View Full Version : Immunomodulatory Agents (IMiDs) and Proteasome Inhibitors in Multiple Myeloma
01-31-2013, 04:26 PM
One of the highlights of the 2010 San Antonio ASH meeting, was two recent classes of treatments that have come onto the scene - immunomodulatory agents (IMiDs) and proteasome inhibitors - making myeloma one of the most dynamic areas in oncology. Multiple myeloma affects approximately 20,000 new patients in the United States annually and for a long time was a disease stuck for new therapeutic options.
According to Dr. Neil Love of Reserach To Practice, it’s difficult to figure out exactly what led to this encouraging state of affairs, but those in the middle of it all claim that an effective partnership between academia, industry and unusually active advocacy groups made it happen. One might also consider that perhaps there was a unique and fortunate tumor biopharmacology at work here.
Regardless of the source of this important progress, currently, lenalidomide, bortezomib and to a lesser extent thalidomide are helping patients with myeloma live longer and feel better. Perhaps even more importantly, two exciting but not yet approved agents — carfilzomib and pomalidomide — seem poised to further transform the classic paradigms of this enigmatic disease.
Several related ASH data sets provide a glimpse of what the future may hold for these unique classes of agents:
1. Subcutaneous bortezomib
A large (n = 222) international Phase III study demonstrated similar efficacy but markedly less neurotoxicity when SC bortezomib was compared to IV administration in the refractory setting. These intriguing findings suggest that higher peak drug levels occurring with IV treatment may correlate with neuronal damage and that the SC approach may offer obvious patient care advantages. Investigators are very quickly attempting to further validate this interesting concept. Another important clinical research avenue with bortezomib as presented by Antonio Palumbo and others is weekly dosing of the agent, which seems to be equally efficacious and much less neurotoxic.
Two more Phase II studies of this fascinating and well-tolerated IMiD combined with dexamethasone demonstrated substantial antitumor effect in almost half of the trial participants, all of whom were considered refractory to both bortezomib and lenalidomide. Clinicians seem ready to use this drug now.
Again, significant activity was seen in later-line treatment in two separate Phase II studies, with minimal neurotoxicity, including a lack of worsening of this challenging adverse effect in patients with baseline peripheral neuropathy. A current compelling Phase III study is randomly assigning patients to either CRD or Rd in the search for the “R-CHOP” of myeloma. As with pomalidomide, oncologists again seem ready and interested in utilizing this agent.
Source: Research To Practice
01-31-2013, 04:35 PM
The rapid evolution of effective agents in multiple myeloma over the past few years has changed the face of the disease by tripling average overall survival rates from approximately 2-3 years to about 7-8 years. At ASH 2012, this inspiring march of progress continued most notably with the presentation of definitive data on the third-generation, orally administered immunomodulatory (IMiD) agent pomalidomide. These were accompanied by provocative findings on a new predictor of clinical benefit for this class of drugs and several other related data sets.
Dr Meletios Dimopoulos’ made a presentation of the Phase III study comparing high-dose dexamethasone (HDD) to pomalidomide/low-dose dexamethasone (dex) in patients with a median of 5 prior treatments — including bortezomib and lenalidomide. Among the results that were unveiled, were hazard rates for both progression-free and overall survival of about 0.5 despite the fact that 29% of patients crossed over to pomalidomide after progression on HDD.
This and prior work has shown that the drug is generally well tolerated except for some myelosuppression, and as with the other IMiDs thromboprophylaxis with at least low-dose aspirin is recommended. Even without these Phase III data many believed the FDA was poised to approve pomalidomide based on impressive Phase II results in patients with extensive prior treatment. It seems that oncologists will have access to yet another option for patients with relapsed/refractory disease, less than a year after the approval of carfilzomib.
