Acta Oncologica
`
`ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
`
`Treatment Approaches for Relapsing and
`Refractory Multiple Myeloma
`
`Joan Bladé, Jordi Esteve
`
`To cite this article: Joan Bladé, Jordi Esteve (2000) Treatment Approaches for Relapsing and
`Refractory Multiple Myeloma, Acta Oncologica, 39:7, 843-847, DOI: 10.1080/028418600750063604
`To link to this article: https://doi.org/10.1080/028418600750063604
`
`Published online: 08 Jul 2009.
`
`Submit your article to this journal
`
`Article views: 210
`
`View related articles
`
`Citing articles: 20 View citing articles
`
`Full Terms & Conditions of access and use can be found at
`http://www.tandfonline.com/action/journalInformation?journalCode=ionc20
`
`Download by: [38.122.49.66]
`
`Date: 20 November 2017, At: 13:55
`
`ALVOGEN, Exh. 1035, p. 0001
`
`

`

`ORIGINAL ARTICLE
`
`Treatment Approaches for Relapsing and Refractory
`Multiple Myeloma
`
`Joan Blade´ and Jordi Esteve
`
`From the Institute of Hematology– Oncology, Department of Hematology, Institut d’Investigacions
`Biome` diques August Pi i Sunyer (IDIBAPS), Hospital Clõ´nic, University of Barcelona, Barcelona, Spain
`
`Correspondence to: Dr Joan Blade´ , Hematology Department, Hospital Clõ´nic, Villarroel 170, 08036 Barcelona,
`Spain. Fax: »34 93 227 54 28
`
`Acta Oncologica Vol. 39, No. 7, pp. 843 ± 847, 2000
`
`Relapsing patients with multiple myeloma show a response rate higher than 50% with the resumption of the initial chemotherapy.
`However, since the duration of second responses are short, HDT:autotransplantation is recommended in patients with sensitive relapse.
`In patients with primary refractory myeloma the best treatment approach seems to be early HDT:autotransplantation. It is crucial to
`recognize a subset of patients who do not respond to the initial chemotherapy but who have non-progressive disease in order to avoid
`the administration of salvage regimens until clinical disease progression occurs. The treatment of patients with refractory relapse is
`disappointing. The most promising agent in this situation is thalidomide. Patients with late relapse after autologous transplantation can
`bene® t from a second autologous transplant. The results of the allogeneic transplantation after autotransplantation are disappointing. In
`heavily pretreated resistant patients a conservative approach with alternate day prednisone (30 to 50 mg) along with pulse cyclophos-
`phamide (800 to 1200 mg every 2 to 3 weeks) is recommended.
`
`Recei×ed 29 No×ember 1999
`Accepted 3 April 2000
`
`Patients with multiple myeloma (MM) who fail to re-
`spond, relapse or become refractory to ® rst-line treatment
`show a low response rate and usually a short survival to
`subsequent salvage therapies (1± 3). The management of
`these patients with refractory myeloma is truly challenging.
`First, we brie¯ y review the treatment of patients with
`relapsing MM. Secondly, we summarize the treatment
`options for primarily refractory myeloma (progression or
`no response to initial therapy) and secondarily resistant
`myeloma (refractory relapse). Finally, we discuss the sal-
`vage treatment approaches after relapse from allogeneic or
`autologous transplantation as well as the treatment recom-
`mendations for heavily pretreated patients.
`
`RELAPSE OFF THERAPY
`
`In patients who respond to the initial treatment and re-
`lapse once the induction therapy has been completed, the
`resumption of the same chemotherapy results in a response
`rate higher than 50% (4, 5). However, the duration of
`response signi® cantly decreases with successive relapses
`and the median survival from relapse is about one year.
