Maintenance Therapy For Multiple Myeloma Research Articles

Results of a Multicenter Randomized Phase II Trial of Thalidomide and Prednisone Maintenance Therapy for Multiple Myeloma after Autologous Stem Cell Transplant

We report a multicenter, randomized phase II trial conducted to assess the tolerability of combined thalidomide and prednisone maintenance in multiple myeloma. Eligibility required administration of melphalan (200 mg/m2) with blood stem cell support within 1 year of treatment onset and initiation of maintenance within 60 to 100 days after stem cell infusion. All patients received 50 mg of prednisone by mouth on alternate days and thalidomide at a starting dose of either 200 or 400 mg daily by mouth. The primary end point was the incidence of dropout or dose reduction due to treatment toxicity within 6 months. Sixty-seven patients were enrolled. Median follow-up is 36.8 months. The primary end point was reached by 31% of patients on the 200 mg of thalidomide arm and 64% of patients on the 400 mg of thalidomide arm. Allowing for dose reduction, 76% of patients assigned to the 200 mg of thalidomide arm and 41% of patients assigned to the 400 mg of thalidomide arm remained on any maintenance therapy 18 months after registration. Eighty-eight percent of all patients dose-reduced thalidomide and 72% of all patients dose-reduced prednisone within 2 years of beginning maintenance. The median progression-free survival post-transplant is 32.3 months, or 42.2 months from diagnosis. Only the 200 mg of thalidomide arm of this trial met our definition of a tolerable maintenance therapy, defined as no dose reductions or discontinuation due to toxicity in at least 65% of patients for a minimum of 6 months, thus establishing a dosing schedule for phase III trials.

Rituximab Administration Following Autologous Stem Cell Transplant for Multiple Myeloma Is Associated with Severe IgM Deficiency.

Clonotypic B cells are frequently isolated from the peripheral blood of patients with multiple myeloma (MM). These clonotypic B cells may be clonogenic cells of MM. We hypothesized that rituximab may be a useful maintenance therapy in MM after autologous stem cell transplant (ASCT). The rationale was that CD20 antibody would deplete the clonotypic and, hence, clonogenic B cells to reduce the risk of disease relapse.ASC were mobilized with Cytoxan (3g/m2) and G-CSF from patients with MM. Two weeks after ASC collection, high dose IV melphalan (200 mg/m2) was administered followed 24 hours later by the infusion of at least 2x106/kg CD34+ cryopreserved ASC. Rituximab infusion (375 mg/m2) was started on day +30. Each patient received one antibody infusion every 3 months for 2 years or until disease progressed. All patients continued on monthly zoledronate and did not receive any other antimyeloma treatment. A total of 10 patients have been treated. Seven patients who have had post-transplant follow-up periods of >12 months were evaluated. The immunoglobulin recovery and incidence of infections in this group of patients were compared to 6 patients with MM who have undergone an ASCT without rituximab maintenance.The total normal IgM level in all 7 patients was severely depressed following rituximab administration. IgG and IgA were variably affected in these patients. The IgM immunosuppression was prolonged and consistent, being seen in all patients, regardless of the disease status after transplantation. In contrast, the control group showed normalization of the total IgM levels by 3 months after transplant. Two patients treated with rituximab received pneumococcal vaccines 12 months after transplant and neither developed any IgG response to the vaccines. The data indicate that rituximab infusion following ASCT for MM severely impaired B-cell immune reconstitution.Six of the 7 patients developed moderate to severe infections during the first 12 months after initiation of rituximab infusion. There were a total of 23 episodes of infections: 21 pneumonia and 2 septicemia (one pneumococcus and one Pseudomonas). A patient died in CR due to pneumonia. In contrast, only one episode of pneumonia was observed in the control group during the same follow-up period. Therefore, the IgM deficiency probably predisposed the patients to infection.Of the 7 patients who have had more than 12 months of follow-up periods, 4 had disease refractory to standard induction chemotherapy. Of all the 10 patients treated, 6 achieved CR (2 were in CR before treatment, 2 achieved CR 3 months and 2 achieved CR 6 months after starting rituximab). All 4 patients with refractory MM (all had a follow-up of more than 12 months) achieved CR, one before and 3 after starting rituximab. One of the refractory patients has since relapsed, one died of pneumonia in CR 12 months and the other 2 have remained in CR 12+ and 18+ months after ASCT. With a follow-up of 29 months after transplant, the progression-free survival was 56.5% and the overall survival 71.4%.Rituximab infusion after ASCT for MM is therefore associated with severe IgM deficiency and an increased risk of infection. Further works are needed to determine the antitumor activities of rituximab in MM in the setting of minimal residual disease, but this should only be carried out with special attention to the prevention of infection.

