Value of novel agents and intensive therapy for patients with multiple myeloma.

We conducted a retrospective evaluation of response and survival for 293 patients with multiple myeloma treated since June 2000 with primary thalidomide- or bortezomib-based combinations, of whom 207 patients received intensive therapy supported by autologous blood stem cells within the first year. Survival times were calculated after a landmark of 1 year from start of therapy, so that subsequent median survival was 8.9 years for patients with CR, 4.9 years for those with PR and 0.6 year for patients with NR (P<0.001). Multivariate analyses confirmed CR or PR as the major favorable factors with less impact on prognosis for age or disease stage. Both novel agents and high-dose therapy (HDT) resulted in high frequencies of PR or CR, with early HDT useful for many patients with NR or PR in improving response status and subsequent survival.

Rapid control of previously untreated multiple myeloma with bortezomib-lenalidomide-dexamethasone (BLD).

Between April 2006 and June 2009, 34 newly diagnosed patients with multiple myeloma received one to three courses of bortezomib 1.3 mg/m(2) i.v. four times, lenalidomide 25 mg p.o. daily for 21 days and dexamethasone 20 mg/m(2) p.o. for 4 days beginning on days 1, 9 and 17 (BLD). There was rapid onset of remission in 30 patients (88%) similar to the frequency of 87% induced by a previous combination of bortezomib-thalidomide-dexamethasone (BTD). After a median of 3.6 months, 28 patients received intensive therapy with high-dose melphalan supported by autologous blood stem cells, so that the overall frequency of complete remission (CR) was 44%, similar to the frequency of 37% observed previously. Side effects due to thalidomide with previous BTD were less frequent and severe with BLD. The combination of BLD given for one or two courses was an effective primary treatment for newly diagnosed patients with multiple myeloma.

CR represents an early index of potential long survival in multiple myeloma.

To assess the impact of CR on survival in multiple myeloma. Retrospective evaluation of response and survival among 758 consecutive patients with multiple myeloma treated at a single center, of whom 395 patients received intensive therapy supported by autologous stem cells within the first year. Survival times were calculated after 1 and 2 years from the start of chemotherapy. On the basis of the response status after a 2-year landmark, the subsequent median survival was 9.7 years for patients with CR, 4.4 years for those with PR and 2.7 years for patients with NR (P<0.001). Longer survival was attributed in part to intensive therapy that converted the myeloma of 67% of patients with NR to PR or CR, and induced CR in 26% of patients with PR. Intensive therapy did not prolong survival for patients with CR after primary therapy. For patients with multiple myeloma, Cox regression analyses showed that CR was the dominant prognostic factor for long survival, followed by stage I disease, PR and intensive treatment as independent factors. A cure fraction of 2% was identified for nine patients who have remained in CR >10 years.

Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma.

In a previous trial among 137 previously untreated patients with multiple myeloma, the combination of thalidomide-dexamethasone induced remission in 66% of patients, including complete remission in 13%. In an attempt to induce more frequent remissions, we added bortezomib to this program. Between 7/03 and 3/06, 38 newly diagnosed patients with multiple myeloma received at least one, but no more than 3, courses of bortezomib in a dose of 1.3 mg/m(2) IV x 4; dexamethasone 20 mg/m(2) PO for 4 days beginning on days 1, 9, 17; thalidomide 100 mg PO daily increasing to a maximum of 200 mg. There was rapid onset of remission in 33 patients (87%) including 6 patients with complete remission (16%). Most side effects were preventable, but otherwise were usually mild and reversible. After a median of 4 months, 25 eligible patients received intensive therapy with high-dose melphalan supported by autologous blood stem cells, so that the myeloma was in complete remission in 14 patients (37% of all patients). The combination of bortezomib-thalidomide-dexamethasone was a highly effective primary treatment for newly diagnosed patients with multiple myeloma.

International uniform response criteria for multiple myeloma.

New uniform response criteria are required to adequately assess clinical outcomes in myeloma. The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system. Categories for stringent complete response and very good partial response are added. The serum free light-chain assay is included to allow evaluation of patients with oligo-secretory disease. Inconsistencies in prior criteria are clarified making confirmation of response and disease progression easier to perform. Emphasis is placed upon time to event and duration of response as critical end points. The requirements necessary to use overall survival duration as the ultimate end point are discussed. It is anticipated that the International Response Criteria for multiple myeloma will be widely used in future clinical trials of myeloma.

Prognostic significance of magnetic resonance imaging of bone marrow in previously untreated patients with multiple myeloma.

