View Full Version : Multiple myeloma: a paradigm for translation of the cancer stem cell hypothesis
11-18-2011, 10:53 PM
According to Dr. Jayesh Mehta, director of the Hematopoietic Stem Cell Transplantation Program at Northwestern University Feinberg School of Medicine, the goals of stem cell transplant for myeloma are to increase the level/depth of response (e.g. achieve a complete remission), keep the response sustained for a longer period of time, and improve survival.
The aim is also to improve quality of life. If a robust response is achieved with a stem cell transplant, sustained pressure of ongoing intensive therapy may not be needed - giving patients a much-needed break from constant side effects of treatment if these have been troublesome.
The potential outcomes are:
- Death from toxicity. This is very rare - seen in the 1-2% range of patients.
- Reduction in disease burden if there is active disease. This is common - seen to at least some extent in about 80% of patients - including achievement of comple remission in 30-50%.
- Improvement in survival. This is common based on clinical trial data - and averages a couple of years. However, the magnitude of benefit can be less or substantially more - and is virtually impossible to quantify in an individual patient.
Anticancer Agents Med Chem. 2010 Feb;10(2):116-20.
Multiple myeloma: a paradigm for translation of the cancer stem cell hypothesis.
Agarwal JR, Matsui W.
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Despite recent advances in drug development, multiple myeloma (MM) remains incurable for the majority of patients due to relapse and disease progression. The cancer stem cell (CSC) hypothesis may provide an explanation for these clinical findings. It suggests that the long-term proliferative potential responsible for disease initiation, maintenance, and relapse is contained within specific subpopulations of biologically distinct tumor cells. Data in MM suggest that CSCs represent a rare cell population phenotypically resembling normal memory B cells. Compared to MM plasma cells, MM CSCs also appear to be relatively resistant to a wide variety of standard anti-cancer agents suggesting they may persist following treatment and mediate tumor re-growth and relapse. A unique property CSCs share with their normal counterparts is the potential for self-renewal that likely maintains the malignant clone over time. The development of therapeutic strategies targeting the signaling elements contributing to cancer cell self-renewal has been limited primarily because the cellular processes involved are poorly understood. However, it is common that the signaling pathway components regulating normal stem cell self-renewal are aberrantly activated in human cancers and may serve as potential therapeutic targets. One class of shared regulatory pathways are those active during normal embryonic patterning and organ formation such as Hedgehog (Hh), Notch and Wingless (Wnt), and emerging data suggest that these may play a role in CSCs. Here we review the identification and characterization of MM CSCs, the role of Hh in MM, and issues to be considered during the early clinical testing of CSC targeting agents.
11-18-2011, 10:57 PM
Blocking the embryonic signalling pathway, known as Hedgehog (Hh), could form a basis of new treatments. By using drugs to inhibit the Hedgehog signalling, they should be able to increase the effectiveness of chemotherapy and reduce the risk of cancer relapse.
Erivedge (vismodegib) is such a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), and has produced promising anti-tumor responses in clinical studies of cancers driven by mutations in this pathway.
Cancer stem cells (CSCs), are aggressive cells thought to be resistant to current anti-cancer therapies and which promote metastasis, are stimulated via a pathway that mirrors normal stem cell development. Disrupting the pathway, researchers are able to halt expansion of CSCs.
One approach is to force the CSCs into a differentiated state, thereby impairing stem characteristics, such as self-renewal. Interference with the Notch, Wnt, or Hedgehog pathways that are thought to regulate differentiation, are strategies that have been proposed.
Cell-based functional profiling labs have recognized the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. This lead to their focus on the human tumor primary culture microspheroid (microclusters), which contains all of these elements.
In their earlier work, they endeavored to isolate tumor cells from their benign constituents so as to study "pure" tumor cells. As time went on, however, they found that these disaggregated cells were artificially sensitized to the effects of chemotherapy and provided false positive results in vitro.
Early work by Beverly Teicher and Robert Kerbel that examined cells alone and in three-dimensional (3D) structures, lead to the realization that cancer cells inhabit a microenvironment. Functional profiling labs now study cancer response to drugs within this microenvironment, enabling them to provide clinically relevant predictions to cancer patients.