`Thus, the Canadian group reported that 36 out of 63
`(57%) patients relapsing off therapy (unmaintained remis-
`sions) achieved a second response with the resumption of
`melphalan:prednisone (MP) (4). In this study, a logistic
`
`regression analysis showed that the degree of reduction in
`the M-protein size with the initial
`treatment and the
`absence of symptoms at the time of relapse were the
`factors associated with a signi® cantly higher probability of
`achieving a second response (4). In the study by Paccag-
`nella et al. (5), 26 out of 38 (69%) patients responded when
`the M2 protocol (VBMCP) was re-initiated at the time of
`relapse. This study clearly showed a signi® cant shortening
`in the median duration of response after the initial ther-
`apy, ® rst re-treatment and second re-treatment with the
`same VBMCP regimen (22 vs. 11 vs. 6 months,
`respectively).
`Taking these results into account, particularly the short
`duration of second responses, high-dose therapy (HDT)
`followed by stem cell
`rescue
`should be considered
`whenever possible in patients with sensitive relapse. In
`fact, in a randomized trial designed to assess the optimal
`timing of HDT followed by peripheral blood stem cell
`(PBSC) rescue, patients who underwent a rescue trans-
`plant, because of either primary resistance to VCMP or
`relapse, had a survival identical to that of patients receiv-
`ing HDT:autotransplantation as part of up-front therapy
`(6). An interesting ® nding is that the 2-years’ survival after
`relapse in 45 relapsing patients was 59%. Although there
`are no randomized trials comparing the ef® cacy of HDT:
`
`© Taylor & Francis 2000. ISSN 0284-186 X
`
`Acta Oncologica
`
`Downloaded by [38.122.49.66] at 13:55 20 November 2017
`
`ALVOGEN, Exh. 1035, p. 0002
`
`

`

`844
`
`J. Blade , J. Este×e
`
`Acta Oncologica 39 (2000)
`
`autotransplantation versus conventional chemotherapy in
`relapsing patients, there is general agreement in that HDT:
`PBSC rescue should be considered whenever possible in
`MM patients with sensitive relapse.
`
`PRIMARY RESISTANCE
`
`The median survival of patients with primary refractory
`MM is about 15 months (4). Patients with primary resis-
`tant disease seem to bene® t
`from early myeloablative
`therapy followed by autotransplantation, since tumor re-
`sistance can be transiently overcome with HDT. In fact, it
`has been suggested that this subset of patients is the one
`most likely to bene® t from HDT:autotransplantation (7).
`However,
`it is crucial to identify patients with primary
`refractory myeloma early in the course of the disease in
`order to prevent the emergence of resistant subclones. In
`the MD Anderson series, 19 out of 27 (70%) patients with
`primary resistant disease who received a rescue transplant
`during the ® rst year after diagnosis achieved an objective
`response (7). Furthermore, patients who were given an
`early transplant survived signi® cantly longer than 60 pa-
`tients with primary resistant disease who were continued
`on conventional chemotherapy. Response rate, progres-
`sion-free survival and overall survival were also signi® -
`cantly lower in those primary resistant patients treated
`with rescue transplant later in the course of the disease (7).
`In a multivariate regression analysis, including 135 patients
`with resistant MM from the University of Arkansas who
`were given HDT, the two variables most signi® cantly
`associated with a longer event-free and overall survival
`were: 1) a low b2-microglobulin serum level and 2) pri-
`mary resistance (as opposed to resistant relapse) (8). In
`this study, the response rate among 72 primary resistant
`patients was 62%, while the median event-free and overall
`survival were 21 and 47 months, respectively.
`When HDT is not feasible, treatment with VAD or
`dexamethasone alone produces a 25% response rate in
`alkylating resistant disease (9). In the PETHEMA experi-
`ence, the response to VBAD in primary resistant patients
`was signi® cantly higher than that in patients who became
`resistant after a prior response Ð
`refractory relapse Ð
`(48%
`vs. 24%, respectively) (10).