01-31-2013, 04:50 PM
One of the more pleasant-sounding myeloma acronyms is BiRD, a regimen that was pioneered by Cornell’s Dr Ruben Niesvizky that combines lenalidomide and dexamethasone, with a fascinating and unusual ingredient, the macrolide antibiotic clarithromycin, which is purported to slow the hepatic clearance of dexamethasone and to possess immunomodulatory properties. Perhaps the lack of Phase III supporting data is why BiRD is not commonly used in practice today, and one has to wonder if these promising Phase II results will be enough to help this approach, which replaces lenalidomide with pomalidomide, gain traction. Regardless, the findings provide even more validation of the substantial activity of pomalidomide.
ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma
Dr. Antonio Palumbo has been evaluating regimens that can be administered without complications for prolonged durations — particularly in elderly patients — because he believes the key to long-term success is long-term therapy. In that vein, prednisone — an all-oral regimen that after 6 cycles drops the C and continues pomalidomide/prednisone until disease progression — not only produced impressive disease control (51% PR/CR with median PFS 10.4 months) but was also very well tolerated.
Pomalidomide Cyclophosphamide and Prednisone (PCP) Treatment for Relapsed/Refractory Multiple Myeloma
01-31-2013, 05:00 PM
Dr. Keith Stewart noticed a Japanese paper in Science demonstrating that the clear-cut mechanism of teratogenicity for thalidomide was binding to CRBN, an adaptor protein that is part of the E3 ubiquitin ligase complex. A logical extension of this concept was the theory that this interaction was also the basis for the profound, yet somewhat obscure, antimyeloma action of IMiDs.
After obtaining strong in vivo supporting evidence, Dr. Stewart, his Mayo Clinic team and other sites set out to correlate CRBN levels in myeloma cells with the clinical activity of this class of agents. Two ASH papers — one in patients receiving lenalidomide/dexamethasone and another in patients receiving pomalidomide/dexamethasone — moved this important initiative closer to a clinical reality by demonstrating a tripling of response and survival in individuals with higher versus lower CRBN levels.
Although the ideal method to measure CRBN and the clinical applicability of these results are still being determined and debated, it seems quite plausible that in the not-too-distant future a related predictive assay will become an important part of myeloma practice.
Cereblon Expression Correlates with Efficacy of Immunomodulatory Drugs
01-31-2013, 05:07 PM
It's a bit ironic that although monoclonal antibodies (moAbs) have been utilized in a variety of solid tumors and hematologic cancers, none have been found useful in this disease, which is defined by abnormal antibody production. However, at ASH, evidence was shown that this phenomenon may change based on encouraging data with elotuzumab, which targets the CS1 antigen, and daratumumab, an anti-CD38 antibody.
Elotuzumab is farther along in development, and although it has minimal single-agent activity, there appears to be a true, perhaps immunologically based synergy with IMiDs. At ASH, data from a Phase II study of lenalidomide/elotuzumab/dexamethasone demonstrated an encouraging overall response rate of 84% and a PFS of more than 18 months. Ongoing Phase III studies will soon determine the future of this regimen. Importantly, myeloma is not the only place where the intuitive concept of combining an immune modulator and a monoclonal antibody is being explored, as the “R squared” combination of len/rituximab has demonstrated impressive activity in B-cell lymphoma/CLL.
Updated Results of a Phase II Study of Elotuzumab/Lenalidomide/Low-Dose Dexamethasone for Relapsed/Refractory Multiple Myeloma
04-01-2013, 11:37 AM
The oral therapy pomalidomide (Pomalyst, Celgene) was approved by the US Food and Drug Administration today for use in the treatment of multiple myeloma.
The new drug is specifically indicated for patients who have received at least 2 prior therapies, including lenalidomide (Revlimid, Celgene) and bortezomib (Velcade, Millennium Pharmaceuticals), and whose disease did not respond to treatment and progressed within 60 days of the last treatment.
"Treatment for multiple myeloma is tailored to meet individual patient’s needs, and today’s approval provides an additional treatment option for patients who have not responded to other drugs," Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, said in a press statement.
Pomalidomide is the second drug approved in the past year to treat multiple myeloma, pointed out Dr. Pazdur. Carfilzomib (Kyprolis, Onyx Pharmaceuticals) was approved in July. Both new drugs were approved under the FDA’s accelerated approval program.