BACKGROUND: Magnetic resonance imaging (MRI) has been a useful technique for the assessment of patients with multiple myeloma (MM). We evaluated the prognostic significance of different MRI patterns in symptomatic patients with MM. PATIENTS AND METHODS: A total of 142 symptomatic MM patients underwent MRI before treatment. MRI patterns of involvement were correlated with known prognostic variables, including the International Staging System (ISS), response to treatment and survival. RESULTS: Focal marrow lesions were identified in 50% of patients, diffuse marrow replacement in 28%, a variegated pattern in 14% and normal pattern in 8%. When patients with the diffuse pattern were compared with patients with the other MRI patterns, they had features of more advanced disease such as higher ISS, anemia, hypercalcemia, elevated lactate dehydrogenase and extensive marrow plasmacytosis. Response rate was similar among patients with different MRI patterns. Median survival was 24 months for patients with the diffuse pattern, 51 months for those with the focal pattern, 52 months for those with the variegated pattern and 56 months for patients with the normal pattern (P = 0.001). The presence or absence of a diffuse MRI pattern separated patients with ISS stages I and II into two subgroups with significantly different survival times of 28 months and 61 months, respectively (P = 0.01). Furthermore, a diffuse MRI pattern predicted inferior outcome regardless of whether or not patients had received high-dose therapy with autologous stem cell transplantation. CONCLUSION: Diffuse marrow replacement on MRI adds to the evaluation of patients with multiple myeloma and their management.

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells.

Multiple myeloma (MM) accounts for 1 % of all cancer deaths. Although treated aggressively, almost all myelomas eventually recur and become resistant to treatment. Atiprimod (2-(3-Diethylaminopropyl)-8,8-dipropyl-2-azaspiro[4,5] decane dimaleate) has exerted anti-inflammatory activities and inhibited oeteoclast-induced bone resorption in animal models and been well tolerated in patients with rheumatoid arthritis in phase I clinical trials. Therefore, we investigated its activity in MM cells and its mechanism of action. We found that Atiprimod inhibited proliferation of the myeloma cell lines U266-B1, OCI-MY5, MM-1, and MM-1R in a time- and dose-dependent manner. Atiprimod blocked U266-B1 myeloma cells in the G(0)/G(1) phase, preventing cell cycle progression. Furthermore, Atiprimod inhibited signal transducer and activator of transcription (STAT) 3 activation, blocking the signalling pathway of interleukin-6, which contributes to myeloma cell proliferation and survival, and downregulated the antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1. Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase. Finally, Atiprimod suppressed myeloma colony-forming cell proliferation in fresh marrow cells from five patients with newly diagnosed MM in a dose-dependent fashion. These data suggest that Atiprimod has a role in future therapies for MM.

A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma.

In a phase 2 open-label study of the novel proteasome inhibitor bortezomib, 54 patients with multiple myeloma who had relapsed after or were refractory to frontline therapy were randomized to receive intravenous 1.0 or 1.3 mg/m(2) bortezomib twice weekly for 2 weeks, every 3 weeks for a maximum of eight cycles. Dexamethasone was permitted in patients with progressive or stable disease after two or four cycles respectively. Responses were determined using modified European Group for Blood and Marrow Transplantation criteria. The complete response (CR) + partial response (PR) rate for bortezomib alone was 30% [90% confidence interval (CI), 15.7-47.1] and 38% (90% CI, 22.6-56.4) in the 1.0 mg/m(2) (8 of 27 patients) and 1.3 mg/m(2) (10 of 26 patients) groups respectively. The CR + PR rate for patients who received bortezomib alone or in combination with dexamethasone was 37% and 50% for the 1.0 and 1.3 mg/m(2) cohorts respectively. The most common grade 3 adverse events were thrombocytopenia (24%), neutropenia (17%), lymphopenia (11%) and peripheral neuropathy (9%). Grade 4 events were observed in 9% (five of 54 patients). Bortezomib alone or in combination with dexamethasone demonstrated therapeutic activity in patients with multiple myeloma who relapsed after frontline therapy.

Clinical outcomes with intensive therapy for patients with primary resistant multiple myeloma.