`
`NON-RESPONDING, NON-PROGRESSIVE
`MYELOMA
`
`It is important to recognize the subgroup of patients with
`the so-called `non-responding, non-progressive’ myeloma
`(4, 11). In our experience, these patients usually present
`with a high serum M-protein, frequently of IgG type, a
`high proportion of bone marrow plasma cells, moderate
`anemia, and symptoms of hyperviscosity or bacterial infec-
`tions, particularly pneumoccocal pneumonia. However,
`they do not have lytic bone lesions, hypercalcemia, renal
`failure or extramedullary plasmacytomas. In fact, these
`
`patients have a high-mass, smoldering disease. The reason
`for treatment is usually the presence of a certain degree of
`anemia or recurrent infections. If, for any reason, these
`patients are treated and no changes in their paraprotein
`levels and clinical status are observed after 4 to 6 courses
`of chemotherapy, these patients should not be given sal-
`vage chemotherapy regimens unless disease progression
`occurs. Although these patients are normally classi® ed as
``non-responders’ , they in fact have a prolonged survival
`because of the temporarily `non-progressive’ nature of the
`disease (12, 13). It is likely that the small proportion of
`long-survivors that appears at the end of survival curves of
`resistant patients mainly comprises this subset of patients.
`
`REFRACTORY RELAPSE TO ALKYLATING
`AGENTS
`
`Second-line treatment for refractory myeloma produces
`disappointing results because of both a low response rate
`to salvage therapy and the short duration of clinical
`response. With the combination of vincristine, BCNU,
`doxorubicin and prednisone (VBAP), response rates of
`about 25% as well as survival prolongation for responding
`patients have been reported (13, 14). A modi® cation of the
`VBAP regimen,
`in which prednisone was replaced by
`dexamethasone (VBAD), produced a response in more
`than one-third of the patients (10). The highest response
`rate in patients with MM refractory to alkylating agents
`has been reported with the four-day continuous infusion of
`vincristine and adriamycin, along with high-dose dexam-
`ethasone (VAD) (15). The inconveniences of VAD are that
`vincristine and doxorubicin have to be given through a
`central venous catheter and that there is a signi® cant
`steroid toxicity, particularly infections and miopathy. An-
`other aspect of the VAD treatment that has not received
`much attention is that the median duration of response is
`usually less than 9 months (15± 17). High-dose glucocorti-
`coids, particularly dexamethasone, produce a response rate
`of 20 to 25% in refractory patients (9). It is of interest that
`VAD or dexamethasone alone are equally effective in the
`treatment of patients with primary refractory myeloma,
`while VAD is superior to dexamethasone alone for relaps-
`ing refractory patients (9). It is our current policy to treat
`patients with alkylating resistant relapse with courses of
`VBAD administered every 4 weeks, giving the dexam-
`ethasone on days 1± 4 and 9 ± 12 of each course.
`It has been suggested that the lack of response to VAD
`in MM is due to the expression of the multidrug-resistant
`phenotype (MDR). Multidrug resistance is characterized
`by the expression of glycoprotein p-170 encoded by the
`MDR-1 gene. Attempts to prevent or overcome the MDR
`in resistant myeloma with verapamil or quinine have been
`disappointing (18). It has been reported that clinical resis-
`tance to VAD could be overcome by adding cyclosporin A
`to chemotherapy (19). However, in a subsequent study, no
`
`Downloaded by [38.122.49.66] at 13:55 20 November 2017
`
`ALVOGEN, Exh. 1035, p. 0003
`
`

`

`Acta Oncologica 39 (2000)
`
`Management of refractory multiple myeloma
`
`845
`
`association could be found between response to VAD and
`MDR-1 expression, which suggests that in MM there are
`mechanisms of resistance other than MDR (20, 21). The
`ef® cacy of the association of VAD with the cyclosporin
`analog PSC 833, which is a potent chemosensitizer and less
`nephrotoxic and immunosuppressive than cyclosporin A,
`is currently being investigated in prospective trials in re-
`lapsed and refractory patients.
