The final update lecture was given by this year’s Kyle Award winner, Dr. Antonio Palumbo of Torino, Italy, a leader in the area of treatment of older myeloma patients. He is first author of a new IMWG publication on geriatric risk stratification. Dr. Palumbo has for the first time defined the criteria for assessing risk and treating frail and/or elderly patients. Doctors around the world will have clear guidelines for managing the care of these at-risk patients who too often die during the first months of treatment, when they are most vulnerable. Frail patients, in particular, must be treated with great care and with reduced doses of medication. A frail patient is defined as one who has comorbidities (other illnesses, particularly heart disease, infections, gastrointestinal problems, and blood clots) and has difficulty with or cannot accomplish the activities of daily living. 15% of younger patients are frail, as are 35-40% of patients who are 80 years or older. These patients require reduced drug intensity (2 drugs in combination rather than 3 or more) and reduced drug dosage. The goal of treatment should be disease control rather than disease eradication, especially in the first 2-3 months of therapy.
To help further define a frail patient, Dr. Palumbo set forth 4 parameters on which doctors can base their assessments: patient age; presence of comorbidities; patient autonomy (does the patient have the ability to get to the clinic for treatments and assessments?); and patient mindset (is the patient able to remember and adhere to his or her treatment regimen?). The data gathered and presented demonstrates that progression-free and overall survival (PFS and OS) rates with reduced doses of drugs for the frail and/or elderly are equal to those of stronger patients given standard doses. Dr. Palumbo’s overall message is sound advice for any physician: be aware of the risks of mortality and toxicity in older and weaker patients, and do not over-treat them. Pushing these patients to CR with high-doses, 3-drug combinations, and continuous therapy is not appropriate in this patient population.
Discussion centered on better defining when frailty arises as a result of the myeloma itself or as a result of comorbidities. Sometimes patients are frail because the myeloma is uncontrolled, and they do much better after therapy. In these cases, it’s better to reduce the myeloma tumor burden first, and then reassess the patient after therapy to see if he or she is now ready for more aggressive treatment. During the discussion, Dr. Palumbo emphasized the necessity of assessing heart function in all patients before the start of therapy.
The next segment of the Summit was conducted in serio-comic debate format. The first battle of words was between Dr. Xavier Leleu of Hopital Claude Huriez in Lille, France, and Dr. Maria Victoria Mateos of the University of Salamanca, who took opposing views of the role of melphalan versus continuous Revlimid/dexamethasone (Rd) in the frontline treatment of older (non-transplant) patients. Dr. Leleu, using data from the FIRST trial presented at the ASH meeting six months ago, championed continuous Rd, which clearly bested MPT and fixed-dose Rd in this large 3-arm study. He humorously called his presentation “Exit Melphalan,” stating that the only reason it is still used after almost 50 years is that it is “cheap.” He sited its risk in causing second malignancies, particularly in combination with Revlimid, and called for a practice paradigm change in these days of better drugs with better response rates. Doublet therapy with Rd, he claimed, is safer and more effective than three-drug combinations with melphalan for elderly patients.
Dr. Mateos, who worked with principal investigator Jesus San Miguel on the original VMP “VISTA” trial, used the analogy of blue jeans to defend melphalan: jeans may have been around for a long time, but with the right cut and the right accessories, they are always in style. Melphalan, she claimed, is also always in style. It has been, and should continue to be, the backbone of treatment for elderly patients in Europe. In combination with novel agents, it has been an excellent “accessory.” Drawing laughter from the attendees, Dr. Mateos asked, “If melphalan adds no advantage in combination with Revlimid, then what does that say about Revlimid?” Acknowledging that IMiDs Thalomid and Revlimid are not the best partners for melphalan, she championed VMP and the “total therapy” approach to treating the elderly, adding that new drug combinations such as carfilzomib/melphalan/prednisone are now showing promise. Moreover, a new form of melphalan currently demonstrating its efficacy in clinical trials, melflufen, may well make melphalan an even stronger partner in combination therapies.
