BY ROBERT H. CARLSON
NEW YORK -- As novel treatments for multiple myeloma continue to impress, and median survival times increase, the question of whether or not to use maintenance therapy arises more frequently.
At a session here of the International Congress on Hematologic Malignancies, two experts shared different perspectives and rationales on maintenance therapy for patients with high-risk myeloma.
Leif Bergsagel, MD, Professor of Medicine at Mayo Clinic Cancer Center in Scottsdale, Ariz., focused on what clinicians can take from recent advances in genomics, and stressed that less than therapeutic maintenance levels might do more harm than good.
And A. Keith Stewart, MD, Dean for Research, also at the Mayo Clinic Cancer Center there, described how he defines and manages high-risk multiple myeloma, including a maintenance regimen. (Both speakers spoke from off-site in Arizona via a Skype-like setup due to snowstorms that had grounded airplanes going to New York.)
Leif Bergsagel: Avoid Suboptimal Therapy
Bergsagel, well known for his research in the molecular pathogenesis of multiple myeloma, said that the heterogeneity of clones in high-risk multiple myeloma advises against maintenance therapy, which by nature is sub-therapeutic: “We tend to not use therapeutic doses in maintenance -- we tend to use more tolerable doses that patients can maintain over the long term.
“But sub-therapeutic therapy in the absence of measurable benefit is of no benefit and may be harmful in high-risk multiple myeloma.”
For example, he said, suboptimal bortezomib treatment, typically given at one-third the standard dose, has been seen in a mouse model of myeloma to alter the disease course by selecting for the most aggressive clones. “If you do this with patients with high-risk disease with a lot of tumor heterogeneity, that would actually make the outcome worse,” he said.
Bergsagel pointed to the results of the British MRC Myeloma IX trial (Morgan et al: Blood;2012:5:7-15) in which thalidomide maintenance significantly increased progression-free survival and was associated with a trend for increased overall survival in patients with favorable interphase FISH (iFISH) results. Conversely, in patients with adverse iFISH assays (representing about 44 percent of patients in the trial), maintenance did not prolong progression-free survival and was associated with significantly shorter overall survival.
Those authors wrote that this effect in the high-risk subgroup was not the result of the relapse therapy, which raises the concern that thalidomide maintenance may have selected clones with more aggressive clinical behavior at relapse.
Bergsagel also cited an abstract from the most recent ASCO Annual Meeting (Boccadoro et al: Abstract 8509), showing that lenalidomide maintenance improved progression-free survival rates in good-risk myeloma patients, but did not prolong progression-free survival in high-risk patients.
“A previous study has shown that lenalidomide, if given at full doses at relapse, prolongs progression-free survival of patients with t(4;14) myeloma by eight months,” Bergsagel said, citing a 2009 study in Blood (Reece et al: Blood 114: 522-525). “But if [lenalidomide is] used in a way that is suboptimal -- that is, maintenance -- you lose any advantage from the drug effects; it seems better to use full-dose lenalidomide at relapse.”
He also described clonal tides seen in mouse models, in which aggressive myeloma clones stimulate, maintain, or eradicate other clones, including indolent myeloma -- illustrating the importance of targeting clonal heterogeneity in high-risk myeloma, he said.
He noted that heterogeneous myeloma clones, which occur in the growth cycle and are responsible for the immortalization of the myeloma clone, are present in every stage of disease, including monoclonal gammopathy of undetermined significance (MGUS).
The most common genetic mutation in myeloma is the rearrangement of the MYC gene, one of the mutations associated with progression from MGUS to myeloma. Clonal heterogeneity is also related to response status, Bergsagel said.
“It is probably much more important in high-risk myeloma to achieve a complete response and remove as many clones as possible.” In contrast to the 85 percent of patients with standard-risk myeloma, in the 15 percent of patients with high-risk disease, a complete response is actually associated with markedly improved survival, illustrating the importance of targeting clonal heterogeneity in these patients.
“Clonal heterogeneity is going to be a challenge in treatment going forward,” he said.
After his presentation, Bergsagel was asked by the meeting’s program director, Andrew D. Zelenetz, MD, PhD, Vice Chair for Medical Informatics at Memorial Sloan Kettering Cancer Center, whether he would select patients for maintenance by risk group, or would he instead not to give maintenance to anyone.