`The combination of etoposide, dexamethasone, cytara-
`bine and cisplatinum (EDAP) produced a 40% response
`rate in heavily pretreated patients, but this regimen was
`extremely myelosuppressive and the patients’ median sur-
`vival was short (22). Other recently introduced intensive
`regimens consisting of cyclophosphamide:etoposide (23),
`cyclophosphamide:teniposide:dexamethasone (24), or cy-
`clophosphamide:dexamethasone:idarubicin:etoposide (25),
`usually given with cell growth factors, produce a high
`response rate. However, the duration of both response and
`survival is short. In addition, these regimens produce a
`severe myelosuppression, as well as being costly. When
`considering the treatment of resistant myeloma, toxicity,
`which results in a decrease in the quality of life, and cost
`should be weighed against a doubtful prolongation of
`survival when compared with more conservative ap-
`proaches. Probably these regimens should only be indi-
`cated to rapidly decrease the tumor burden of patients in
`whom a subsequent HDT followed by autologous or allo-
`geneic stem cell rescue is planned (23).
`The results of monotherapy with a number of different
`agents (hexamethylmelamine, high-dose cytarabine, choro-
`zotocin, mitoxantrone, vincristine, vindesine, m-AMSA,
`VM-26,
`deoxicoformycine,
`epirubicin,
`2-clorodeoxi-
`adenose, retinoic acid, clarithromycin,
`interferon -IFN-)
`have been disappointing (1 ± 3). San Miguel et al. (26)
`treated 51 refractory patients with IFN-alpha2b plus high-
`dose dexamethasone. Thirty-seven of these patients com-
`pleted the induction period and 18 (48%) attained an
`objective or partial response. In contrast, Alexanian et al.
`(27) reported that the combination of dexamethasone or
`VAD with IFN-alpha did not improve either the response
`duration or survival when compared with historical con-
`trols using dexamethasone or VAD alone.
`Topotecan, a topoisomerase I inhibitor, was adminis-
`tered to 43 patients with relapsing (25 pts) or primary
`resistant (18 pts) myeloma in a SWOG trial (28). All of
`these patients had each received only one chemotherapy
`regimen. The overall response rate was 16%. Responses
`were observed in both relapsed and refractory patients.
`The median progression-free survival was 13 months and
`the median overall survival was 28 months. The major
`limiting toxicity of topotecan was myelosuppression, par-
`ticularly grades 3 and 4 granulocytopenia, which occurred
`in 93% of the patients (28).
`The preliminary results of a trial associating vinorelbine
`and high-dose dexamethasone in 39 evaluable relapsing
`
`patients have shown an encouraging objective response
`rate of 46% (18:39) plus 31% (12:39) of minimal responses
`(29). Of the 18 patients who achieved an objective re-
`sponse, 11 were in response at the time of the report with
`a median duration of response still not reached with a
`range from 71 to 907 » days. Based on these encouraging
`results, a large phase III trial comparing vinrelbine:dexam-
`ethasone versus dexamethasone alone is currently in
`progress.
`Treatment with anti-interleukin-6 antibodies was admin-
`istered to 10 patients with advanced MM (30), resulting in
`the inhibition of C-reactive protein (CRP) production and
`in a decrease in the plasma cell LI. Unfortunately, no
`improvements in the patients’ clinical status or decreases in
`the amount of M-protein were observed. It is of interest,
`however,
`that one patient with primary plasma cell
`leukemia, who was producing low amounts of IL-6, had a
`complete inhibition of C-reactive protein production and
`achieved a 30% reduction in the M-component size for 2
`months, but a relapse occurred after treatment with anti-
`IL-6-MoAb was stopped (30).Thalidomide, an antiangio-
`genic agent, was given to 89 high-risk refractory myeloma
`patients (31). A decrease in M-protein of more than 50%
`was observed in 20% of the patients, while an additional
`14% achieved a reduction in M-protein of between 20 and
`50%. Of note, 46% of responders in whom a bone marrow
`aspiration was carried out showed a disappearance of the
`bone marrow plasmacytosis. The thalidomide toxicities
`were: neurologic (75%), gastrointestinal (66%) and consti-
`tutional symptoms (60%). At the time of the report, the
`follow-up was still too short to give a reliable assessment
`of the duration of response.