Clinical outcomes were evaluated in 89 consecutive patients with multiple myeloma that had not responded to dexamethasone-based primary therapy, who received early intensive therapy supported by autologous stem cell transplantation. Results were compared with those of 45 comparable patients who refused or were unable to receive intensive treatment for socioeconomic reasons. Following high-dose therapy, the response rate was 69% including 16% with CR. Survival of 14 patients with CR (median >7.0 years) was significantly longer than those of 47 patients with PR (median 4.5 years) or of 28 patients who remained NR (median 2.2 years). CR occurred in 43% of patients with serum myeloma protein <1.5 gm/dl, in contrast to 7% of those with higher values, a finding similar to that observed previously for patients consolidated in PR. No prognostic factor was associated with PR and, in view of the high frequencies of PR or CR, all patients with primary resistant myeloma should be considered for early intensive therapy. The limited improvement of lifespan and disease-free survival for those in PR indicated the need for further treatment to achieve CR, the major surrogate marker for long survival.

Outcomes of autologous stem cell transplantation in patients with multiple myeloma who received dexamethasone-based nonmyelosuppressive induction therapy.

High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) improves survival in myeloma (MM). The role of induction therapy on outcomes of ASCT in MM has not been systematically studied. Nonmyelosuppressive (NMS) steroid-based induction can be used in MM, with the potential of reducing neutropenias and other toxic effects prior to ASCT. NMS induction however could be associated with poorer outcomes if disease control or stem cell collection were inadequate. We studied outcomes of 136 MM patients who underwent HDC and ASCT as part of their initial therapy between March 1998 and December 2000. Of these, 46 received HDC and ASCT without any exposure to myelosuppressive agents, 39 received myelosuppressive therapy for disease control and/or stem cell collection, and 51 received alkylating agent-based initial treatment. We compared OS and EFS rates, stem cell collectability, and contamination of the grafts with monoclonal plasma cells. After a median of 33 months, response rates, EFS and OS rates were comparable in the three groups of patients. Adequacy of stem cell collection and plasma cell contamination were similar. Our data support the hypothesis that NMS induction for patients with MM is safe and effective and does not compromise the results of HDC.

Asymptomatic Waldenstrom's macroglobulinemia.

A study was undertaken to evaluate the frequency and natural history of disease in patients with asymptomatic Waldenstrom's macroglobulinemia (WM). Among 132 consecutive, newly diagnosed patients with monoclonal IgM, 82 (27%) had symptomatic WM indicated by anemia, lymphadenopathy, or splenomegaly. Thirty-one patients had similar clinical features but were asymptomatic and followed without therapy until disease progression. There were 19 patients with monoclonal gammopathy of undetermined significance of IgM type (MGUS). In comparison to overt WM, patients with asymptomatic WM had significantly higher hemoglobin (Hgb) level (median, 12.1 v 9.7 g/dL), lower serum beta(2)-microglobulin (B(2)M) level (median, 2.4 v 3.4 mg/L), and similar IgM peaks (median, 2.2 and 1.8 g/dL). The IgM component was 3.6 g/dL or less in all patients with asymptomatic disease. For asymptomatic WM, median time to disease progression was 6.9 years with rare morbidity. Prognostic factors for early progression were Hgb <11.5 g/dL, B(2)M >or= 3.0 mg/L, and IgM peak >3.0 g/dL. Combinations of these variables defined three risk groups for progression with markedly different median times to progression of >5 years, 2 years, and 0.5 year, respectively. Response rate and survival after institution of treatment were similar to those of patients treated promptly for overt disease. We conclude that, among patients with WM, 27% were asymptomatic with slow disease progression before the need for chemotherapy. Since disease outcomes after treatment were similar to those of patients treated at diagnosis, patients with asymptomatic disease should be identified and followed without treatment for as long as risks of complications remain low.

Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma.

The purpose of the study was to determine the feasibility and efficacy of a reduced intensity conditioning regimen of fludarabine and melphalan for allogeneic transplantation in patients with multiple myeloma. From August 1996 to December 2000, 22 patients received a reduced intensity conditioning regimen with fludarabine and melphalan. Median age was 51 years (range, 45-64), median time from initial therapy to transplant was 36 months (range, 3-135 months). Disease phase prior to transplant was primary refractory in two patients, refractory relapse in 11 patients, sensitive relapse in eight patients and initial remission consolidation in one patient. The median number of prior therapies was five (range, 1-7), and median beta 2 microglobulin prior to transplant was 3.0 mg/l (range, 1.0-7.3). All patients received unmanipulated grafts from either HLA matched sibling donors (n = 13) or matched unrelated donors (n = 9). Eighteen patients received fludarabine 30 mg/m(2) for 4 days with melphalan 140 mg/m(2) as a single dose and four patients received fludarabine 25 mg/m(2) for 5 days with melphalan 90 mg/m(2) daily for 2 days. All 21 patients evaluable for engraftment achieved a neutrophil count of >0.5 x 10(9)/l after a median of 12 days (range, 9-24), 18 patients achieved platelet transfusion independence after a median of 14 days (range, 8-47). All engrafting patients had 100% donor cell engraftment. Seven patients achieved a complete remission. Six patients are currently alive with a median follow-up of 15 months (range, 10-47 months). The actuarial survival and progression-free survival is 30 +/- 11% and 19 +/- 9% at 2 years. Non-relapse mortality at 100 days was 19 +/- 10% and 40 +/- 10% at 1 year. Fludarabine/melphalan combinations are feasible and allow consistent engraftment of allogeneic progenitor cells from both related and unrelated donors in patients with multiple myeloma and should be explored in patients with less advanced disease.