Bergsagel said he and colleagues follow the mSMART stratification for myeloma and risk-adapted therapy criteria (msmart.org) -- “even though there is hardly any guidance for high-risk disease.”
“We have decided to use RVD [lenalidomide-bortezomib-dexamethasone], and continue with RV [lenalidomide-bortezomib] as maintenance,” he said, explaining that this would not be a sub-therapeutic dose because the combination therapy is more active against subclones. But he would not recommend maintenance with lenalidomide alone, he said.
Keith Stewart: Multiple Clones, Variable Drug Sensitivity
Stewart, in his presentation, elaborated on Bergsagel's description of clonal tides in the unstable genome of high-risk myeloma: “There is massive genomic instability in high-risk myeloma over time, unlike the majority of low-risk patients in whom the genome is completely or relatively stable.”
Clones in high-risk myeloma have a variable response to therapy, he said, illustrating the waxing and waning of clones with a description of a case in which five unique clones were found in a patient's tumor at diagnosis: One dominant clone was quite responsive to lenalidomide-dexamethasone, and after treatment with that combination, it became a minor clone. That was replaced by another clone that had obviously been growing in the presence of lenalidomide-dexamethasone and was therefore resistant to therapy with those drugs.
Treatment was then switched to carfilzomib and the second clone disappeared, indicating that it had been very proteasome-inhibitor sensitive. But while the clone that was proteasome-inhibitor sensitive was being eradicated, the lenalidomide-responsive clone reappeared.
Ultimately it was a plasma cell leukemia clone that emerged from the mix, completely drug resistant, and that was lethal to the patient. “In this case a minor drug-resistant clone was the one to worry about, and the one that had to be eradicated,” Stewart said. “The implication is that there are multiple clones with variable drug sensitivity, making combination therapy a necessity, particularly for patients with high-risk disease, and I would argue for all patients.”
Combination therapy means more than adding dexamethasone, he said. Drug-sensitive clones can be suppressed, but when they reemerge, they may be sensitive to a different regimen. “Once resistant, not always resistant,” he said.
Stewart offered a list of treatments that are not effective in high-risk myeloma:
· Four cycles of bortezomib-dexamethasone;
· Continuous lenalidomide-dexamethasone;
· Tandem autologous transplant;
· Maintenance thalidomide; and
· Allogeneic transplant.
Maintenance Does Work in High-Risk Myeloma
Stewart said that overall survival can improve with longer-duration bortezomib, including maintenance bortezomib. He cited a Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON)-65 study (Sonneveld et al: JCO 2012; . 30:2946-2955) in which patients were randomly selected to receive two years of maintenance with either thalidomide or bortezomib.
The three-year overall survival rates for high-risk patients were particularly impressive, he said: 60 percent for t(4;14) patients receiving bortezomib versus 40 percent for thalidomide; and 61 percent for 17p-deletion patients versus 17 percent, respectively.
And in a more recent trial, RVD maintenance for high-risk myeloma (Nooka et al: Leukemia; doi:10.1038/leu.2013.335) was associated with three-year overall survival rate of 93 percent for patients with 17p deletion.
Stewart said the key to treating patients with high-risk myeloma is to use a combination of all effective drugs early, so he starts with four cycles of carfilzomib-lenalidomide-dexamethasone (KRD) or cyclophosphamide-bortezomib-lenalidomide-dexamethasone (CVRD), followed by autologous stem cell transplant for eligible patients.
He said he recently started adding maintenance with one year of continuous bortezomib every two weeks plus lenalidomide, followed by two years of lenalidomide alone. Continuation of maintenance is guided by minimal residual disease status.
For transplant-ineligible patients, treatment begins with bortezomib-lenalidomide-low dose dexamethasone (VRd) until maximum response, and then continues with the same maintenance plan as for transplant patients.
After the presentation Stewart was asked by Steven Vogl, MD, an oncologist in Bronx, NY, whether maintenance would help low-risk patients as well.
Stewart said he believed it could, but it would not be routinely used because of the tradeoff of efficacy with toxicity.