Results of a Multi-Center Randomized Phase II Trial of Thalidomide and Prednisone Maintenance Therapy for Multiple Myeloma Following Autologous Stem Cell Transplant.

Multiple myeloma (MM) patients benefit from high dose chemotherapy, however relapse is inevitable and novel means of maintaining remission are required. Although oral thalidomide is an attractive agent for maintenance studies no careful dose finding studies have been performed in this setting. Given uncertainties about the long-term tolerability and the appropriate therapeutically active dose of thalidomide in this situation, we completed a prospective multi-center, randomized phase II trial to assess the tolerability of combined thalidomide and prednisone maintenance in MM and to select a preferred dose of thalidomide to eventually test in the phase III setting. Enrolment was from July 2000 to September 2001. Eligibility required administration of melphalan 200mg/m2 with blood stem cell support within one year of treatment onset and initiation of maintenance within 60–100 days post stem cell infusion. All patients received prednisone 50mg p.o. on alternate days and thalidomide at a starting dose of 200mg escalating to a target dose of either 200mg or 400mg p.o. daily. The primary endpoint was the incidence of dropout or dose reduction due to treatment toxicity within 6 months. Because of an excess of treatment - related toxicity, entry to the 400 mg dose arm was closed after completing the first stage of the projected sample size. Sixty Seven patients were enrolled. Median follow-up is 36.8 months. The primary endpoint was reached by 31% of patients on the thalidomide 200mg arm and 64% of patients on the thalidomide 400mg arm. Allowing for dose reduction, 76% of patients assigned to thalidomide 200mg and 41% of patients assigned to thalidomide 400mg remained on any maintenance therapy 18 months after registration. The median cumulative dose of thalidomide received is 83.5g (range 16–1626g) on the 200mg arm, while it is 76.9g (range 66–3520g) on the thalidomide 400mg arm. Thus, patients on the higher thalidomide starting dose cumulatively received less drug overall as a consequence of toxicity. Eighty eight percent of all patients dose reduced thalidomide and 72% of all patients dose reduced prednisone within 2 years of beginning maintenance. Using EBMT response criteria 15% of patients at study entry had attained a complete or near complete remission post-transplantation. During follow up, the best response achieved was upgraded in 53% of evaluable patients with 38% assessed as achieving a complete or near complete remission one year after study entry. Median time from start of therapy to registration was 9.9 months. Progression free survival from time of registration post transplant was 32.3 months (42.2 months PFS from beginning of therapy). Seventeen of the 67 patients have died by August 2004; one year survival was 91%.Only the thalidomide 200mg arm of this trial met our definition of a tolerable maintenance therapy defined as no dose reductions or discontinuation due to toxicity in at least 65% of patients for a minimum of 6 months. A randomized Phase III trial is now testing this maintenance regimen versus placebo.

Severe hypothyroidism after thalidomide treatment

A man aged 49 reported lethargy and back pain and was found to have multiple myeloma. The treatment began with radiotherapy to the spine and repeated courses of vincristine, doxorubicin and dexamethasone. Then, on reaching plateau phase, he underwent autologous stem-cell transplantation following high-dose melphalan. This led to complete remission of the myeloma. As a part of a clinical trial investigating thalidomide as maintenance therapy for multiple myeloma, he was randomized to receive this drug, initially at 50 mg/day. The dose was increased to 100 mg/day after two weeks and to 200 mg/day after eight weeks. Three months after starting thalidomide, he reported increasing lethargy, constipation and cold intolerance. He had slow-relaxing ankle jerks. There was no goitre. Thyroid function tests revealed gross biochemical hypothyroidism, with thyrotropin (TSH) 4100 mu/L (normal range 0.25–5.5) and free T4 (FT4) 1.8 pmol/L (9.7–25.7). Thyroid peroxidase (TPO) antibodies were present. Two days before starting thalidomide his thyroid function had been essentially normal (TSH 0.21 mu/L, FT4 23.4 pmol/L), and there was no family history of thyroid disease. After the diagnosis of hypothyroidism he was taken off thalidomide and started on thyroxine, with resolution of his symptoms. On thyroxine 125 mg daily he remained euthyroid and his multiple myeloma was still in remission eighteen months from diagnosis. The UK Committee on Safety of Medicines say that they received no other reports of thalidomide-induced hypothyroidism between 1966 and 2003.