Pomalidomide is an immunomodulatory drug from the same stable as thalidomide (Thalomid, Celgene) and lenalidomide, but this new drug "is the most active by far," said David Siegel, MD, PhD, chief of multiple myeloma at the John Theurer Cancer Center at Hackensack University Medical Center, in New Jersey. He is an investigator of the drug and recently spoke to Medscape Medical News.
Pomalidomide is more potent than the other 2 drugs when measured on the in vitro assay of TNF-alpha inhibition, and more potent clinically, giving "more response for less drug when compared to thalidomide and lenalidomide," he said. Because it is more active, pomalidomide can be used at a much lower dose, which decreases the risk for adverse events, including peripheral neuropathy and bone marrow suppression, he said.
The dose for pomalidomide is 4 mg, compared with 25 mg for lenalidomide and 800 mg for thalidomide, he noted.
The drug's potent activity means that it can overcome resistance to the other immunomodulatory agents. "This is significant," Dr. Siegel said. The new drug offers a treatment for those patients who have stopped responding to thalidomide and lenalidomide, he added.
Pomalidomide safety and effectiveness were evaluated in a clinical trial of 221 patients with relapsed or refractory multiple myeloma in which patients were randomly assigned to receive pomalidomide alone or pomalidomide with low-dose dexamethasone, a corticosteroid.
Results showed that 7.4% of patients treated with pomalidomide alone achieved an objective response rate (ORR), which was the primary outcome. The median duration of response has not yet been reached in these patients. However, in patients treated with pomalidomide with low-dose dexamethasone, 29.2% achieved ORR with a 7.4-month median duration of response.
Common adverse effects include neutropenia, fatigue and weakness, low red anemia, constipation, diarrhea, thrombocytopenia, upper respiratory tract infections, back pain, and fever.
Pomalidomide carries a boxed warning indicating that the drug should not be used in pregnant women because it can cause severe life-threatening birth defects and can cause blood clots.
Because of pomalidomide’s embryo-fetal risk, it is available only through a Risk Evaluation and Mitigation Strategy (REMS) program.
Data from the MM-003 study of pomalidomide were presented in December 2012 at the annual meeting of the American Society of Hematology (ASH) by Meletios Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the Alexandra Hospital in Athens, Greece.
Dr. Dimopoulos told journalists that great progress has been made in recent years in the treatment of multiple myeloma. The overall survival has increased from around 3 years to more than 10 years, he said. This is largely due to the availability of newer and more active drugs, he said, and treatment usually consists of both an immunomodulatory agent (given orally) and a proteasome inhibitors, which are administered intravenously, such as bortezomib or carfilzomib.
However, when patients become resistant to these therapies, there is little hope, Dr. Dimopoulos said. Once they become resistant to the best of these therapies, including bortezomib and lenalidomide, the prognosis becomes grim — the median overall survival is only about 8 months.
The phase 3 MM-003 study involved 455 such patients with resistant and refractory multiple myeloma, and showed that pomalidomide offers hope in this patient population.
In the trial, patients were randomly assigned in a 2:1 ratio to either a combination of pomalidomide with low-dose dexamethasone (n = 302) or high-dose dexamethasone (n = 153).
Pomalidomide was taken at a dose of 4 mg once daily; it was taken orally on days 1 to 21 in combination with low-dose dexamethasone 20 mg in patients older than 75 years and 40 mg in younger patients, also taken orally, on days 1, 8, 15, and 22.
In the comparator group, dexamethasone was given in the same doses of the steroid, but more frequently, on days 1 to 4, 9 to 12, and 17 to 20 in a 28-day cycle. This is the standard of care, but it is a palliative treatment, and patients often cannot tolerate these high doses of steroids, Dr. Dimopoulos commented.
The results after a median follow-up of 18 months showed a significant increase in progression-free survival, up to 15.7 weeks on the combination of pomalidomide with low-dose steroid vs 8 weeks on the high-dose steroid (hazard ratio [HR], 0.45; P < .001).
