الفهرس 
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Abstract
Multiple myeloma (MM) is an incurable neoplasm of plasma cells that affects more than 20,000 people annually in the United States. Treatment of MM involves induction chemotherapy followed usually by an autologous hematopoietic stem cell transplantation (auto-HCT) and maintenance therapy.
For transplant eligible patients, the options include auto-HCT or allogeneic-HCT. Auto-HCT is generally offered to majority of the patients while allogeneic-HCT is reserved for selected high-risk myeloma patients due it its high early transplant related mortality (TRM) and significant side effects. Some patients can benefit from a tandem auto-HCT, particularly those not achieving at least very good partial response (VGPR) after first auto-HCT.
Consolidation therapy refers to a defined course of treatment administered after an initial disease response is achieved while maintenance therapy involves prolonged administration of agents with low toxicity profiles in an attempt to prevent progression of disease. While the benefit of maintenance therapy on progression-free survival (PFS) is well established, the overall survival (OS) advantage is less clear.
Maintenance therapy has evolved over time. Early trial used interferon, which had modest PFS benefit but significant toxicity. In late 1990s and early 2000s thalidomide was frequently used. It conferred a PFS advantage but was not easily tolerated by the patients, particularly due to significant long-term toxicities such has peripheral neuropathy and venous thromboembolism, leading to therapy discontinuation in a substantial number of patients (30 to 80 percent by two years). More recently, lenalidomide, an immunomodulatory agent (IMiD) became standard choice for the post auto-HCT maintenance after large prospective randomized trials showed better tolerance, consistent PFS advantage and also possibly OS advantage. Proteasome inhibitors (PI) are also used routinely in the maintenance setting particularly in patients with high-risk cytogenetic abnormalities. However, it is not clear, which maintenance option; IMiD or PI offers the best long-term outcome.
This is a retrospective chart based review. At MD Anderson cancer center in Houston Texas 750 myeloma patients who received an autologous-Hematopoietic cell transplantation HCT patients who received maintenance therapy after the transplant from January 1, 2007 until December 31, 2015 as part of first line therapy.
In our population the majority were males 430 patients (57%), median Age at transplant 60.8 years ranging from 31.9 to 80.3 years. Most of the population were White 504 patients (67%). Patients were running an ISS stage at diagnosis, stage I at 273 patients (44%), stage II186 patients (30%), and stage III 164 patients (26%), Missing ISS stage of 129 patients, Immunoglobulin subtype, IgG 448patients (60%), IgA 152 patients (20%), Light chain only 119 patients (16%), IgD11 patient (1%), Plasma cell leukemia 9 patients (1%), Non-secretory in 5 patients (1%), Biclonal in 4 patients (1%), IgM in 4 patients (1). The cytogenetic risk category was standard risk in most of the patients 586 of them (79%), High risk category was found in 153 patients (21%) it was Missing in 13 patients. BM plasma cell percentage was found for 719 patients and its median was 40 percent and it ranged from zero to 100 percent, LDH was done for 496 patients and its median was 405.5 unit per liter and was ranging from 78.0 to 8868 unit per liter, Creatinine was found for 708 patients also with a median of 1 mg per decileter ranging from zero till 28.5 mg per decileter. β2-microglobulinwas found for 629 patientsand its median 3.4 mg per deciliter and ranged from 0.9 till 42.7 mg per deciliter. The Calcium level was found for 668 patients and its median was 9.5 mg per deciliter and ranged from (4.2 – 24.9), the Hemoglobin level was736 patents median was 10.9 grams per deciliter and range is (4.2 – 17.0). the performance status of the patients at diagnosis according to Karnofsky performance status KPS was more than half of them were 90 percent , with a median of 90 percent and a range from 60 till 100 percent. The majority of the patients were induced with combined approach using proteasome and an immunomodulatory drugs with 364 patients at forty eight percent while with PI in 38 percent with 284 patients and 93 patients and 12 percent, Induction therapy was done with a doublet 225 patients (30%), Triplet in 471 patients (63%), Quadruplet in 44 patients (6%), chemotherapy in 11 patients (1%) and one patient missed data from his induction. Mobilization was done with Growth factors only in 471 patients (71%), Chemo-mobilization in 193 patients (29%), 88 patients had missing data for their mobilization methods. Disease status at transplant after the induction according to international myeloma working group response criteria IMWG was a stringent complete response in five percent 36 patients. Complete response in 19 patients (3%), very good partial response VGPR in 208 patients (28%), partial response PR in 337 patients (45%), stable disease SD in 41 patients (5%),progressive disease PD in 34 cases (5%). The median range of Months from diagnosis to transplant, 6.9 months and the range is (1.7 – 170.2). The conditioning regimen used for the transplant of our patient