During post-debate discussion, Dr. Meletios Dimopoulos of the University of Athens, Greece, pointed out that melphalan’s stiffest competition may well come from another old, inexpensive drug, cyclophosphamide, which has more predictable and reversible toxicities than melphalan. Dr. Kyle concurred that cyclophosphamide has a lower risk rate for myelodysplastic syndrome (damage to the bone marrow that can lead to acute leukemia) than melphalan, and that the cyclophosphamide/lenalidomide/dexamethasone regimen does not prevent stem cell collection, unlike melphalan-containing regimens. The consensus was that alkylating agents are here to stay, and that cyclophosphamide is the alkylator of choice.
The second debate concerned the role of transplant as first-line therapy, with Dr. Michele Cavo of Bologna, Italy, arguing in favor and Dr. Shaji Kumar of the Mayo Clinic arguing against. Dr. Cavo argued that early stem cell transplant combined with novel therapies produces the best possible outcome for the standard-risk patients who comprise 70% of the transplant-eligible population. Although he conceded that we don’t yet have the results of two large trials comparing novel therapy followed by early transplant versus novel therapy alone with transplant at relapse, he pointed to available long-term data from the E4A03 study (which compared R/high-dose dex to R/low-dose dex) and from the MPR vs. tandem auto transplant study to demonstrate that PFS and CR rates were double for patients who had early transplant. Because neither of these trials was powered to answer the question of early vs. delayed transplant, however, he is eagerly awaiting validation of his position when the final data are in from the IFM/Dana Farber and EMN02 trials designed to answer this question.
Dr. Kumar posed the question at the heart of the debate: “Do we really have to do up-front stem cell transplant to get the kind of deep responses we need?” His answer is a resounding “no,” and he points to the FIRST trial, where continuous Rd was an effective method to produce deep and long-term remissions. Although he strongly believes that auto transplant still plays in important role and should be incorporated into therapy at some point for some patients, he contends that it can be performed as a relapse therapy, and needn’t be done up front. Dr. Kumar pointed to data demonstrating equivalent overall survival outcomes with early vs. delayed transplant, and urged the use of novel therapies alone up front, avoiding the toxicities of transplant. He summarized by describing and nicknaming two paradigms for treatment: sequential therapy—the “hit and pause” method, and intense and prolonged therapy—the “hit and keep hitting” approach. He asked if SCT must be part of that package, and Dr. Palumbo agreed that it does not need to be. He pointed to data from his cyclophosphamide/Rev/dex with or without transplant trial, where there has been no difference in OS thus far. He believes that transplant is an excellent tool to achieve a goal, but not a hammer to hit every nail. The art is in deciding which patients are the best candidates for transplant. He further noted that diagnosis is not the best time to determine a patient’s fitness for transplant, given that most patients are at their sickest when they are diagnosed. Further, in Europe particularly, basing transplant eligibility on age (65 years or younger) is arbitrary, and eliminates many otherwise eligible patients from clinical trials. Dr. David Siegel of Hackensack University in New Jersey countered that duration of response is shorter with delayed transplant, and that the patients on the E4A03 trial who were transplanted early had better quality of life and survival data. Debate raged on among the experts in the audience, with Dr. Kumar finally likening upfront transplant to radical mastectomy in breast cancer: a very aggressive treatment that was widely used and then later proven unnecessary. The consensus among all the experts gathered was, finally, that there is no dogma concerning upfront transplant, and that we must wait for the phase III data from the two definitive trials, one of which is soon to be published in the New England Journal of Medicine.
The remainder of the full morning program consisted of presentations on exciting new fields of therapy and genetic risk stratification. Dr. Ed Stadtmauer from the University of Pennsylvania led off with an overview of his pioneering work in the field of immunotherapy with transgenic (“engineered”) T cells and chimeric antigen receptors. He gave an overview of the history of immunotherapy approaches in myeloma, and called autologous transplant a good platform for immunotherapy, although his new approach with genetically altered NYESO T cells has produced responses even without transplant. Twenty-seven clinical trials using chimeric antigen receptor T cells (CART) are now being conducted at 10 centers in the US. Best results thus far have been seen in ALL patients. Adverse events have been hypogammaglobulinemia, tumor lysis syndrome, and cytokine release syndrome. Two myeloma patients died of heart failure in the MAGE A3 trial. No efficacy data other than stable disease has yet been seen in myeloma patients. These are still early days for this developing therapy in myeloma.
