” Raje said. “We have some data, but I’m sure there will be more data at ASH this year. It’s an exciting avenue.”
Minimal residual disease
In September, the FDA granted marketing authorization to the first next-generation sequencing-based test designed to detect MRD among patients with myeloma or acute lymphoblastic leukemia.
The clonoSEQ Assay (Adaptive Biotechnologies) is an in vitro diagnostic that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from bone marrow.
Standard detection methods include flow cytometry assays or polymerase chain reaction-based assays, many of which can measure MRD to levels as low as 1 per 100,000 cells.
The clonoSEQ Assay can detect MRD at levels below 1 per 1 million cells, according to an FDA-issued press release.
“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last,” FDA Commissioner Scott Gottlieb, MD, said in the release.
The FDA evaluated data from a retrospective analysis of samples obtained from 1,029 patients with myeloma. The clonoSEQ Assay showed MRD-negative patients achieved longer PFS, while those with higher MRD assay results achieved shorter PFS.
The availability of such a highly sensitive test can help providers manage their patients’ care, Gottlieb said.
“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving next-generation sequencing tests are accurate and reliable,” Gottlieb said. “At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA. We’re doing as much as we can to advance these opportunities for patients under our current authorities.”
Effective tests could help guide treatment and better understand disease progression.
“There are lots of tools out there,” Raje said. “How we use them and where we use them will be the challenge going forward.”
Fung and Raje said they hope furthering the understanding of MRD may help define “cure” for patients with myeloma.
“How do we know if myeloma is cured?” Fung said. “If I have patients who have had disease control for more than 10 years, are they cured? And what treatment did they have? Who are these people? We need to determine how to define ‘cure.’”
Progress definitely has been made, Raje said.
“I think the excitement is the fact that we’re even talking about ‘cure’ at this stage because we do strongly believe we have the tools in place to be able to get there,” Raje said.
Collaboration is key
Collaboration and data sharing have been — and will continue to be — important to advancing myeloma treatment.
“How can you get all these patients on study?” Fung asked. “It’s a very rare disease, and many of them have comorbidities. This has to be addressed through more collaborations.”
ASH has embraced this approach through its newly created multiple myeloma registry.
Academic institutions, pharmaceutical companies and international partners can contribute data, and researchers and clinicians can use the registry to answer clinically relevant questions.
“Myeloma is an orphan disease, so no one center can collect enough data in order to understand the complexity of the biology and the implications it has for treatment,” Kenneth C. Anderson, MD, program director of Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, told HemOnc Today.
“ASH is an international organization focused on hematologic disorders and blood cancers and is the ideal setting in which to collect this data internationally so that we can, on the one hand, answer relevant scientific and clinical questions and queries and, on the other hand, ultimately help to inform clinical practice,” added Anderson, who served as ASH president in 2017.
The registry includes patient-level data that is clinically annotated and often genomically profiled. The data is deidentified to comply with HIPAA.
ASH built the registry so data can be deposited in an ongoing fashion, evolving as myeloma therapies change.
The Biden Foundation, which launched the Biden Cancer Initiative, featured the ASH multiple myeloma registry as one of the innovative collaborative collections of data that could change cancer treatment.
“We have all of the relevant stakeholders — including clinicians, research, industry and FDA — as members all pulling together on behalf of, and to make sure that, patients benefit from the wonderful scientific advances and that they really benefit in terms of diagnostic, prognostic and treatment advances,” Anderson said.
The ASH registry is still in the data collection phase. An oversight committee has been established, as has a myeloma registry subcommittee that will oversee the data collection and use.
“While the excitement in science and clinical medicine is palpable these days, it really only matters if we can ultimately make these advances come to the bedside — not only in North America but around the world,” said Anderson, chair of the registry subcommittee. “I do think that the ASH registry will really help fast-forward that goal and assure that patients internationally benefit from all of this progress.” – by Cassie Homer
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For more information:
Kenneth C. Anderson, MD, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Mayer 557, Boston, MA 02215; email: firstname.lastname@example.org.
Henry Chi Hang Fung, MD, FACP, FRCPE, can be reached at Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111-2497; email: email@example.com.
Noopur S. Raje, MD, can be reached at Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114; Twitter: @NoopurRajeMD; email: firstname.lastname@example.org.
David S. Siegel, MD, PhD, can be reached at John Theurer Cancer Center, Hackensack University Medical Center, 92 Second St., Third Floor, Hackensack, NJ 07601; email: email@example.com.
Saad Z. Usmani, MD, FACP, can be reached at Levine Cancer Institute at Atrium Health, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: firstname.lastname@example.org.
Disclosures: Anderson reports advisory board roles with Celgene and Millennium. Fung reports consultant roles with Amgen and Sanofi. Raje reports consultant roles with Amgen, Bristol-Myers Squibb, Celgene, Janssen and Takeda. Siegel reports speakers bureau roles with Amgen, Bristol-Myers Squibb, Celgene, Janssen and Takeda. Usmani reports consultant/advisory or speakers bureau roles with Amgen, Celgene, Janssen, Millennium, Onyx, Sanofi, Skyline and Takeda, as well as research funding from Array BioPharma, Bristol-Myers Squibb, Celgene, Janssen, Onyx, Pharmacyclics, Sanofi and Takeda.