It is their capacity to study human tumor microenvironments that distinguishes them from other lab platforms in the field. And, it is this capacity that enables them to conduct discovery work on the most sophisticated classes of compounds that influence cell signaling at the level of notch, hedgehog and WNT, among others (Gonsalves, F, et al. (2011).
An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of WNT/wingless signaling pathway (PNAS vol. 108, no. 15, pp. 5954-5963). With this clinically validated platform they are now positioned to streamline drug development and advance experimental therapeutics.
Source: Dr. Robert Nagourney; Rational Therapeutics, Inc.
03-26-2012, 02:37 PM
Lenalidomide Maintenance After Lenalidomide/Melphalan/Prednisone for Elderly Patients with Newly Diagnosed Multiple Myeloma
Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 475
A Phase 3 Study Evaluating the Efficacy and Safety of Lenalidomide (Len) Combined with Melphalan and Prednisone Followed by Continuous Lenalidomide Maintenance (MPR-R) in Patients (Pts) 65 Years (Yrs) with Newly Diagnosed Multiple Myeloma (NDMM): Updated Results for Pts Aged 65–75 Yrs Enrolled in MM-015
Antonio Palumbo, MD 1, Zdenek Adam 2, Martin Kropff, MD 3, Robin Foà 4, John Catalano, MBBS FRACP FRCPA 5, Heinz Gisslinger, MD 6, Wieslaw Wiktor-Jedrzejczak, MD, PhD 7, Michel Delforge, MD, PhD 8, Katja Weisel, MD 9, Nicola Cascavilla, MD 10, Jan Van Droogenbroeck 11, Genadi Iosava, MD 12, Michele Cavo, MD 13, Joan Blade 14, Meral Beksac, MD 15, Ivan Spicka, MD, PhD 16, Torben Plesner, MD 17, Zhinuan Yu 18, Lindsey Herbein 18, Jay Mei, MD, PhD 18, Christian J. Jacques 18 and Meletios Athanasios Dimopoulos, MD 19
1. Myeloma Unit, Division of Hematology, University of Torino, AOU S. Giovanni Battista, Torino, Italy,
2. Dept. of Internal Medicine - Hematooncology, University Hospital, Brno, Czech Republic,
3. Medical Clinic A, University of Münster, Münster, Germany,
4. Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Roma, Italy,
5. Haematology/Oncology, Peninsula Private Hospital, Frankston, Australia,
6. Medical University of Vienna, Vienna, Austria,
7. Department of Hematology and Oncology, Medical University of Warsaw, Warsaw, Poland,
8. Department of Hematology, University Hospital Leuven, Leuven, Belgium,
9. Medical Center, Department of Hematology, Oncology, University of Tuebingen, Tuebingen, Germany,
10. Casa Sollievo della Sofferenza, Division of Hematology, San Giovanni Rotondo, Italy,
11. AZ Sint-Jan AV Brugge, Brugge, Belgium,
12. Institute of Hematology and Transfusiology, Tbilisi, Georgia,
13. Bologna University School of Medicine, Bologna, Italy,
14. Hematology, Institut d'Investigacion Biomediques Agusti Pi i Sunyer, Barcelona, Spain,
15. Department of Hematology, Ankara University, Ankara, Turkey,
16. First Faculty of Medicine 1st Medical Department - Clinical Department of Hematology, Charles University Hospital, Prague, Czech Republic,
17. Dept. of Hematology, Vejle Hospital, Vejle, Denmark,
18. Celgene Corporation, Summit, NJ, USA,
19. Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece
An IMiDs immunomodulatory agent, Len has a dual mechanism of action: its tumoricidal effect directly leads to tumor cell death, and its immunomodulatory effect may keep the tumor in remission. A phase 3, randomized, placebo (Pbo)-controlled trial, MM-015 compares MPR-R with fixed-duration MPR and MP induction in transplant-ineligible NDMM pts. Interim results showed unprecedented reduction in disease progression risk with MPR-R (Palumbo et al, IMW 2011); this analysis focuses on pts aged 65–75 yrs in whom the greatest benefit was observed.