Dr. Stephen Russell of the Mayo Clinic in Rochester was next to present his data on oncolytic virotherapy. Dr. Russell had previously presented his research at the 2011 IMWG meeting in London, and it was gratifying to see that recent data from the phase I measles virus trial have demonstrated “proof of principle” that viruses can eliminate disseminated disease. He explained why myeloma cells are the perfect targets for the measles virus, and why a massive dose of the engineered virus—enough to create vaccine for 10 million patients—is required. None of the patients enrolled in the trial who had immunity to the virus responded to the therapy. The trial has been ongoing since 2006, but only in the past year has the dose been escalated to its present effective level. The trial protocol has now been amended to include an even higher viral dose. Next steps include opening a phase II trial in September, when enough of the virus will have been engineered. Eligible patients must be resistant to proteasome inhibitors and immunomodulatory agents, and must also have relapsed after having been treated with an alkylating agent. Most importantly, they must be antibody-negative for the measles virus. Even if patients have had measles in the past, they may have low or no antibody titers because of the myeloma. Dr. Russell is performing further research to determine if “cell carriers” can be engineered to circumvent neutralizing antibodies and make the vaccine effective even in those with anti-measles immunity. Dr. Russell is also working on a virotherapy using the vesicular stomatitis virus (VSV), to which human beings do not develop immunity.
Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston gave an overview of the new therapies currently in clinical trials, including second-generation proteasome inhibitors; immune therapies; new “older” drugs like melflufen and ARRY-520, which are “new-age” chemotherapy agents; monoclonal antibodies (MAb); and histone deacetylase (HDAC) inhibitors. He reviewed the positive trial data for each drug (see the MT article in this issue on the data from the ASCO meeting), the new anti-CD 38 monoclonal antibodies in particular, and reinforced the feeling of optimism among the meeting’s attendees. During the panel discussion, concern was raised about data from the recent panobinostat trial presented at ASCO, which revealed high trial discontinuation rates and a small improvement in progression-free survival. Although these phase III trial results with the HDAC inhibitor panobinostat demonstrated only an additional 4 months of PFS with pano/Vel/dex versus Vel/dex, Dr. Richardson believes that this is about the same PFS that were seen in other novel therapies when they were tested in relapsed and refractory patients. Patients with high-risk disease were among those who benefited most. With side effects causing a lot of patients to drop out of the trial, Dr. Richardson feels that we will see far more tolerability in the new panobinostat/Vel/dex trial, which features once-weekly SQ Velcade and dose reduction of panobinostat for side effects. Myeloma remains a robust field for the development of new and effective agents that can be used in countless combinations. We have many new drugs in the pipeline, some of which have demonstrated single-agent activity—a hallmark of high efficacy.
Dr. Saad Usmani, formerly of the University of Arkansas and now of the Carolinas Medical Center in Charlotte, North Carolina, addressed the question of whether treatment can be individualized based on risk stratification. He began by pointing out that myeloma is not a single disease entity, and that research conducted by Drs. Bart Barlogie and Pieter Sonneveld has identified 10 distinct genetic signatures that are evident from MGUS on through active MM. He stated that 10-15% of myeloma patients, many of them lost to follow-up, are currently cured. We now know that the evolution from MGUS to MM is branching, or “Darwinian,” rather than linear, and that clonal selection occurs under duress from therapy. Disease burden, disease biology, and host factors all play a role in determining risk. He pointed to prior trial data and to data that is currently being analyzed from the phase III trial of elotuzumab/Rev/dex in relapsed/refractory patients in which sub-group analyses have been undertaken among patients with various high-risk genetic mutations.