Overall survival was also longer in the combination group. Although the median has not yet been reached, it is expected to be around 11 to 12 months, Dr. Dimopoulos said, compared with a median of 35 weeks in the comparator group (HR = 0.53; P < .001).
These results led to a discontinuation of the comparator group, because an independent review by the study's data safety monitoring board recommended that all patients in the high-dose steroid group be switched over to treatment with pomalidomide and low-dose steroid.
The combination was well tolerated, although there were some expected toxicities in both groups, including neutropenia (reported in 42% of patients in the combination group and 15% in the comparator group), thrombocytopenia (21% vs 24%), and fever (7% vs 0%). The primary reason for discontinuation was progressive disease (in 35 vs 49 patients, respectively). Around 25% of patients in both groups died during the study, primarily from progressive disease and infections.
"We are excited about these results, as they show that a combination approach with pomalidomide and low-dose dexamethasone offers superior results to those seen with current treatment options for hard-to-treat myeloma patients," Dr. Dimopoulos commented in a statement at the time.
"We believe this study provides the basis to consider this combination as a new standard of care for patients who have exhausted most standard treatments to treat their refractory disease and may offer even greater benefit if studied among less heavily treated patients as a first-line therapy," he added. Such trials are now in progress, he said.
Asked how pomalidomide compares with the newly launched carfilzomib in the highly resistant multiple myeloma patient population, Dr. Dimopoulos told Medscape Medical News that it was not possible to compare the 2 because there have not been any head-to-head trials, but he added that both new drugs offer hope of responses in this very hard-to-treat patient population.
Dr. Siegel agreed and added that both new drugs are more active than their predecessors, and the fact that each is in a different class of drugs is useful; eventually they may be used in combination with each other.
The MM-003 trial was funded by Celgene. Dr. Dimopoulos reports receiving honoraria from Celgene, and several investigators are company employees. Dr. Siegel is on the speakers' bureaus for Celgene, Onyx, and Millennium.
Citation: FDA Approves Pomalidomide for Multiple Myeloma. Medscape. Feb 08, 2013
03-13-2014, 04:57 PM
According to Dr. Neil Love of Research To Practice, one might view current clinical research in multiple myeloma (MM) as being in a consolidation phase after the introduction of proteasome inhibitors, immunomodulatory drugs and bisphosphonates brought forth a wave of progress. This idea if reflected in many of the new MM reports presented in New Orleans, where data was presented not only to help optimize the impact of current tools but also to uncover novel agents that will launch a new era with even better outcomes. Dr. Rafael Fonseca comments on a handful of papers that help take the next step in what will hopefully be another leap forward in the corner of oncology.
* More on up-front carfilzomib/lenalidomide/ dexamethasone (dex) (CRd)
MM is only one of a number of tumor types in oncology today for which there is considerable interest in moving newly approved agents up earlier in the course of the disease. In this regard, we have already seen preliminary data from Andrzej Jakubowiak, and at ASH the NCI presented another major single-arm study evaluating induction CRd followed by maintenance therapy — in this case lenalidomide. As in the work presented by Dr Jakubowiak, in this study patients received long-term maintenance and transplant was optional, and with the extraordinary risk-benefit value of this regimen (near complete response [CR] or better in 73% of the 43 patients, 100% minimal residual disease negativity assessed by flow cytometry among 27 patients with near CR or stringent CR and no Grade 3 or 4 neuropathy), Dr Fonseca can foresee a time when treatment will be individualized based on depth of response, with transplant avoided in some patients and survival extended significantly. However, in terms of current practice, like most MM investigators Dr Fonseca believes that while preliminary data on this and similar regimens are very encouraging, carfilzomib should not be used up front outside of a trial setting and recommends that patients interested in this approach be referred to the major Intergroup study comparing CRd to RVD.
