Immunotherapy, triplet regimens drive ‘unprecedented’ progress in myeloma

Treatment advances have nearly doubled short-term survival for patients with multiple myeloma in the past 40 years.

Despite the progress, 5-year survival — which stood at 25% in 1975 — still remains below 50%, according to SEER data.

Further, relapse rates are high, and standard-of-care protocols for untreated and relapsed multiple myeloma — including proteasome inhibitors like bortezomib (Velcade, Millennium Pharmaceuticals) and chemotherapy — do not consistently yield positive outcomes.

Multiple myeloma, a hematologic malignancy that inhibits the development of healthy blood cells, remains relatively rare. Approximately 27,000 people will be diagnosed with the disease in 2015, and fewer than 100,000 people currently live with the disease in the United States, according to SEER data.

Despite the rarity of the disease, the advent of immunotherapy and use of monoclonal antibodies have created new avenues for research and treatment. Investigators presented several studies of novel agents or combination therapy at this year’s ASCO Annual meeting.

Photo by Claudia Morales de Partovi

“We have patients who need effective treatment despite receiving many prior therapy lines,” Elisabet E. Manasanch, MD, MHSc, assistant professor in the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “The field of immunotherapy is growing, and there has been a lot of interest in testing these drugs in multiple myeloma and other hematologic malignancies.”

Yet, with so many novel agents under investigation, researchers must determine the ideal settings for each. Patient selection and each agent’s unique toxicity profile are key considerations.

It also is unclear whether positive results observed in clinical trials can be replicated in larger patient populations.

“Clinical trials are the best way that we have to evaluate new medications and determine their efficacy for the treatment of multiple myeloma,” Manasanch said. “They are also important for patients to be able to access treatments that would otherwise not be available to them. The myeloma community, including patients, caregivers, physicians and other health care providers, and industry partners have been very successful in working together to develop new, more effective treatment options, as reflected by the ever-improving outcomes.”

HemOnc Today spoke with multiple myeloma specialists about the multitude of clinical trials underway, the encouraging results presented thus far, and the challenges inherent in studying and treating a rare and often aggressive disease.

A refractory population

The ASCO Annual Meeting spotlighted tremendous advances in clinical research in multiple myeloma, especially for the treatment of patients with relapsed disease.

Proteasome inhibition and immunomodulatory drugs — such as lenalidomide (Revlimid, Celgene) and pomalidomide (Pomalyst, Celgene) — have been the cornerstones of multiple myeloma treatment, Noopur Suresh Raje, MD, director of the Multiple Myeloma Program at Massachusetts General Hospital, told HemOnc Today. “However, patients continue to relapse after treatment with bortezomib and other standard agents,” Raje said.

Consequently, new treatment options are urgently needed for patients in the relapsed setting.

Results of the multicenter, open-label, randomized phase 3 ENDEAVOR trial — presented at ASCO by Dimopoulos and colleagues — showed the second-generation proteasome inhibitor carfilzomib (Kyprolis; Onyx Pharmaceuticals, an Amgen subsidiary) and dexamethasone significantly extended PFS compared with standard bortezomib in patients with relapsed multiple myeloma (18.7 months vs. 9.4 months). Further, significantly more patients assigned the carfilzomib combination responded to treatment (76.9% vs. 62.6%; P < .0001), with more than half of patients achieving a very good or better partial response (54.3% vs. 28.6%).

“It is important to appreciate the patient population for the ENDEAVOR trial,” Saad Z. Usmani, MD, director of clinical research and plasma cell disorders in the department of hematologic malignancies at Levine Cancer Institute at Carolinas HealthCare System and a HemOnc Today Editorial Board member, said in an interview. “Over half of the patients were exposed to immunomodulatory drugs or had lenalidomide as part of their initial therapy. A little less than 50% had exposure to bortezomib in the past, but they were not refractory to it. If you have a patient who originally had a bortezomib-based regimen, this would be one of the possible treatment options for such a patient.”

However, the fact that many patients had already received bortezomib may call the results of ENDEAVOR into question, Raje said.

“Carfilzomib was used in higher doses [in the ENDEAVOR trial than we use in practice],” Raje said. “Because so many patients had been treated with bortezomib, what we were likely seeing was retreatment with bortezomib versus treatment with carfilzomib. Although carfilzomib does seem to have a fair amount of efficacy in the higher doses, I don’t think this is the fairest of randomized trials. It was designed in such a way that carfilzomib would win.”