Dr. Jesus San Miguel of Navarra University in Pamplona, Spain, followed with a discussion of another type of “ultra-high-risk” patient: not one with smoldering myeloma, but one with active disease and risk factors that lead to short overall survival. Patient-specific risk—frailty—is more important than lab abnormalities, as we saw during Dr. Palumbo’s presentation. Disease-specific risk derives from genetic mutations, but not all patients with high-risk mutations have short survival. What we do know is that patients with three or more genetic abnormalities, or “ultra-high-risk” patients, have an overall survival of less than 19 months; that relapse less than one year following stem cell transplant is the norm for these patients; and that certain mutations, such as trisomy (three copies of a chromosome), mitigate high risk. Thus, as Dr. San Miguel acknowledged, patients with t(4;14) alone, t(4;14) with trisomy, and t(4;14) with deletion 17p all have different outcomes. Poor risk factors include circulating plasma cells, primary plasma cell leukemia, extramedullary disease at diagnosis, and frailty, all of which trump cytogenetics as features of ultra-high risk and short overall survival. Current analyses indicate that maintenance therapy has been effective in patients with 17p-, but not in patients with t(4;14), and that Velcade offers a clear benefit to high-risk patients with t(4;14), but not to those with 17p-. We are now seeing emerging data from the carfilzomib/pomalidomide/dexamethasone trial that PFS and OS are the same for patients with t(4;14) and/or 17p- as for standard-risk patients, perhaps indicating that the combination of a second-generation proteasome inhibitor and IMiD may overcome high risk. Dr. Gosta Gahrton’s long-term follow-up of allogeneic transplant published earlier this year in Blood demonstrated that PFS and OS were equivalent in patients with or without t(4;14) and 17p-.
The consensus was that we need further studies of allogeneic transplant in high-risk patients to know if it can abrogate adverse prognosis. Another proposed trial is one in which either carfilzomib/Rd or VRD plus an anti-CD 38 MAb and double autologous transplant are used to treat ultra-high-risk patients. The consensus, summarized by Dr. Sundar Jagannath, is that not all high-risk deletions are the same, and that we need to see more data parsed out from more trials before we can determine which agents are most effective in which combinations for this population.
The final aspect of the Summit was breakout sessions in which the pressing current issues raised in the general session were discussed with an aim to forming action plans for next steps. These topics included frontline therapy in non-transplant candidates: the role of melphalan and continuous therapy; the role of transplant as first-line therapy; new active therapies; and updated risk stratification. Following those breakouts, time was reserved for the doctors to meet in their ongoing work groups in the areas of renal impairment, bone and imaging with MRI and PET/CT, plasma cell leukemia and extramedullary disease, and treatment of the elderly with geriatric risk stratification. Reports from each of these breakout sessions and working group meetings were presented to the entire IMWG the following morning.
Highlights of the reports from the breakout sessions are as follows:
- Consider new trial structures for rapid assessment such as “pick the winner” trials with many arms;
- Don’t limit testing to relapsed/refractory patients, who are often too heavily pretreated to accurately assess efficacy and tolerability;
- Establish a better “standard of care” comparator (control arm) consistent with 2014 practice;
- Establish a new benchmark for survival with the available drugs;
- Perform trials in which patients have had a maximum of 1-3 prior lines of therapy;
- Use MRD as a regulatory endpoint to speed approval;
- Write an IMWG paper on the lessons to be learned from successes and failures of past trials;
- Write an IMWG paper on how patients should be managed in the relapsed/refractory setting with practical recommendations for the community physician.
Front-line therapy in non-transplant candidates: the role of melphalan and continuous therapy
- Plan a randomized trial with auto transplant versus optimal non-transplant therapy for the fit elderly;
- The new standard of care for the elderly should be Rd;
- Continuous therapy has been amply demonstrated in both Spanish and Italian trials to be superior to fixed-duration therapy;
- Trials should be planned with or without fixed-duration therapy according to MRD level;
- Trials should be planned to evaluate treatment-free intervals.
Transplant as first-line therapy
- The current consensus is that autologous transplant is the standard of care;
- There is currently no consensus on early vs. late transplant; randomized trial results from the IFM/DFCI and EMN02 studies will be available to determine this issue, as well as the duration of maintenance therapy, in 2015-2016;
- There is a consensus that all transplant-eligible patients should harvest and systematically store stem cells up front;
- The issue of single versus tandem transplant is difficult to resolve and there will be no consensus until 4 trials are completed and the data is analyzed, including the BMT/CTN trial in the US, which compares VRD + maintenance to VRD + tandem auto transplant + maintenance, to VRD + single auto transplant + maintenance;
- There is no consensus on the benefit of auto-mini allo; phase II trials are needed using upfront auto-mini allo for patients with 17p-.