* Carfilzomib/cyclophosphamide/dex (CCd) up front in elderly patients
In the same vein as the previous study, another ASH data set reported on recent efforts to incorporate carfilzomib into popular and currently employed bortezomib-based up-front regimens. This Phase II trial looked at CCd (similar to CyBorD) induction in 55 evaluable patients aged 65 and over with newly diagnosed MM. The bottom line is that despite significant activity (47% near CR or better) and relatively good tolerability (14% of patients discontinued treatment because of toxicity, which is considerably fewer than in prior studies for elderly patients), Dr Fonseca — a major proponent of CyBorD — urges us all to hold off on CCd outside a clinical trial.
* Pomalidomide (POM)/carfilzomib/dex in relapsed/refractory (RR) disease
Combining the 2 new kids on the block, POM and carfilzomib, always seemed like a natural next step, and at ASH we saw encouraging data with this appealing regimen. A multicenter Phase I/II effort for patients with heavily pretreated lenalidomide-refractory MM (a median of 5 prior treatments) resulted in a 70% overall response rate among 79 evaluable patients and a manageable toxicity profile. Even more, this report demonstrates that the regimen is not only a viable option in very advanced disease but also an approach that is of great interest in up-front trials.
In a related manner, ASH also featured 2 data sets providing updates from trials evaluating POM with low-dose dex in RR disease. Dr Fonseca’s take-away from these presentations is that while patients with extensive prior treatment and adverse cytogenetic profiles often benefit from this therapy, myelosuppression in these individuals must be managed carefully with dose adjustments and growth factors.
* An all-oral “RVD”
For the past several years we have profiled the early development of the oral proteasome inhibitors ixazomib and oprozomib, and at ASH Paul Richardson presented more data from his Phase I/II study looking at ixazomib/ lenalidomide/ dex in previously untreated MM. This study, which evaluated twice-weekly ixazomib, revealed activity (94% response rate among 62 patients) similar to what is typically seen with RVD but slightly more peripheral neuropathy (PN) (Grade 3 in 5% of 64 patients) than has been observed in trials using weekly administration of this fascinating agent. Not surprisingly, Dr Fonseca is eagerly and optimistically awaiting the results of ongoing Phase III trials.
* Cool new compounds
For the immediate future most myeloma investigators like Dr Fonseca believe monoclonal antibodies represent the most likely path to dramatically catapult survival in this disease, and there is great hope that a rituximab-like agent may be identified. The 2 compounds we have heard the most about up to now are the anti-CD38 antibody daratumumab, which has garnered FDA breakthrough therapy status, and elotuzumab, which is directed against human CS1 (a cell surface antigen glycoprotein that is highly expressed on MM cells) and appears to result in an R-squared-like synergy with lenalidomide.
Similar to daratumumab, this anti-CD38 antibody was shown to have significant single-agent efficacy in patients with relapsed MM (31% response rate among 13 patients receiving the 10-mg/kg dose every 2 weeks) and minimal toxicity other than manageable infusion reactions. Dr Fonseca stated that “this is probably one of most important molecules for future MM therapy.”
A report from a Phase II trial of this selective inhibitor of kinesin spindle protein alone or in combination with dex demonstrated a 15% response rate among 55 evaluable patients receiving the combination and manageable toxicity. What seems most exciting about this data set is that activity was absent in patients with high serum levels of α-1 acid glycoprotein (which binds the drug, making it unavailable), potentially opening the door for a predictive biomarker.
AKT is a critical signaling node in MM, and this single-arm Phase IB trial evaluated the potent AKT inhibitor afuresertib in combination with dex and bortezomib in 81 patients with relapsed or refractory disease. The overall response rate was 65% and the clinical benefit rate was 73% among 37 patients in the safety expansion cohort. The results are favorable enough to justify further study, but of particular interest was the demonstration of consistent increases in the levels of the phosphorylated form of the drug target in MM cells.