Researchers also are evaluating the efficacy of monoclonal antibodies for the treatment of relapsed multiple myeloma.

Daratumumab (Janssen and Genmab) is a monoclonal antibody that attaches to CD38-expressing cancer cells — prevalent in multiple myeloma — and induces cell death, Usmani said.

Sagar Lonial, MD, chief medical officer of Winship Cancer Institute of Emory University, professor and executive vice chair of the department of hematology and medical oncology at Emory University School of Medicine and a HemOnc Today Editorial Board member, and colleagues evaluated single-agent daratumumab in a phase 2 trial of patients with heavily pretreated multiple myeloma refractory to proteasome inhibitors and immunomodulatory agents.

“This is an area of need within multiple myeloma,” said Usmani, who served as an investigator on the daratumumab trial. “The median prior lines of therapy for this patient population was five and beyond, which is a very refractory patient population.”

Results — presented at ASCO — showed responding patients had a median response duration of 8 months and a median PFS of 3.7 months.

“We found that 29% of patients had a 50% or better reduction to their multiple myeloma burden,” Usmani said.

These results are quite stunning given the patient population, Lonial told HemOnc Today.

“The response rate [to daratumumab] was independent of how many prior lines of therapy a patient had or whether they were refractory to carfilzomib, pomalidomide or both,” Lonial said. “It is worth noting that there were three patients on this trial who achieved a stringent complete response and 10 patients who achieved a very good partial response. Using a novel mechanism of action, we were able to achieve not just any response, but complete responses and very good partial responses. That is quite notable.”

Daratumumab has demonstrated the most significant single-agent activity of a monoclonal antibody in this setting to date, according to Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Kipper Multiple Myeloma Center at Dana-Farber Cancer Institute, professor of medicine at Harvard Medical School and a HemOnc Today Editorial Board member.

“There are breakthrough data,” Richardson told HemOnc Today. “[This trial] included an end-stage population of patients with an unmet medical need. It is a very exciting time in multiple myeloma, and these antibodies are arguably the biggest breakthrough.”

Triplet therapies

Three-drug combinations of novel monoclonal antibodies or proteasome inhibitors, immunomodulatory drugs and standard regimens have also shown promise for patients with relapsed multiple myeloma. The phase 3 ELOQUENT-2 trial — the results of which Lonial and colleagues presented at ASCO — evaluated the addition of the immunotherapeutic monoclonal antibody elotuzumab (Bristol-Myers Squibb and AbbVie) to lenalidomide and dexamethasone.

“Phase 1 and phase 2 data showed that the overall response rate and duration of response for patients treated with elotuzumab were better than historical cohorts of patients who received lenalidomide and dexamethasone alone,” Lonial said. “The early trials showed us that the response rates were better [with elotuzumab] and the durations of response were two to three times longer, which gave rise to a phase 3 trial.”

The analysis included 646 patients with relapsed multiple myeloma who previously underwent one to three lines of treatment. Thirty-five percent of patients in the trial were refractory to their most recent therapy.

The researchers observed a median PFS of 19.4 months (95% CI, 16.6-22.2) among patients assigned the elotuzumab combination, compared with 14.9 months (95% CI, 12.1-17.2) among patients assigned lenalidomide and dexamethasone alone.

Further, elotuzumab conferred a 30% reduction in the risk for progression (HR = 0.7; 95% CI, 0.57-0.85).

“The results of ELOQUENT-2 convincingly demonstrate that there is a clinical benefit — or clinical advance — with elotuzumab use, with an impressive PFS advantage,” Richardson said. “Three-drug combinations appear to have won the day.”

However, the fact researchers evaluated elotuzumab in a triplet must be considered when evaluating the agent’s efficacy, Raje said.

“Elotuzumab has no single-agent activity,” Raje said. “As long as lenalidomide and dexamethasone remain the comparison, the addition of elotuzumab might deepen the responses, — which ELOQUENT-2 showed — translating to the 4- to 5-month PFS benefit.”

Jakubowiak and colleagues also presented data at ASCO evaluating elotuzumab in combination with bortezomib for patients with relapsed/refractory multiple myeloma.