- There is a consensus that FISH is at best an educated guess that misses important genetic changes;
- Trials are needed to assess GEP, GWAS (genome-wide analysis of SNPs), and mutation analysis of most relevant genes by exome analysis or RNA sequencing;
- DNA/RNA of patients in clinical trials must be stored for analysis;
- Paired sampling and analysis of newly diagnosed and relapsed/refractory samples must be performed;
- Continue with MRD testing;
- The IMF should support the above initiatives.
- There is consensus to change the “R” in the CRAB diagnostic criteria from creatinine level to eGFR (estimated glomerular filtration rate) <40 mL/minute;
- In the diagnostic evaluation of MGUS, both free light chain analysis and baseline 24-hour urine testing for total protein and UPEP must be done to assess for cast nephropathy, light chain deposition disease, or amyloidosis;
- Cystatin-C and NGAL are possible markers of early renal damage that are not affected by age, sex, or muscle mass and may be useful criteria to validate;
- Amyloidosis is a separate disease from myeloma, and we need to maintain disease boundaries, not assume that it is a subset of myeloma.
- New diagnostic criteria should replace the skeletal x-ray survey with whole-body low-dose CT scan, which takes less than 2 minutes, is widely available, and uses low-dose radiation; 2 studies are currently in progress to validate this approach;
- >1 focal lesion detected by MRI is a sign of progression in SMM; MRI does not detect lytic lesions, but serves an important prognostic function;
- >/= 2 focal lesions by MRI is an ultra-high-risk feature with 80% risk of progression within 2 years;
- There is value to performing a second MRI 3-6 months after the first one to see if there is deterioration;
- MRI helps in differentiating benign versus malignant osteoporosis, which shows a diffuse pattern around a myelomatous lesion;
- Osteoporosis cannot be used to determine disease progression in SMM;
- We need a prospective study to determine whether or not bisphosphonate therapy should be given to patients in CR/VGPR;
- We need studies of serial markers of bone loss such as NTX and CTX.
Extramedullary disease (EMD) and plasma cell leukemia (PCL)
- A proposal has been made for a PCL joint study with MD Anderson and the University of Salamanca;
- Definitions have been proposed for the different types of EMD:
- EMD arising from focal bone involvement
- Hematogenous EMD that arises outside the bone marrow and spreads via the blood
- EMD that is triggered by invasive procedures;
- Prognosis for hematogenous disease is much worse, with the lowest rate of response and highest rate of disease progression;
- Molecular studies of EMD and PCL are needed, including GEP, cytogenetics, and epigenetics;
- Studies are needed on drug sensitivity and resistance in this population;
- There is a planned study led by Dr. Laura Rosinol (Barcelona, Spain) in collaboration with Dr. Roman Hajek (Brno, Czech Republic) and possibly UAMS to include 27 patients with EMD and a matched control group without EMD.
- Proposed therapeutic regimens for hematogenous EMD are anti-MM regimens up front, lymphoma-like regimens at relapse with ASCT or allo in selected patients, and in those patients with hematogenous EMD, poor-risk cytogenetics, and ISS 3, allogeneic transplant.
Geriatric treatment and risk stratification
- The new geriatric assessment tool is better than using age alone to assess fitness;
- Every older patient must be assessed for fitness or frailty at diagnosis to prevent under- or over-treatment;
- Trials are needed to assess auto transplant for geriatric patients;
- Trials are needed for 3-drug versus 2-drug combination therapies for geriatric patients;
- A quality of life assessment tool is needed;
- A quick geriatric assessment tool should be developed as an app for the phone or tablet.
With this last report the Summit was concluded and the doctors set off for the EHA meeting, full of resolve and eager to accomplish the tasks outlined in the small group presentations. We can look forward to another robust group of IMWG consensus guidelines in the coming months.