A total of 459 pts aged 65 yrs with NDMM were enrolled. Induction consisted of nine 28-day cycles of melphalan 0.18 mg/kg (D1-4), prednisone 2 mg/kg (D1-4), and Len 10 mg (D1-21) (MPR-R and MPR) or melphalan and prednisone with Pbo (MP). After induction, MPR-R pts received Len 10 mg (D1-21) maintenance until progression; MPR and MP pts received Pbo. Pts with progressive disease (PD) could enroll in an open-label extension phase to receive Len 25 mg (D1-21) ± dexamethasone 40 mg (D1-4, 9–12, and 17–20). This analysis includes data up to Feb 28, 2011 (median follow-up, 30 mos).
There were 116/152 (76%), 116/153 (76%), and 116/154 (75%) of MPR-R, MPR, and MP pts, respectively, aged 65–75 yrs. Nearly 50% had ISS stage III disease, > 40% had β2-microglobulin > 5.5 mg/L, and 40% had CrCL < 60 mL/min.
With a median follow-up of 30 mos, MPR-R reduced progression risk by 70% and significantly prolonged median PFS (31 mos) vs MP (12 mos; hazard ratio [HR]: 0.30 [95% CI, 0.20–0.45]; P <.001). PFS benefits were observed regardless of response quality or risk factors. Response rates were higher (79% vs 47%; P <.001) and of better quality (35% vs 10% very good partial response; P <.001) for MPR-R vs MP with shorter median time to response (2 vs 3 cycles; P =.002). There is a trend for extended OS with MPR-R vs MP (Kaplan-Meier estimated 3-yr OS rates: 73% vs 65%; P =.254).
MPR-R significantly extended median PFS vs MPR (31 vs 15 mos; HR: 0.44 [95% CI, 0.30–0.66]; P <.001). A preplanned landmark analysis calculating PFS from maintenance entry (MPR-R and MPR) demonstrated that Len maintenance reduced the risk of progression by 68% (HR: 0.32 [95% CI, 0.20–0.52]; P <.001). Similar results were observed in patients > 75 years old. Response rates and quality were similar.
MPR induction alone provided a significant PFS benefit vs MP (15 vs 12 mos; HR: 0.64 [95% CI, 0.45–0.90]; P =.009).
MPR induction had an acceptable safety profile, allowing the majority of pts to reach maintenance. During induction, discontinuation due to adverse events (AEs) occurred in 13% of MPR and 4% of MP pts. The most common induction grade (Gr) 4 hematologic AEs for MPR-R, MPR, and MP were neutropenia (39%, 29%, and 7%) and thrombocytopenia (33%, 12%, and 4%). Febrile neutropenia was low for all arms (1%, 1%, and 0%). The most frequent Gr 3/4 nonhematologic AE was bone pain (3%, 3%, and 4%).
Len maintenance was generally well tolerated, with no evidence of cumulative toxicities. Only 5% of Len maintenance pts discontinued due to AEs. The most frequent Gr 4 hematologic AEs were thrombocytopenia (5%), neutropenia (4%), and anemia (3%); and Gr 3/4 nonhematologic AEs included bone pain (5%) and diarrhea (5%).
Hematologic second primary malignancies (SPMs) during induction and maintenance were 3 (2 AML, 1 ALL), 1 (MDS), and 0 in the MPR-R, MPR, and MP arms, respectively. These corresponded to incidence rates (IRs) per 100 pt-yrs of 1.8, 0.7, and 0. Solid tumor SPMs occurred in 2 pts per arm, were heterogeneous and balanced across arms; IRs were 1.2, 1.4, and 1.6, respectively.
Continuous Len treatment with MPR-R significantly reduced disease progression risk compared with MP and MPR in pts aged 65–75 yrs. MPR induction significantly extended PFS vs MP. To date, MPR-R has provided one of the longest median PFS (31 mos) among other available regimens (bortezomib, melphalan, prednisone: 24–27 mos; melphalan, prednisone, thalidomide: 28 mos; bortezomib, melphalan, prednisone, thalidomide: 37 mos). The PFS benefit in the landmark analysis supports continuous treatment to suppress disease in all patient age groups. Management of toxicities is essential to allow pts to continue therapy and receive full benefits. Although hematologic SPMs were imbalanced, the risk of PD/death clearly outweighs the risk of SPMs. MPR-R should be considered a standard of care in transplant-ineligible NDMM pts aged 65–75 yrs.