“I was not impressed by the phase 2 data combining elotuzumab with bortezomib,” Raje said. “The PFS benefit was 2 or 3 months, which was statistically significant. But anything can be statistically significant if you enroll the right number of patients on the trial.”

Despite elotuzumab’s lack of single-agent activity, the combination therapy may represent a breakthrough for immunotherapy in this patient population, Usmani said.

“We have to recognize that the way elotuzumab works is different from other agents,” Usmani said. “Elotuzumab works with lenalidomide and dexamethasone to increase natural-killer cell activity against myeloma cells. The investigators have shown that some of the patients who are responding have very durable responses, which is a change in paradigm — using the immune system through monoclonal antibodies to maintain patient response.”

Stewart and colleagues presented data on a promising triplet for multiple myeloma at the ASH Annual Meeting and Exposition in December. Researchers designed the phase 3 ASPIRE trial to evaluate the addition of carfilzomib to standard lenalidomide and dexamethasone.

Patients assigned the triplet achieved a median PFS of 26.3 months (95% CI, 23.3-30.5), which was significantly longer than the 17.6-month (95% CI, 15-20.6) median PFS observed among patients assigned lenalidomide and dexamethasone alone (P < .0001). Although median OS had not yet been reached at the time of the analysis, patients assigned the triplet demonstrated a trend toward improved survival.

“ASPIRE validated the synergy of a proteasome inhibitor–immunomodulatory platform, compared with an immunomodulatory and steroid platform alone,” Richardson said. “The improvement in PFS was dramatic.”

Further, more patients assigned the triplet achieved 24-month EFS (73.3% vs. 65%). The ORR appeared higher with the carfilzomib combination (87.4% vs. 66.9%), and 31.8% of patients assigned the triplet achieved a stringent complete response or complete response compared with 9.4% of patients in the comparison arm.

Based in part on the results of the ASPIRE trial, the FDA in July expanded the approval of carfilzomib to include use in combination with lenalidomide and dexamethasone for patients who received one to three prior lines of therapy.

“Three-drug platforms are being validated in study after study,” Richardson said. “In the relapsed setting, clinicians should be generally thinking about a triplet, especially in a case of aggressive relapse. Moving outside of clinical trials, three drugs seems to make more sense than two.”

Although the initial results of these trials have largely been positive, it may take time before clinicians can determine the appropriate setting for each new therapeutic regimen, Lonial said.

“We need a little bit more data and a little bit more follow-up,” Lonial said. “Survival data are going to be very important. Once we gather a bit more data, we can properly assess which patients would benefit the most from any given treatment.”

Lingering questions: Populations, toxicities

Standards of care differ from country to country, largely because of treatment practices and the availability of therapeutic agents.

“U.S. trials have great relevance to U.S. populations,” Richardson said. “Simply extrapolating from what is available offshore and saying that this is what should guide American practice is something to be taken with great caution.”

The ASPIRE trial recruited patients from 20 treatment centers, many of them outside of the U.S. Consequently, the results may not translate to a U.S.-specific patient population, according to Raje.

“There would have been very few patients in the U.S. who would have qualified for the ASPIRE trial,” Raje said. “These patients had to be lenalidomide sensitive, and they should not have previously had carfilzomib. The way practice is today, most patients in the U.S. receive lenalidomide maintenance if they have undergone a transplant, and if they progress, they progress on lenalidomide. Although we will likely see some benefit, I do not think we will see the same level of benefit that we saw in the trial setting.”

However, this issue extends beyond the ASPIRE trial.

“Most phase 3 trials in myeloma — especially in the relapsed or refractory space — have historically accrued better in Europe than the U.S.,” Usmani said. “Most European countries do not have access to drugs unless a patient is on a clinical trial. Eighty percent of cancer care [in the U.S.] is done in the community setting, so only a small portion takes place at an academic center. It is challenging to enroll patients who have not been exposed to carfilzomib or pomalidomide, because community practitioners are very comfortable prescribing these drugs.”

The ability to include American patients in clinical trials will determine how treatment of multiple myeloma evolves in the United States, Richardson said.