population was melphalan 200 mg per meter square in 507 patients (68%), Melphalan one hundred and forty milliegrams per meter square was used in 243 patients (32%). The minimal residual disease was assessed using next generation flow cytometery according to the EuroFlow protocols and turned out to be MRD pre-transplant was done in only 247 patients and was positive in 161 of them 64 percent and negative in 86 patients 34 percent. MRD pre-maintenance, Positive in 197 patients (41%), Negative in 279 patients (59%) and Missing in 276 patients. The toxicity of maintenance is generally rare to occur and if occurred it generally mild and acceptable. The most commonly observed toxicity encountered during the maintenance phase of therapy for MM was infection which occurred in 41 percent of the subjects and they ranged from grade one to four. No cases had grade five i. re died of their infection. The second most commonly observed toxicity was second primary malignancy at the rate of 4 percent and 33 events among 750 patients whom were included in the study group. Of these the most commonly encountered was myelodysplasia where 8 cases where diagnosed and this is a rare complication to occur and understandable in the pathogenesis of the myeloma itself being heterogenous and impaired immune environment of the bone marrow. The exposure to alkylating agent as the melphalan is also a risk factor by itself, in addition to the use of Lenalidomide was reported to carry hazard of myelodysplasia.
Our data which analyzed a large patient population of 750 patients treated at MD Anderson cancer center from the period of 2007 till 2015. We described this population’s demographic data which is comparable to other patients populations reported from North America CALGB 100104 and those reported from the French group Intergroupe Francophone du Myélome (IFM) 2005-02, also those from the Italian group Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209. As regards age, immunoglobulin subtype of MM, creatinine and calcium level and induction regimen for CALGB. While IFM cohort is comparable to ours regards the gender, ISS stage, Beta 2 microglobulin, type of the immunoglobulin myeloma and cytogenetic risk category.
Although demographic data from the CALGB provided that their ISS stage was more stage one with 77 percent of their patient population, response to transplant was more favorable in their group with more complete response ranging around 20 percent while in our cohort is 8 percent which may be attributed to more patients in CALGB of earlier stage of myeloma. Also the cytogenetic risk category was not reported in the CALGB trial while it is emphasized in our cohort. The mean time from diagnosis to transplant in the CALGB was 3.3 months while in our cohort was around 6 months which may reflect that our population were more difficult to treat as MD Anderson is a referral center in which patients may take time from being diagnosed till the initiation of treatment.
The French group Intergroupe Francophone du Myélome (IFM) 2005-02 differs from our population their population median age was generally younger than ours with 55 years versus 60 years, in that a group of their patients they used DCEP chemotherapy to reinforce their conditioning during the transplant while we used melphalan only. Twenty percent of their population had two transplants which was obviously reflected on their response categories with more than 60 percent of the patient had a VGPR or better while this was around forty percent in our cohort.
The Italian group Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209 population were generally older with 71 years at median, their gender was 45 percent males , their KPS lower than our group 80 percent versus 90 percent, had more advanced disease aound half of their patients running a stage 3 disease according to international staging system, but their cytogentic risk category were generally less aggressive as only around 10 percent had high risk genetic abnormality of the forty percent of their patient whom had data about their cytogenetics risk category.
As regarding the safety data CALGB cohort had more bone marrow suppression in the lenalidomide maintenance arm together with more second primary malignancies around 8 percent which is very high in comparison to our modest four percent, with half of their patients running a hematologic malignancy which can be attributed to differences in the patient population or pharmacokinetics and dynamics of lenalidomide should be explored in subsequent trials. The Italian group Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209 saftey data coincides with our group reporting mild hematologic toxicity around 3 percent and rare incidence of second primary cancer also around 2 percent. The French group Intergroupe Francophone du Myélome (IFM) 2005-02 reported comparable hematologic toxicities and no reporting for second primary malignancies.
The trials described our patient population seen at the MD Anderson cancer center to be rather heterogenous with more difficult to treat patients and reported that maintenance should be used in the treatment of MM due to its benefit on progression free and overall survival. Also that this approach could be done using various drugs and combinations all of which are rather safe with low incidence of mild toxicities.