Consolidation therapy of multiple myeloma with thalidomide-dexamethasone after intensive chemotherapy.

BACKGROUND: After myeloablative therapy for multiple myeloma, progression-free survival is shorter for disease in partial remission rather than complete remission. In an attempt to induce more frequent complete remission, we assessed thalidomide-dexamethasone in patients with stable partial remission after intensive therapy. PATIENTS AND METHODS: Twenty-one patients with multiple myeloma were identified with disease in stable partial remission after prior intensive therapy. Thalidomide-dexamethasone was given within 15 months after intensive therapy provided myeloma protein production had been reduced by >75% to a constant level for at least 4 months. Thalidomide was begun at a dose of 100 mg each evening, with increments of 50 mg every 7 days to a maximum of 300 mg. Dexamethasone was given concurrently in a dose of 20 mg/m(2) each morning for 4 days on days 1-4, 9-12 and 17-20, with resumption on day 35. The combination was continued for at least 3 months and patients with marked reduction of myeloma were maintained on thalidomide alone until disease progression. RESULTS: Marked further reduction of myeloma by at least 90% occurred in 12 patients (57%), including four (19%) with disease converted to complete remission. Disease has progressed in six of 21 patients, whose median total remission was 22 months. Common side effects of constipation, fatigue, paresthesias and dry skin were mild, dose-related and reversible. CONCLUSIONS: The combination of thalidomide-dexamethasone reduced tumor mass markedly in 57% of patients with stable, residual disease after myeloablative therapy. Such an effect may produce longer disease-free survival and/or preserve tumor sensitivity to later retreatment with previously effective drugs.

Cytogenetic findings in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Chromosomal abnormalities are associated with the polymorphous subtype and an aggressive clinical course.

We correlated bone marrow cytogenetic findings with morphologic and immunophenotypic data in 37 patients with lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM). Each LPL/WM case was classified as lymphoplasmacytoid (n = 18), lymphoplasmacytic (n = 10), or polymorphous (n = 9) using the Kiel criteria. Of 12 cases with chromosomal abnormalities, a single numeric abnormality was present in 4 and a complex karyotype in 8. The most common numeric abnormalities were and -8 in 3 cases each; the most common structural abnormality was del(6q) in 6 cases. Cytogenetic abnormalities were significantly less common in the lymphoplasmacytic and lymphoplasmacytoid groups (5/28 [18%]) compared with the polymorphous group (7/9 [78%]). Clinical follow-up was available for 28 patients for a median of 36 months. Six (67%) of 9 patients with aneuploid tumors, including 4 with polymorphous subtype, subsequently had clinical progression or developed high-grade lymphoma. In contrast, 4 (21%) of 19 patients with diploid tumors, including 1 of polymorphous type, developed clinical progression or high-grade lymphoma. We conclude that abnormal cytogenetic findings in LPL/WM correlate with the polymorphous subtype and poor prognosis.

Standard-dose therapy for multiple myeloma: The Southwest Oncology Group experience.

We summarize the Southwest Oncology Group (SWOG) experience with standard therapy for multiple myeloma by reviewing and updating data from seven consecutive SWOG trials. Some modest progress has been made since the introduction of melphalan and prednisone (MP) for induction therapy, using regimens that involve vincristine and doxorubicin, and which save alkylating agents for possible later high-dose therapy. For maintenance, it appears that prednisone plays a useful role. We demonstrate the use of the data collected in these trials with a proposed new staging system.

Thiotepa, busulfan, cyclophosphamide (TBC) and autologous hematopoietic transplantation: an intensive regimen for the treatment of multiple myeloma.