“Encouraging American patients [who are eligible] to participate in clinical trials is not only important for the field based on the help it could provide future patients, but for helping themselves,” Richardson said. “When we look at offshore data, it is important to remember that it is influenced by what goes on in those countries’ health care systems, which is not superimposable on what we do in the U.S.”

Manasanch agreed.

“Most patients want to help, if they can,” she said. “Trials are much better at constructing more open inclusion criteria now, as well. Myeloma trials are becoming more and more reasonable. For example, the recent daratumumab study shows evidence of an excellent collaboration where the patient population clearly reflects what we see in the clinic on a daily basis.”

Significant toxicities that occurred during clinical trials have been another area of concern.

“The ENDEAVOR trial uncovered some of the toxicities that we have always been worried about with carfilzomib,” Richardson said. “Namely, we saw cardiac failure, pulmonary events and renal failure at higher rates among patients who received carfilzomib.”

Patients assigned carfilzomib in the ASPIRE trial experienced higher rates of thrombocytopenia (16.6% vs. 12.3%), dyspnea (22.4% vs. 18%), hypertension (all grade: 14.3% vs. 6.9%; grade 3: 4.3% vs. 1.8%) and cardiac failure (6.4% vs. 4.1%) than patients assigned the two-drug combination. Based on these data, the FDA required new label warnings for venous thromboembolism, cardiac toxicities, acute renal failure, pulmonary toxicities and hypertension, as well as increased safety risks and mortality warnings for elderly patients. “This is the opposite of what you see with bortezomib,” Richardson said. “I think it would be premature, then, to say that carfilzomib is replacing bortezomib.”

More than 40% of patients assigned daratumumab in the trial conducted by Lonial and colleagues experienced a grade 1 or grade 2 infusion-related reaction. However, only 4.7% of patients discontinued treatment due to adverse events.

“The infusion reactions were the only real adverse event of note,” Lonial said. “And 90% of the [patients who] had a reaction had it with their first dose.”

Potential for cure

The abundance of positive data from phase 3 trials has many investigators in the field convinced this is a watershed moment for multiple myeloma.

“These last 6 months have been unprecedented — not just in the number of advances being reported, but also in the breadth of advances,” Richardson said.

In light of this progress, the potential for a cure for multiple myeloma seems as strong as ever, Lonial said.

“We are going to cure a much higher percentage of patients with multiple myeloma in 10 years than we are now,” Lonial said. “The ability to use monoclonal antibodies is going to be a huge breakthrough for our patients. We are now using second- or third-generation proteasome inhibitors and immunomodulatory drugs, where you may improve potency or adverse-event profiles with the same mechanism as what we have had. Antibodies and other immune-based therapies will offer us the ability to think about long-term strategies of managing multiple myeloma that will allow the host immune system to play an important role.”

Despite the positive outcomes, the idea of curing multiple myeloma in the near future might be premature, Richardson said.

“We have to be very careful talking about a cure,” Richardson said. “Many people still die too quickly from this disease. This remains a very formidable and dangerous illness, even as we have improved outcomes over the last decade, with significant gains in disease control for longer periods. Arguably, we may be getting closer to what I may consider a ‘functional cure,’ meaning that patients are more likely to die from something else.”

Raje emphasized it will be important to study not only which drugs work, but how they work as they become available outside of clinical trials.

“A challenge for the future — and we can view it as a good challenge — is how to use these drugs most efficaciously,” Raje said. “These drugs are not cheap, so a big part of development will be determining how long patients can remain on treatment. We will need to learn how we can use them to the best of our ability.”

Although the survival rate for multiple myeloma remains lower than that of other cancers, there is reason to not only hope for a cure, but to view it as a distinct possibility, Manasanch told HemOnc Today.

“When I started working at MD Anderson I was very fortunate to be able to see some patients treated by Raymond Alexanian, MD, after he retired from his clinical practice after spending many years in the myeloma field,” Manasanch said. “One of his patients that had been diagnosed with a severe case of myeloma 20 years prior came to clinic and still remained free of disease. Although this is not yet the norm and more research is needed, some patients are probably already achieving functional cures.” – by Cameron Kelsall

References:

Lonial S, et al. J Clin Oncol. 2012;doi:10.1200/JCO.2011.37.2649.

Stewart AK, et al. Abstract 79. Present at: ASH Annual Meeting; December 6-9, 2014; San Francisco.