`The ® rst studies of HDT:autotransplantation in MM
`were performed in patients with advanced refractory dis-
`ease. Although the response rate was high (50 ± 85%), the
`event-free and overall survival were short, ranging from 4
`to 6 months and 4 to 15 months, respectively (32± 34). In
`a large, single institution series, including 63 patients with
`refractory relapse MM, the early death rate after HDT:au-
`totransplantation was 14% and the overall response rate
`59% (8). Median event-free and overall survival were 8 and
`15 months, respectively. As mentioned above, in the latter
`series, patients with primary resistant disease had a more
`favorable outcome than those with a refractory relapse (8).
`In a recently published cooperative study by the SWOG,
`including 66 assessable (intent-to-treat) patients with re-
`fractory MM (80% refractory relapse, 20% primary resis-
`tance),
`the response rate was 58% and the median
`progression-free and overall survival periods from initial
`registration were 11 and 19 months, respectively (35). The
`actuarial 3-year progression-free and overall survival rates
`were 25% and 31%, respectively. Although these results are
`better than those previously published, patients with re-
`fractory relapse do not seem to be the best candidates for
`HDT.
`
`Downloaded by [38.122.49.66] at 13:55 20 November 2017
`
`ALVOGEN, Exh. 1035, p. 0004
`
`

`

`846
`
`J. Blade , J. Este×e
`
`Acta Oncologica 39 (2000)
`
`RELAPSE AFTER TRANSPLANTATIO N
`
`Relapse after allogeneic transplant
`
`One of the major obstacles to the success of allogeneic
`transplantation for myeloma is failure to eradicate the
`disease in the majority of cases. According to the European
`Registry experience, 40% of evaluable patients do not achieve
`a complete remission post-transplant. Furthermore, the
`probability of relapse in those patients who do enter
`complete remission (CR) is 45% at 5 years and late relapse
`continues to occur (36). A graft-versus-myeloma effect of
`donor lymphocyte infusions (DLI) has been demonstrated
`in patients with MM (37± 39). Despite its ef® cacy, DLI is
`associated with signi® cant morbidity and mortality. Thus,
`graft-versus-host disease (GvHD) has been reported in up
`to 80% and marrow aplasia in up to one-third of patients
`(40). These complications result
`in a treatment-related
`mortality of around 20%. It has been reported that 8 out
`of 13 patients with relapsed myeloma after allogeneic bone
`marrow transplantation responded to DLI (41). Acute and
`chronic GvHD occurred in 66% and 55% of all patients,
`respectively, and two patients developed fatal marrow
`aplasia. The factors associated with response to DLI were
`a T-cell dose \1× 108:Kg and the occurrence of GvHD (41).
`
`Relapse after autologous transplantation
`
`High-dose therapy followed by autologous stem cell rescue
`is increasingly being performed as part of up-front therapy
`in MM. However, the majority of patients receiving an
`autograft will subsequently relapse and will require salvage
`therapy. Tricot et al. (42) reported the results with salvage
`therapy in 94 patients who had relapsed after autotransplan-
`tation. Salvage treatment consisted of standard chemother-
`apy in 53 patients and a rescue transplant in the remaining
`41 (31 autologous, 10 allogeneic). The projected survival at
`18 months after salvage therapy for all 94 patients was 59%.
`In a multivariate regression analysis, low beta-2M (B 2.5
`mg:l) and late relapse (\ 12 months) were identi® ed as the
`independent factors signi® cantly associated with a favorable
`outcome. Thus, the CR rate and overall survival rate at 18
`months for the 51 patients who had at least one favorable
`variable were 18% and 79%, compared with 2% and 38% for
`the remaining 43 patients with no favorable parameters.