Renal safety evaluation of zoledronic acid and thalidomide when used as post-stem cell transplant maintenance therapy in multiple myeloma

6655 Background: Anecdotal reports suggest that combination therapy with zoledronic acid (ZA) and thalidomide (T) in multiple myeloma (MM) patients may increase the risk of renal dysfunction compared to ZA alone. As part of a multicentre Phase III trial of post autologous stem cell transplant (ASCT) T maintenance therapy we have compared renal function in MM patients receiving ZA with or without concomitant T. Methods: A multicentre, open label, randomised trial of T 200mg p.o daily for 12 months post-ASCT in patients with non-progressive MM. All patients also received ZA 4mg IV over 15 minutes every 28 days and alternate day prednisolone 50mg. A subset of patients underwent ZA Cmax and AUC (0–48) determinations for the first two ZA doses. Univariate analysis was conducted using student t-tests and chi-square tests for equal proportion. Multivariate analysis was conducted using a repeat measures analysis of variance. Differences in creatinine (Cr) between arms over time were determined by fitting an interaction between dose and arm, with dose and arm treated as linear predictors. Results: To-date 83 patients have commenced maintenance therapy (T=40), received a median of 9 (T) or 8 (no T) ZA doses and 15 patients have completed the PK study (T=8). The arms were well matched for gender, age, pre-ASCT B2microglobulin and baseline Cr. Four patients have had ZA withheld because of a rise in Cr (T = 1, no T=3). No ZA-related serious adverse events have occurred. Multivariate analysis demonstrated that higher Cr levels were associated with male gender and pre-ASCT B2M >4mg/L (both p<0.001). The relationship between Cr and cumulative ZA dose demonstrated no significant difference between the two arms (p =.12, for T vs no T). Peak drug concentrations (Cmax) and overall drug exposure (AUC 0–48) were similar between the two arms, both at day 1 and day 29 (p = ns, student t-test), and there was no suggestion of accumulation or changed PK profile after the second ZA dose. Conclusions: There is no evidence for a PK interaction by T on ZA. ZA was found to be safe in this previously treated MM population irrespective of concomitant T administration. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals; Novartis Pharmaceuticals Australia Pty Ltd. Novartis Pharmaceuticals Novartis Pharmaceuticals Pharmion Pty Ltd. Novartis Pharma; Amgen Australia Pty Ltd.; Pharmion Pty Ltd.

Renal safety evaluation of zoledronic acid and thalidomide when used as post-stem cell transplant maintenance therapy in multiple myeloma

6655 Background: Anecdotal reports suggest that combination therapy with zoledronic acid (ZA) and thalidomide (T) in multiple myeloma (MM) patients may increase the risk of renal dysfunction compared to ZA alone. As part of a multicentre Phase III trial of post autologous stem cell transplant (ASCT) T maintenance therapy we have compared renal function in MM patients receiving ZA with or without concomitant T. Methods: A multicentre, open label, randomised trial of T 200mg p.o daily for 12 months post-ASCT in patients with non-progressive MM. All patients also received ZA 4mg IV over 15 minutes every 28 days and alternate day prednisolone 50mg. A subset of patients underwent ZA Cmax and AUC (0–48) determinations for the first two ZA doses. Univariate analysis was conducted using student t-tests and chi-square tests for equal proportion. Multivariate analysis was conducted using a repeat measures analysis of variance. Differences in creatinine (Cr) between arms over time were determined by fitting an interaction between dose and arm, with dose and arm treated as linear predictors. Results: To-date 83 patients have commenced maintenance therapy (T=40), received a median of 9 (T) or 8 (no T) ZA doses and 15 patients have completed the PK study (T=8). The arms were well matched for gender, age, pre-ASCT B2microglobulin and baseline Cr. Four patients have had ZA withheld because of a rise in Cr (T = 1, no T=3). No ZA-related serious adverse events have occurred. Multivariate analysis demonstrated that higher Cr levels were associated with male gender and pre-ASCT B2M >4mg/L (both p<0.001). The relationship between Cr and cumulative ZA dose demonstrated no significant difference between the two arms (p =.12, for T vs no T). Peak drug concentrations (Cmax) and overall drug exposure (AUC 0–48) were similar between the two arms, both at day 1 and day 29 (p = ns, student t-test), and there was no suggestion of accumulation or changed PK profile after the second ZA dose. Conclusions: There is no evidence for a PK interaction by T on ZA. ZA was found to be safe in this previously treated MM population irrespective of concomitant T administration. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals; Novartis Pharmaceuticals Australia Pty Ltd. Novartis Pharmaceuticals Novartis Pharmaceuticals Pharmion Pty Ltd. Novartis Pharma; Amgen Australia Pty Ltd.; Pharmion Pty Ltd.

Maintenance with Pamidronate Following First-line MP or VAD Therapy in Multiple Myeloma

We investigated the anti-tumor effect of pamidronate after obtaining a decrease of serum monoclonal immunoglobulin (Ig) level by conventional chemotherapy in patients with multiple myeloma (MM) in order to evaluate whether the drug is useful as maintenance therapy for MM. Eight patients with MM received 60 mg/d pamidronate every third week for 6-18 months without chemotherapeutic agents or corticosteroids after the treatment with melphalan and prednisolone, or vincristine, adriamycin and prednisolone. Serum Ig and β 2-microglobulin (b2MG) levels were maintained at the levels obtained after the termination of chemotherapy in six and four out of eight patients, respectively. Hemoglobin levels were maintained at, or increased to more than, the levels observed at the end of chemotherapy in six patients. Decreased plasma cells in the bone marrow after the chemotherapy were evident in five patients. Two patients were categorized as non-responders, because Ig and b2MG increased and anemia progressed after treatment with the drug. Despite the very small numbers, the results suggest that pamidronate may have anti-tumor activity and be useful for treatment after the conventional chemotherapy in some cases of MM.