The following were presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Dimopolous MA, et al. Abstract 8509.

Jakubowiak AJ, et al. Abstract 8003.

Lonial S, et al. Abstract 8508. Lonial S, et al. Abstract LBA8512.

For more information:

Sagar Lonial, MD, can be reached at Winship Cancer Institute of Emory University, 1365 Clifton Road NE, Building C, Atlanta, GA 30322; email: sloni01@emory.edu.

Elisabet E. Manasanch, MD, MHSc, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: eemanasanch@mdanderson.org.

Noopur Suresh Raje, MD, can be reached at Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114.

Paul G. Richardson, MD, can be reached at Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115; email: paul_richardson@dfci.harvard.edu.

Saad Z. Usmani, MD, can be reached at Levine Cancer Institute, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: saad.usmani@carolinashealthcare.org.

Disclosure: Lonial reports consultant roles with Bristol-Myers Squibb, Celgene, Janssen, Millennium, Novartis and Onyx. Manasanch reports an advisory role with Seattle Genetics. Raje reports consultant roles with Amgen, Celgene, Janssen, Millennium, Novartis and Takeda. Richardson reports advisory roles with Genmab, Millennium, Onyx and Takeda. Usmani reports consultant and speakers bureau roles with Celgene, Millennium, Onyx and Sanofi, as well as research funding from Array BioPharma, Celgene, Janssen, Millennium and Onyx.

 

 

Should stem cell transplantation remain the preferred first-line treatment for patients with multiple myeloma?

Autologous stem cell transplant continues to be recommended as part of first-line therapy in eligible newly diagnosed patients.

The use of the novel agents thalidomide (Thalomid, Celgene), lenalidomide (Revlimid, Celgene) and bortezomib (Velcade; Takeda, Millennium) in combinations and with dexamethasone in newly diagnosed patients with multiple myeloma (MM) have remarkably improved the overall response rate (ORR), depth of response (DOR), length of response (LOR) and OS compared with older agents — vincristine/doxorubicin/dexamethasone or cyclophosphamide combination.

On average, ORR has improved from 50%-60% to 80%-100%, complete response from 16%-25% to 40%-60%, 5-year OS from 30%-40% to 60%-80%, and LOR from 15 months to 25-30 months. The LOR is now even better with the use of maintenance — low-dose therapy — after initial treatment with induction with or without autologous stem cell transplant (ASCT), with an average improvement from 23-27 months to 41-53 months among patients who undergo ASCT and from 14 months to 31 months among patients who do not.

The standard of treatment in MM is induction — initial chemotherapy to reduce burden of the disease — followed by consolidation with ASCT, followed by maintenance. The use of ASCT as a consolidation treatment after induction treatment in eligible newly diagnosed patients with MM has been the standard of care since the 1990s after several studies showed its benefits. These studies were of course done before the use of the novel agents. The two trials definitively supporting early ASCT were from the French Intergroup study (IFM90) and the Medical Research Council Myeloma VII trial, which demonstrated an approximate 12-month improvement in OS for patients aged younger than 65 years. The studies showed both an improved LOR and OS by 12 to 15 months. Smaller trials that demonstrated only an improvement in LOR for transplant added less effective agents (eg, total body radiation or busulfan) to the conditioning regimen. An earlier transplant also was shown to improve quality of life more than a later transplant. A meta-analysis that combined all of these studies showed a significant benefit for early ASCT.

With the improvement in all of the above spectra with the use of the novel agents, the use of early ASCT as part of first-line treatment is now being questioned. The big question is, “Can ASCT be delayed until relapse or progression?” This question is not fully answered. The study by the Italian group suggests that early ASCT continues to be beneficial. In this study, 273 newly diagnosed patients were initially treated with lenalidomide and dexamethasone for four cycles followed by either two ASCT cycles then maintenance with lenalidomide (ASCT arm) or treatment with melphalan/lenalidomide/prednisone (non-ASCT arm) for six cycles then maintenance. Results showed that the average LOR was better in the ASCT arm (54.7 mos) than the non-ASCT arm (34.2 mos). The 5-year OS was not significantly different (78.4% vs. 70.2%). The DETERMINATION (IFM/DFCI2009; NCT01191060) study — composed of over 1,500 patients and conducted in France and in the United States — will hopefully give us the final answer. In this study, eligible patients are treated with bortezomib/lenalidomide/dexamethasone (VRd) for three cycles, then randomly assigned to either ASCT followed by two cycles of VRd then maintenance lenalidomide (ASCT arm) or continuation of VRd for five more cycles followed by maintenance lenalidomide (non-ASCT arm). PFS serves as the primary endpoint. A difference in the two studies is that the IFM gives maintenance for 1 year, whereas maintenance in the DFCI study is until disease progression, a standard of practice in the United States. A preliminary report of the IFM study is scheduled for presentation at the ASH Annual Meeting and Exposition in December 2015.

