BROOKLYN, NY—According to Christian mythology, the Holy Grail was the dish, plate, or cup used by Jesus at the Last Supper, and was said to possess miraculous powers. Using that as a non-literal analogy, some physicians who treat patients with multiple myeloma believe that complete response (CR) of disease has a type of miraculous power while others do not believe in that “miracle” of CR. But as one of the participants here in the Great Debates and Updates in Hematologic Malignancies meeting said, the fact that two people vehemently disagree does not mean that the truth lies halfway in between.
If it was possible to achieve a complete response with acceptable tolerability and patients lived longer, who wouldn't want that? asked Kenneth Anderson, MD.
“Until recently, we have not been able to achieve CR.” The first time CR was achieved in myeloma, he noted, was the transplant experience from France in the IFM 90 trial, which showed superior event-free as well as overall survival. “There was an impact of CR and very good partial response on outcome, leading to a statistically significant difference in EFS,” he said, adding that this showed that the quality of response matters.
The French IFM99 trial used double autologous stem cell transplantation and showed the impact of achieving at least a very good partial response after induction therapy with bortezomib-dexamethasone compared with combined vincristine, doxorubicin, and dexamethasone, with higher event-free and overall survival among responders.
“Before transplantation, there was no evidence that we could achieve CR,” said Dr. Anderson. Others, including the University of Arizona total therapy regimens, showed that “transplantation with intensive therapy meant something.”
Adding novel therapies, such as bor-tezomib, into the transplant regimen led to significantly higher CR rates compared with induction with conventional therapies. The IFM2005-01 trial showed that the achievement of at least very good partial responses portends well for overall survival.
“Again, CR means something,” Dr. Anderson said. The results of the Total Therapy 3 regimen showed a markedly increased success rate for patients taking novel therapies. “We can achieve a significant level of CR.”
However, experience with double transplants showed that “if patients achieve a good partial response or better, they don't benefit from a second transplant,” he continued. “This changed the paradigm, and not a lot of second transplants were done.”
The best response to induction with lenalidomide, bortezomib, and dexamethasone is about a 60% CR/near CR (nCR) rate, and about three quarters of patients get a good partial response or better (data from Richardson et al, published in Blood last year). These “unprecedented” responses, Dr. Anderson said, led researchers to ask whether CR was meaningful or not—”We couldn't ask that question before.”
The IFM/DFCI 2009 study now in progress may change the paradigm again. Clinicians will learn from this trial whether transplantation after an induction response adds anything, he said.
All CRs are not the same, though, he noted. Molecular CRs were achieved outside of the allotransplant setting for the first time in multiple myeloma in the EVOLUTION study, which incorporated novel therapies. Minimal residual disease (MRD) negativity was achieved across various arms (Kumar et al, ASH 2010 abstract 621).
Combinations in upfront treatment of multiple myeloma have led to good overall response rates and appreciable CRs. The IFM 2005 02 study of response to lenalidomide consolidation led to an enhanced response rate, with upgrading to a 68% rate of very good partial response with consolidation (Atal et al, ASCO 2010 Annual Meeting).
A Phase III study of bortezomib consolidation following high-dose melphalan found a significant upgrade in response (49% CR/nCR) with bortezomib compared with control individuals (33% CR/nCR) (data from Mellqvist et al at the ASH 2009 Annual Meeting).
An Italian study of the clinical impact of bortezomib, thalidomide, and dexamethasone consolidation showed a 49% rate of very good partial responses and also a 49% rate of CR (Ladetto M et al. JCO 2010;28:2077-2084).
Because not all complete responses are the same, clinical studies have begun to look at molecular CR, gene copy numbers, and the impact of survival, he said. “The clinical impact of MDR is that PCR-negative patients are not relapsing. Maybe this should be the endpoint in future trials.”
CR is also showing an impact in the non-transplant setting among newly diagnosed stem cell transplant-ineligible patients. The addition of a novel agent to melphalan plus prednisone results in a higher response. The bortezomib, melphalan, and prednisone (VMP) combination seems to elicit the highest responses, with a 30% CR rate.