Palumbo: Merck: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Off Label Use: Lenalidomide in newly diagnosed patients with multiple myeloma. Catalano: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gisslinger: Celgene: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; AOP-Orphan: Speakers Bureau. Wiktor-Jedrzejczak: Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria, Research Funding. Delforge: Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Weisel: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Droogenbroeck: Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Janssen Cilag: Consultancy. Cavo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Beksac: Celgene: Honoraria, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau. Spicka: Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Honoraria, Speakers Bureau; Novartis: Honoraria. Yu: Celgene Corporation: Employment. Herbein: Celgene Corporation: Employment. Mei: Celgene Corporation: Employment. Jacques: Celgene Corporation: Employment. Dimopoulos: Celgene: Consultancy, Honoraria.
05-10-2012, 07:02 PM
Second Primary Malignancies in Newly Diagnosed Multiple Myeloma Patients Treated with Lenalidomide: Analysis of Pooled Data in 2459 Patients
Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 996
Antonio Palumbo, MD1, Alessandra Larocca, MD 1, Sonja Zweegman, MD PhD 2, Giulia Lupparelli 1, Agostina Siniscalchi, MD 3, Pellegrino Musto, MD 3, Moshe Levin, MD 4, Henk Lokhorst, MD, PhD 5, Sara Grammatico, MD 3, Lucio Catalano, MD 3, Roberto Ria, MD 3, Anna Marina Liberati, MD 3, Francesca Patriarca, MD 3, Giulia Benevolo, MD 3, Antonietta Pia Falcone, MD 3, Bronno van der Holt, PhD 6, Sylvia Verelst, MSc 6, Davide Rossi 3, Claudia Crippa, MD 3, Sara Bringhen, MD 1, Roman Hajek, MD 7, Andrew Spencer, MD 8, Mario Boccadoro, MD 1 and Pieter Sonneveld, MD, PhD 6
1. Myeloma Unit, Division of Hematology, University of Torino, AOU S. Giovanni Battista, Torino, Italy,
2. Department of Hematology, VU University Medical Center, Amsterdam, Netherlands,
3. Italian Multiple Myeloma Network, GIMEMA,
4. Department of Hematology, Hadassah University Medical Centre,
5. Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands,
6. Department of Hematology, Erasmus Medical Center, Rotterdam, Netherlands,
7. Department o, Internal Medicine and Hematooncology, and Department of Clinical Hematology, University Hospital Brno,
8. Malignant Hematology and Stem Cell Transplantation Service, Alfred Hospital, Melbourne, Prahran, Australia
The risk of developing a tumor is 2.1% per year of life in the general population older than 65 years. In MGUS, the incidence of AML/MDS is increased 8 fold compared with normal population, this observation supports a role for non-treatment related factors in the causation of AML/MDS in plasma-cell dyscrasias (Blood, July 27,2011). In multiple myeloma (MM) patients, the risk of second primary malignancy (SPM) is influenced by age and the use of alkylating agents.
We examined SPM incidence rates (IRs) per 100 person-years in 2459 newly diagnosed MM patients, enrolled in 9 experimental trials of the European Myeloma Network (RVMM EMN 01, RVMM EMN 441, RVMM PI 026, RVMM PI 302, RVMM PI 209, GIMEMA MM 03 05, GIMEMA MM 04 05, GISMM 2001, HOVON 87). 287 patients received cyclophosphamide-lenalidomide-corticosteroids (CRC), 685 melphalan-prednisone-lenalidomide (MPR), 484 high-dose melphalan followed by lenalidomide maintenance (MEL200-R), 164 melphalan-prednisone (MP), 328 MP-thalidomide (MPT), 257 MP-bortezomib (MPV), 254 MP-bortezomib-thalidomide (VMPT). This post hoc analysis was restricted on pooled data from 1798 patients with at least 1 year of follow-up.
As of March 2011 cut-off, median follow-up was 28 months. Median age was 69 years, 49% of patients were aged 65–74 years, and 19% aged 75 years. Total cases of SPMs were 30/1798 (IR 0.72), including 8 hematologic (acute leukemia) and 22 solid cancers (gastrointestinal, lung, breast, skin, gynecologic). No cases of SPMs were reported in patients receiving cyclophosphamide and lenalidomide.