For now, until the studies show otherwise, ASCT continues to be recommended as part of first-line therapy in eligible newly diagnosed patients with MM.

 

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Yvonne Efebera, MD, MPH, is associate professor of internal medicine at The Ohio State University Comprehensive Cancer Center. She can be reached at yvonne.efebera@osumc.edu. Disclosure: Efebera reports advisory roles with Janssen and Takeda Pharmaceuticals.

Novel targeted agents may soon replace autologous stem cell transplantation as the preferred first-line treatment option.

The addition of autologous stem cell transplantation (ASCT) to conventional-dose chemotherapy became a preferred first-line treatment for newly diagnosed symptomatic multiple myeloma patients based on randomized studies performed largely in the 1990s. This approach continues to be supported by consensus guidelines in the current era of novel agents, and this is appropriate until we can show that non-transplant approaches are equivalent or superior. However, with our improved understanding of the pathobiology of myeloma, and the proliferation of novel active targeted agents, a number of arguments support the possibility that we may soon have this capability.

First, even in the conventional agent era, though transplant frequently improved response depth and/or PFS, it did not uniformly enhance OS, which is becoming a key endpoint for regulatory approval of new drugs. Second, current novel agent-based induction regimens provide overall response rates of virtually 100%, and 75% to 100% of patients may achieve minimal residual disease (MRD) negativity based on sensitive flow and next-generation sequencing assays. Notably, these responses are deeper than were possible in the past even with chemotherapy and stem cell transplantation. Third, in the conventional agent era, studies comparing upfront transplant with ASCT as a second-line approach showed no significant OS differences. Importantly, some studies suggest this may be true in the current era, and a key international trial is reassessing this in a randomized fashion (NCT01208662). Fourth, even if patients have relapsed from prior ASCT, modern salvage regimens provide PFS outcomes comparable to those that used to be seen only in newly diagnosed patients after ASCT. Finally, effective immunotherapies, including targeted monoclonal antibodies, as well as chimeric antigen receptor-guided T cells that can persist and traffic to disease sites are showing clinical efficacy. Because these will be incorporated into front-line therapies as part of induction, or as treatment of persistent MRD, we will achieve greater disease cytoreduction than has ever been possible.

Substantial challenges remain to those who would seek to replace our current paradigm for initial therapy of newly diagnosed symptomatic myeloma. The optimal regimen or sequence that would be consistently effective for all patients, or that could be personalized for the molecular and immunologic features of the patient and their disease, needs first to be identified. Next, randomized studies need to be performed to validate this approach using either survival as the key endpoint, or a surrogate marker, such as possibly MRD, that is more reliably associated with an OS benefit than PFS. Also, we need to understand the determinants of primary and secondary resistance so that we can apply follow-up regimens optimal to each patient to eradicate either residual or relapsing disease. Finally, we need to ensure that our approaches provide not only optimal PFS and OS outcomes, but also maximize patient-reported outcomes and minimize the financial burden of treatment. However, these goals seem increasingly achievable, at which point ASCT may not need to be a preferred first-line treatment option.

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Robert Z. Orlowski, MD, PhD, is department chair ad interim of the department of lymphoma/myeloma at The University of Texas MD Anderson Cancer Center. He can be reached at rorlowsk@mdanderson.org. Disclosure: Orlowski reports research funding from and board of directors, speakers bureau or consultant/advisory roles with Acetylon Pharmaceuticals, Array BioPharma, BioTheryX, Bristol-Myers Squibb, Celgene, Forma Therapeutics, Merck, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Spectrum Pharmaceuticals.