Interferon-alpha protects myeloma cell lines from dexamethasone-induced apoptosis.

Because of the increasing use of IFN-alpha in both induction and maintenance therapy for multiple myeloma (MM), its effect on growth and apoptosis of myeloma cells is important to consider. To investigate the role of IFN-alpha on the growth of myeloma cells, we have studied its effects on the response of interleukin 6 (IL-6)-dependent myeloma cell line (ANBL6) and IL-6-independent myeloma cell line (C2E3) in the presence of IL-6 and dexamethasone (Dex). We found that although IFN-alpha is a potent inhibitor of proliferation, it has only a minimal effect on induction of apoptosis. Moreover, we found IFN-alpha as well as IL-6 can significantly suppress dexamethasone-induced apoptosis. The suppression of apoptosis is concurrent with the induction of both AP-1 and STAT binding activity. We also found that IL-6 but not IFN-alpha up-regulates Bcl-X(L) expression. However, IL-6-mediated Bcl-X(L) expression is suppressed in the presence of Dex. Therefore, the expression of Bcl-X(L) does not account for the protection of Dex-induced apoptosis by IFN-alpha and IL-6. Taken together, our results suggest that IFN-alpha may counteract the beneficial effects of corticosteroids or perhaps other apoptosis inducing agents in the treatment of myeloma.

Sensitivity analyses of Q-twist model for interferon maintenance therapy in multiple myeloma

Sensitivity analyses of Q-twist model for interferon maintenance therapy in multiple myeloma

Growth Control Mechanisms in Multiple Myeloma

Interleukin-6 (IL-6) is the major growth factor for the malignant plasma cell clone in patients with multiple myeloma (MM). Although interferon-α (IFN-α) has been widely used as maintenance therapy in MM, controversy exists as to its clinical utility. This review summarizes data showing that cell growth arrest brought about by type I (IFNs-α/β) and type II (IFN-γ) IFNs occurs in part through utilization/modification of various components of the otherwise stimulatory Jak-STAT and Ras signaling pathways triggered by IL-6. Recent experimental results indicating that IFN-α acts as a survival factor for certain myeloma cell lines and frequently induces endogenous IL-6 expression may help to explain the conflicting clinical findings obtained in this heterogeneous disease with this usually potent growth inhibitor. By comparison, consistent antiproliferative activity exhibited by IFN-γ on IL-6-dependent myeloma cell lines and primary myeloma cells from patients suggests that further investigation of the possible value of this cytokine in the treatment of MM may be warranted.

Induction and maintenance therapy in multiple myeloma: a multicenter trial of MP versus VCMP

In a prospective multicenter trial, 320 untreated myeloma patients of stage II and III were randomized for remission induction into two groups receiving six monthly courses of either MP or VCMP treatment. Response rates were equal in both groups: 72% remission, 21% no change, 7% progress for patients evaluable by TCM changes and 56% remission, 11% no change, 33% progress for BJ- and non-secretory myelomas. The overall survival rate was 60% after 4 years. An unexpected finding was the significantly longer survival of MP treated patients compared to the VCMP group. After successful remission induction, patients were randomized into one group receiving maintenance treatment using the induction scheme q 8 weeks, and another group without further chemotherapy. Although patients in the latter group relapsed significantly earlier, differences between both groups concerning acquired resistance to first line therapy or survival have not been noticed to date.

Remission Maintenance Therapy for Multiple Myeloma

The effects of various regimens of melphalan combination chemotherapy were evaluated in 508 patients with multiple myeloma. No value was confirmed from the addition of procarbazine or vincristine sulfate to melphalan-prednisone combinations. Ninety-six patients who responded to treatment were allocated at random to one of three maintenance regimens, namely intermittent courses of carmustine with prednisone, continued courses of melphalan with prednisone, or no chemotherapy. There were no differences in the frequency of relapse, the remission duration, or the survival time among these maintenace groups. The frequencies of pneumonia and herpes zoster were higher in patients receiving continued chemotherapy. Continued melphalan-prednisone chemotherapy after the first year is of no major value to responding patients with multiple cyeloma. Attempts to reduce tumor mass maximally with a change in therapy are justified.

Remission maintenance therapy for multiple myeloma

Remission maintenance therapy for multiple myeloma