SPM: second primary malignancy; CRC: cyclophosphamide-lenalidomide-corticosteroids; MPR: melphalan-prednisone-lenalidomide; MEL200-R: high-dose melphalan followed by lenalidomide maintenance; MP: melphalan-prednisone; MPT: MP-thalidomide; MPV: MP-bortezomib; VMPT: MP-bortezomib-thalidomide
In patients receiving lenalidomide and alkylating agents (CRC/MPR/MEL200-R), the cumulative incidence of death for MM and diagnosis of SPMs at 3 years was 13.8% and 2.0%, respectively. In patients not receiving lenalidomide (MP/MPT/MPV/VMPT), the cumulative incidence of death and SPMs at 3 years was 26.1% and 1.1%, respectively. In the analysis restricted to Italian patients treated with lenalidomide and alkylating agents, we report 11 cases of SPMs. This figure is lower than the 15.6 cases expected from the age/sex adjusted incidence derived form the Italian Cancer Registry, with a standardized incidence ratio of 0.70.
SPM incidence was lower than expected in all treatment groups. At present, the benefits of continuous therapy with lenalidomide outweigh the potential risk of SPMs. Longer follow-up is needed to definitively assess the risk of SPMs in patients receiving lenalidomide with alkylating agents. With the limitation of a short follow-up, the numbers currently support a role for non-treatment related factors as causes of SPMs. Updated data will be presented at the meeting.
Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria. Larocca: Janssen-Cilag: Honoraria. Zweegman: Celgene: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding. Musto: Celgene: Consultancy, Honoraria, Research Funding. Lokhorst: Celgene: Consultancy; Genmab: Consultancy. Ria: celgene: Consultancy. Patriarca: Celgene: Honoraria; Schering-Plough: Honoraria. Bringhen: Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Merck Sharp & Dhome: Membership on an entity's Board of Directors or advisory committees. Hajek: Merk: payment for educational presentation; celgene: Honoraria; Janssen-Cilag: Honoraria. Spencer: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees.
12-20-2012, 02:27 PM
The finding that Revlimid (lenalidomide) delays relapse after stem cell transplantation comes from 2 placebo-controlled phase 3 trials. In the first study (N Engl J Med. 2012;366:1782-1791), conducted in 615 patients younger than 65 years, the disease returned after 41 months with lenalidomide and after 23 months with placebo; after 4 years of follow-up, more than 70% of patients were alive in both groups.
In the second study (N Engl J Med. 2012;366:1759-1769), conducted in 460 patients younger than 71 years, median time to progression was 46 months with lenalidomide and 27 months with placebo. Lenalidomide also increased overall survival (35 deaths in the lenalidomide group and 53 in the placebo group). However, lenalidomide was associated with more adverse events and a higher incidence of second cancers than placebo (7%–8% vs 3%–4%), the report notes.
Revlimid (lenalidomide) combined with dexamethasone has proven to be an effective treatment for patients with newly diagnosed or relapsed/refractory multiple myeloma.
Three new studies, all published in the May 10, 2012 issue of the New England Journal of Medicine, support the use of Revlimid (lenalidomide) as maintenance therapy.
In the first study, conducted in the United States, 100 days after hematopoietic stem-cell transplantation, Revlimid (lenalidomide) maintenance therapy was associated with a significantly longer time to disease progression and significantly better overall survival. The median time to disease progression was 46 months in the lenalidomide group and 27 months in the placebo group (P < .001).
"Lenalidomide can be considered a new standard of care for maintenance therapy for responding patients after a single autologous hematopoietic cell transplant," said lead author Philip McCarthy Jr, MD, director of the Blood & Marrow Transplant Program at Roswell Park Cancer Institute in Buffalo, New York.
"These are all very interesting studies that demonstrate that lenalidomide maintenance therapy is an important component of long-term control of multiple myeloma," he told Medscape Medical News.
The second study, conducted in France, also compared Revlimid (lenalidomide) maintenance therapy with placebo in the transplant setting. Revlimid (lenalidomide) maintenance therapy improved median progression-free survival, compared with placebo (41 vs 23 months; hazard ratio [HR], 0.50; P < .001); this benefit was observed in all patient subgroups. The rate of overall survival at 4 years, however, was similar in the Revlimid (lenalidomide) and placebo groups (73% vs 75%).