The study was designed to evaluate the efficacy and safety of an intensive, tri-alkylator conditioning regimen, consisting of thiotepa, busulfan and cyclophosphamide (TBC), prior to autologous hematopoietic cell transplantation in patients with multiple myeloma (MM) and to analyze factors associated with outcome. One hundred and twenty patients with MM received high-dose chemotherapy with TBC followed by autologous bone marrow (n = 24) or peripheral blood stem cell (PBSC) transplantation (n = 96). Fifty-four patients had chemosensitive disease and 66 had refractory disease at the time of transplantation. The overall response rate was 81% and the complete remission (CR) rate was 26%. Patients with chemosensitive disease had a CR rate of 52% vs 5% for patients with refractory disease. Multivariable analysis determined disease status at transplant as the factor most likely associated with long survival. Estimated median survival was 48, 35 and 9 months for patients with chemosensitive, primary refractory or disease in refractory relapse, respectively. Short interval from diagnosis to transplant among patients with primary refractory disease and younger age were also favorable prognostic factors for survival. Patients with refractory disease pre-transplant who achieved remission criteria rapidly after treatment had a worse outcome than the slow responders. Treatment-related mortality with the introduction of PBSC and better supportive care was 4.8%. In conclusion, TBC is an effective and relatively well-tolerated intensive conditioning regimen in patients with MM. A more favorable outcome was observed in patients with chemosensitive disease and with early treatment for primary refractory disease. TBC merits further study in these subgroups and comparison with alternative regimens in prospective studies is warranted.

High-dose chemotherapy followed by stem cell transplantation in patients with resistant Waldenstrom's macroglobulinemia.

Preliminary evidence suggests that high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation may be effective in some patients with resistant Waldenstrom's macroglobulinemia. During the last 10 years, seven patients with Waldenstrom's macroglobulinemia have received transplants at the MD Anderson Cancer Center, four with autologous and three with allogeneic stem cells. Four patients achieved partial remission, and three patients have remained alive for at least 2 years. Our data confirm the feasibility of high-dose therapy in patients with macroglobulinemia and support the need for prospective studies of this modality in patients with chemosensitive disease.

Impact of complete remission with intensive therapy in patients with responsive multiple myeloma.

Clinical outcomes were assessed in 68 consecutive patients with multiple myeloma of high or intermediate tumor mass that had responded to VAD or dexamethasone-based therapy and were consolidated with early intensive therapy and autologous stem cell transplantation. Results were compared with those of 50 comparable patients who refused or were unable to receive intensive treatment for socioeconomic reasons. Following high-dose therapy, the rate of CR increased from 6 to 37%, with median survival prolonged by 10 months. Survival of 21 patients with disease converted from PR to CR (median 8.3 years) was significantly longer than that of similarly-treated patients who remained in PR (median 5.0 years). CR of myeloma represents the major surrogate marker of long survival and the primary goal of myeloablative treatment for patients in PR. Twelve of 18 patients with rapid reduction of myeloma protein (T(1/2) < 0.5 months), and myeloma protein reduction to <1.0 g/dl after primary therapy achieved CR (67%), identifying pretransplant features favorable to intensive therapy. Among 35 patients with slower reduction or higher residual myeloma protein, CR occurred in eight patients (23%) (P < 0.01), for whom other treatments should be considered. The kinetics of response to initial therapy should be considered in selecting patients more likely to achieve CR and consequent long survival after intensive treatment.

Randomized trial of alpha-interferon or dexamethasone as maintenance treatment for multiple myeloma.

In order to assess the role of alpha-interferon or dexamethasone as maintenance therapy for multiple myeloma, 172 consecutive, previously untreated patients with disease of low or intermediate tumor mass received primary therapy with oral melphalan and intermittent, high-dose dexamethasone (MD), repeated monthly. Within 5 months, 84 responding patients were assigned at random to maintenance treatment with alpha-interferon (3 mU s.c. 3 x weekly) or dexamethasone (20 mg/m2 p.o. each morning for 4 days) repeated monthly until relapse. Upon relapse, MD was resumed for 2 cycles and second responses were maintained with 4-day courses of melphalan-dexamethasone until second relapse. Initial response was achieved in 88 patients (51%) after a median 0.7 month and no more than 3 courses of MD, a frequency of response similar to that observed previously with dexamethasone alone. There were identical median remissions of 10 months with interferon or dexamethasone, both maintenance regimens being associated with infrequent, mild, and reversible side effects. Significantly more patients responded again to resumption of MD after disease relapse to interferon (82%) than to dexamethasone (44%) (P = 0.001). The median remission from randomization to melphalan-resistant second relapse was 32 months for patients maintained initially on interferon compared to 19 months for those on dexamethasone (P = 0.01). These findings supported an advantage for interferon in remission maintenance by increasing the frequency of tumor recontrol with later treatment that included dexamethasone.