* Bonus feature: Two compelling data sets in Waldenström’s macroglobulinemia (WM)
WM is unusual in oncology in that investigators focused on both lymphomas and plasma cell disorders are involved in clinical research and patient care. Most importantly, borrowing from progress in both of these fields, the outlook for the 1,500 US patients diagnosed annually continues to improve as reflected in the following data sets:
The lack of PN with carfilzomib, even in indirect comparison to weekly subcutaneous bortezomib, is particularly appealing in WM, in which PN is part of the disease biology. As such, this agent was evaluated in a Phase II study combining it with rituximab and dex for 31 patients with symptomatic WM. As reported at ASH, this combination resulted in a best overall response rate of 81% and significant IgM declines along with improved marrow profiles and hemoglobin levels. Even more important, PN of Grade 2 or higher was not reported, leading the authors to conclude that the regimen represents a “neuropathy-sparing approach” for the treatment of WM. In relation to these findings, Dr Fonseca verbalized his concern that the rarity of this disease has led to a dearth of FDA-approved therapies, making it a considerable challenge to obtain reimbursement for novel agents with proven patient benefit.
Now approved for mantle-cell lymphoma and chronic lymphocytic leukemia, perhaps it should not be that big of a surprise that ibrutinib is effective in WM, especially since a somatic mutation (MYD88 L265P) that appears to support malignant growth through Bruton tyrosine kinase is present in more than 90% of these patients. Indeed, in this exciting Phase II study 51 of 63 patients (81%) had best overall responses — which were usually rapid, often with rising hematocrit and reductions in serum IgM — strongly suggesting that this agent is destined to have a critical role in the care of these patients.
12-15-2015, 12:32 AM
Arthur N. Brodsky, Ph.D.
Just two weeks after the FDA approved the first immunotherapy drug to treat multiple myeloma, a second immunotherapy drug, elotuzumab (Empliciti), received approval yesterday to treat resistant forms of multiple myeloma in combination with other therapies.
Multiple myeloma is a blood cancer that causes plasma cells—which, normally, help the body fight infection and disease by making antibodies—to grow excessively and crowd out healthy blood cells. This disease is extremely hard to treat, with a 5-year survival rate of 50% after diagnosis, and recurrence is common.
This makes new and improved therapies for multiple myeloma a high priority for clinicians and scientists, especially considering that 27,000 new cases are expected in the United States this year alone. The FDA approval was based on the results of the ELOQUENT-2 study, a phase III trial which examined elotuzumab’s effects on patients with multiple myeloma that had been treated up to three times previously.
When combined with the two standard chemotherapy drugs used to treat myeloma, elotuzumab led to a 30% reduction in the risk of disease progression and death. After 2 years on the elotuzumab regimen, 41% of patients survived without disease progression as compared to 27% of those without the drug. Additionally, the overall response rates were 78.5% versus 65.5% in patients receiving elotuzumab versus those receiving the standard chemotherapy drugs. The beneficial effects of elotuzumab “seemed to get bigger over time, which really speaks to the power of this immune-based approach,” according to Sagar Lonial, M.D., the lead author of the ELOQUENT-2 study.
Importantly, the addition of elotuzumab did not increase the occurrence of adverse effects, such as fatigue and diarrhea, in response to treatment.
While daratumumab (Darzalex) first showed the potential of immunotherapy in treating multiple myeloma, elotuzumab takes this immune approach one step further. To label them for destruction, daratumumab targets the CD38 receptor, which is highly expressed on myeloma cells. But elotuzumab is an antibody that targets the SLAMF7 receptor, which is present on both myeloma cells and natural killer (NK) cells. This enhances the immune response through multiple mechanisms: by attaching to the myeloma cells, it marks them for destruction, and by attaching to the NK cells, it primes the immune cells to search for and attack the myeloma cells.
Prior to this trial, elotuzumab had already received priority review, as well as orphan drug and breakthrough therapy designation, from the FDA. It is also currently under review by the European Medicines Agency, which granted it accelerated assessment. Empliciti is marketed by Bristol-Myers Squibb, while Darzalex is marketed by Janssen Biotech.
Source: Cancer Research Institute
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