The third study, conducted by Italian researchers, evaluated Revlimiid (lenalidomide) maintenance therapy in patients 65 years and older with newly diagnosed multiple myeloma who were ineligible for transplantation. The researchers found that progression-free survival was significantly longer in the group treated with melphalan/prednisone/lenalidomide followed by lenalidomide maintenance therapy than in the group treated with melphalan/prednisone/lenalidomide followed by placebo (31 vs 14 months; P < .001) and than in the group treated with melphalan/prednisone followed by placebo (31 vs 13 months; P < .001). This benefit, however, was not observed in patients older than 75 years.
"Of note, all 3 studies show a time-to-progression benefit for Revlimid (lenalidomide) as maintenance therapy following either induction plus transplant therapy or induction therapy alone," Dr. McCarthy explained.
The lack of overall survival benefit in the French study might be due to the different induction regimens, he noted, or to the use of intensive consolidation therapy in half the patients in both groups and discontinuation of the maintenance therapy.
Standard of Care? Maybe Not Yet
Revlimid (lenalidomide) is a well-known validated therapy for multiple myeloma that has significantly contributed to the improved survival of patients with this incurable disease, said Joseph Mikhael, MD, a hematologist at the Mayo Clinic in Scottsdale, Arizona, in an interview.
These 3 studies provide evidence supporting the benefit of this drug in patients who are eligible or ineligible for autologous stem-cell transplantation, he said.
"It's too early to consider Revlimid (lenalidomide) maintenance as standard of care in all patients after transplant," said Dr. Mikhael, who was not involved in any of the studies. "Although there was a survival advantage in the American study, there was no survival advantage in the French study," he noted. He added that the benefit of this treatment strategy should be considered individually for each patient.
Dr. Mikhael also pointed out that the risks associated with this therapy are real, and include short-term toxicity. "The long-term risk of second cancers must also be considered," he said. "We require more information in the long term about the risk of second cancers, but it must be placed in the context of the proven benefit of this agent to delay progression of the disease," he explained.
He added that overall, "this will likely result in the increased use of this agent as maintenance therapy after transplant, although other approaches, such as more consolidation therapy immediately after transplant — instead of indefinite maintenance — must also be investigated."
An accompanying editorial echoes some of these concerns. Ashraf Z. Badros, MB, ChB, from the University of Maryland School of Medicine in Baltimore, writes that it is debatable whether these data establish a new standard of care for myeloma.
The benefit associated with Revlimid (lenalidomide) seems to outweigh the risk of second cancers, he explains. "Nevertheless, the small increase in the risk of second cancers is significant."
Another concern involves the cost and duration of maintenance therapy. "Lenalidomide costs $447.62 per 10 mg tablet (or $163,381 per year for the average patient)," notes Dr. Badros. "This total does not account for the costs of laboratory monitoring, physician visits, and management of side effects. Is it cost effective?"
The data on progression-free survival support its use as maintenance therapy after careful assessment of the risks and benefits, he notes, adding that other drugs for maintenance therapy are now being tested.
"As myeloma evolves from an 'incurable' cancer to a chronic disease, physicians are faced with the task of maximizing available treatments, not only to improve survival but also to maintain their patients' quality of life," Dr. Badros concludes.
Risk for Second Primary Cancers
Lenalidomide is a derivative of thalidomide and has antiangiogenic and antineoplastic properties. In 2006, it was approved by the US Food and Drug Administration (FDA) for use in combination with dexamethasone in patients with multiple myeloma who have received 1 previous therapy. Since that time, it has become a standard treatment in initial disease and in relapsed disease, and a number of studies have looked at the use of lenalidomide in combination with other drugs and in a range of myeloma settings.
It also has an indication for the treatment of patients with transfusion-dependent anemia resulting from low- or intermediate-risk myelodysplastic syndromes associated with a 5q deletion abnormality with or without additional cytogenetic abnormalities.
However, clinical trials investigating the use of lenalidomide in patients with newly diagnosed multiple myeloma have shown that treatment carries a nearly 3-fold risk for second primary cancers. There seems to be a smaller increased risk for second primary cancer in patients who received lenalidomide for relapsed or refractory myeloma. This prompted the FDA to initiate a safety review last year, and new safety information has now been added to the warnings and precautions section of the lenalidomide label.