In the VISTA trial, for patients who achieve CR, the times to progression and overall survival are both statistically significant, which portends well for survival, he said, citing San Miguel et al: NEJM 2008;359:906-917. In looking at the impact of CR on outcome for patients in the VMP arm, CR is associated with significantly longer time to progression, but there is no significant difference in overall survival, which is likely due to the small number of deaths.
Trials continue to show that as the response to treatment increases, CR rates go higher, and this may make a significant difference in elderly patients, Dr. Anderson noted. The depth of response after induction therapy also has an impact on survival, and CR can be used to predict long-term outcomes of PFS and overall survival.
Dr. Anderson concluded, “It is possible in myeloma to consider that the Holy Grail is achievable with novel therapies in the transplant setting and non-transplant setting as well.”
Taking the contrary view, Dr. Fonseca, said he does not believe that CR, in and of itself, as it is defined today, is truly the Holy Grail in myeloma therapy. “CR is an illusion and does not equal a cure,” he said. “CR or near CR is not the Holy Grail in frontline therapy for multiple myeloma unless you reach a true CR.”
Dr. Fonseca set some ground rules regarding complete response. He said that CR is a prerequisite for cure, and that long-lasting CR is a cure. CR is a surrogate marker of great anti-tumor response. The path to CR needs to be safe and tolerable.
CR in some studies has correlated ultimately with survival, he admitted, and CR is a way to measure disease. But “there is no data to suggest we should intensify treatment before transplantation. Should CR be the goal? Yes, at the start of care when choosing regimens, we aim towards a cure. But not in a post-hoc fashion in those patients who don't get there.”
He asked: Does CR have miraculous powers in myeloma? Some medical crusaders have searched for CR, but “CR may be like a mirage.”
He noted that there are important caveats about obtaining a CR depending on the patient's age. “I don't aim for CR in treating elderly patients with a combination of lenalidomide and dexamethasone. This easy, non-intrusive regimen is good for quality of life,” he said. For younger patients, CR may be the ultimate treatment goal.
CR can be measured in many ways. “We have to analyze data and apply new parameters, such as molecular CR, to see whether CR is important or not,” said Dr. Fonseca. He added that the clinical impact of minimal residual disease is longer duration disease control.
However, the response to treatment, he said, is like the Spanish saying “Ojos que no ven, Corazon que no siente—Eyes that do not see, a Heart that does not feel.
“If eyes don't see, they can be fooled into translating CR into a cure.”
In general, CR is associated with better overall survival in multiple myeloma. But there are exceptions. “Sometimes CR is a bad prognostic marker, and is more a reflection of biology than that of CR,” he said. “Some patients can go back to MGUS state.”
Despite persistent small monoclonal proteins, some myeloma patients do well. “Should we pursue other therapeutic initiatives?” he asked. “We don't have to. Some clones of cells have different susceptibility to chemotherapy. Cells remain in the bone marrow and the patient still does well clinically.”
He noted that in the IFM 99-06 study the addition of thalidomide to melphalan-prednisone led to a slightly higher CR (Facon et al: Lancet 2007; 1209-1218). The difference, however, was due to the duration of treatment, not the depth of response. It is important to know what to look for in the population being treated, he said.
The Total Therapy 4 and 5 trials show that risk stratification is effective. Low-risk patients achieve CR, which bodes well for a cure. After 12 to 24 months, the fraction of low-risk patients in CR does increase, he said. For high-risk patients, the majority in CR have limited survival as compared with low-risk patients.
In the Spanish Total Therapy experience, the long-term outcomes of patients undergoing transplant show that a large percentage of patients (24%) are able to achieve CR. At 11 years, 35% of patients remain in CR. “It appears that CR may lead to a cure for about 50% of patients. But the reality is that half of these patients relapse,” said Dr. Fonseca.
Modern induction therapy with the CyBORD regimen is able to obtain CR rates of about 50%. It is important to assess CR with highly active induction regimens for myeloma, he noted.
In conclusion, Dr. Fonseca said that “CR is a prerequisite for a cure. Better treatment and higher rates of CR can be achieved. But not all therapies need CR to show benefit, and not all patients need to get into CR.”
“Overall, achieving a CR is good, but “it's like getting wealthy: If I do it well and do well, do no harm, and do it without suffering in the process, then it's good.”