The FDA does not recommend delaying, modifying, or restricting the use of lenalidomide in the treatment of conditions for which it is indicated, but advises that the potential benefit of lenalidomide and the risk for a serious adverse event need to be weighed when considering treatment with this agent.
Revlimid (lenalidomide) and Stem-Cell Transplantation
In the American study, Dr. McCarthy and colleagues evaluated whether Revlimid (lenalidomide) maintenance therapy can prolong the time to disease progression after autologous hematopoietic stem-cell transplantation.
Results of the fifth interim analysis of this study were presented last year at the International Myeloma Workshop, and were reported at that time by Medscape Medical News.
In the current analysis, the median follow-up was 34 months.
The authors randomized 460 patients younger than 71 years with either stable disease or a marginal, partial, or complete response 100 days after stem-cell transplantation to lenalidomide (n = 231) or placebo (n = 229).
At the most recent follow-up, 86 patients (37%) in the lenalidomide group and 132 (58%) in the placebo group had disease progression or had died (HR, 0.48). The 3-year rate of freedom from progression or death was higher in the lenalidomide group than in the placebo group (66% vs 39%).
A benefit in overall survival was also seen in this study, the authors note; more patients in the lenalidomide group than in the placebo group were alive at a median follow-up of 34 months (85% vs 77%).
As expected, the cumulative incidence of a second primary cancer was higher in the lenalidomide group ( P = .008), and the cumulative incidence of progressive disease and the incidence of mortality were higher in the placebo group ( P < .001 and P = .002, respectively).
12-20-2012, 02:33 PM
The Italian researchers compared the efficacy and safety of melphalan/prednisone/lenalidomide (MPR) induction therapy followed by lenalidomide maintenance therapy with MPR or melphalan/prednisone (MP) without maintenance therapy. The study, led by Antonio Palumbo, MD, from Turin University, and conducted at 82 centers in Europe, Australia, and Israel, randomized 459 patients to MPR plus lenalidomide maintenance (n = 152), MPR (n = 153), or MP (n = 154).
The patients were 65 years or older with newly diagnosed disease and were not candidates for transplantation.
Partial results of this study were presented in 2009 at the American Society of Hematology annual meeting. At that time, Dr. Palumbo noted that this regimen "can be considered a new standard" for patients older than 65 years newly diagnosed with multiple myeloma.
Dr. Mikhael questions that premise. "This study establishes the feasibility of using this drug in the longer term, but more study is required before it becomes the standard of care, especially as it did not compare this strategy to the current standard of care," he said.
"The lack of overall survival benefit is concerning and requires more follow-up," Dr. Mikhael added. "The lack of improvement in progression-free survival in those older than 75 years also bears consideration."
Median follow-up was 30 months. Median progression-free survival was significantly longer with MPR plus lenalidomide than with MPR or MP. The response rates were better with MPR plus lenalidomide than with MP (77% vs 50%; P < .001) and with MPR than with MP (68% vs 50%; P = .002).
However, the progression-free survival benefit of MPR plus lenalidomide was only seen in patients 65 to 75 years of age, not in those older than 75 ( P = .001 for treatment-by-age interaction). In the older age group, the median progression-free survival was 19 months with MPR plus lenalidomide, 12 months with MPR, and 15 months with MP.
One third of the patients in the MPR plus lenalidomide group and the MPR group experienced a very good partial response or better, compared with only 12% in the MP group.
During induction therapy, the most frequent adverse events were hematologic; these occurred more frequently in the lenalidomide groups. Grade 4 neutropenia was reported in 35%, 32%, and 8% of the MPR plus lenalidomide, MPR, and MP groups, respectively. The incidence of second primary tumors was higher with MPR plus lenalidomide; the 3-year rate of second primary tumors was 7% with MPR plus lenalidomide, 7% with MPR, and 3% with MP.
The American study was funded by the National Cancer Institute. The French study was supported by the Programme Hospitalier de Recherche Clinique, the Swiss Group for Clinical Cancer Research, and a grant from Celgene, the manufacturer of lenalidomide. The Italian study was supported by Celgene.
N Engl J Med. Published online May 10, 2012.
Lenalidomide Maintenance Beneficial in Multiple Myeloma. Medscape. May 10, 2012.
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