`Finally, transplantation performed as salvage therapy was
`associated with a signi® cantly survival prolongation when
`compared with standard treatment. Nevertheless, this might
`simply re¯ ect an unavoidable bias favoring the transplant
`group (i.e. none of the patients in the transplant group had
`previously received two transplants versus 43% in the
`patients given conventional salvage chemotherapy; 61% of
`patients in the transplant arm had low beta-2M compared
`with only 32% of those in the chemotherapy group) (42).
`The results of salvage therapy with allogeneic transplan-
`tation after autologous transplant have been disappointing.
`At the University of Arkansas, 31 patients received an
`allograft as second myeloablative therapy (either as consol-
`
`idation or rescue after relapse) (43). Transplant-related
`mortality within the ® rst 100 days was almost 20%. Although
`42% of patients achieved a complete remission, the median
`event-free and overall survival rates were 19 and 24 months,
`respectively; 19% of patients had grade 3 or 4 GvHD. One
`patient died of cytomegalovirus pneumonia and six from
`invasive aspergillosis (43). In our opinion, the high trans-
`plant-related morbidity:mortality precludes
`allogeneic
`transplantation as a rescue option after relapse from HDT:
`autologous stem cell rescue.
`
`HEAVILY PRETREATED MYELOMA
`
`Unfortunately, all patients with MM will become refractory
`to therapy during the course of their disease. A conservative
`approach is recommended for the management of patients
`resistant to current treatment strategies (i.e. alkylating
`agents, dexamethasone-based regimensÐ VAD or VBADÐ
`and HDT:stem cell rescue) as well as in those in whom the
`above treatments are not feasible (elderly patients, poor
`performance status, severe pancytopenia). Appropriate sup-
`portive care with antibiotics, transfusions, analgesics and
`local radiation is required. Along with these general mea-
`sures we are using a gently chemotherapy approach with
`alternate-day prednisone (30 ± 50 mg) combined with a pulse
`dose of intravenous cyclophosphamide (800 ± 1200 mg) every
`2 to 3 weeks. Although this treatment produces objective
`responses in very few resistant patients, it is a palliative
`regimen that can temporarily control the disease, and with
`a very low toxicity (44). While it is true that intensive
`chemotherapy can transiently overcome drug resistance, the
`responses are usually brief and these approaches are costly
`and life-threatening, resulting in prolonged hospitalization
`in patients with a short life span.
`
`ACKNOWLEDGEMENTS
`
`This work was partly supported by grants from Fondo de Inves-
`tigaciones Sanitarias de la Seguridad Social (FIS95:0828 and FIS
`96:0397) and a grant
`from the Jose Carreras International
`Leukemia Foundation (FIJC-99:PETH).
`
`REFERENCES
`
`1. Buzaid AC, Durie BGM. Management of refractory myeloma:
`a review. J Clin Oncol 1988; 6: 889 ± 905.
`2. Alexanian R, Barlogie B, Venture G. Chemotherapy for
`resistant and relapsing multiple myeloma. Eur J Haematol
`1989; 43 (Suppl 51): 140 ± 4.
`3. Kyle RA, Greipp PR, Gertz MA. Treatment of refractory
`multiple myeloma and considerations for future therapy. Semin
`Oncol 1986; 13: 326 ± 33.
`4. Belch A, Shelley W, Bergsagel DE, et al. A randomized trial
`of maintenance versus no maintenance melphalan and pred-
`nisone in responding multiple myeloma patients. Br J Cancer
`1988; 57: 94 ± 9.
`5. Paccagnella A, Sileni VC, Soesan M, et al. Second and third
`responses to the same induction regimen in relapsing patients
`with multiple myeloma. Cancer 1991; 68: 975 ± 80.
`6. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and
`autologous peripheral blood stem cell transplantation in mul-
`
`Downloaded by [38.122.49.66] at 13:55 20 November 2017
`
`ALVOGEN, Exh. 1035, p. 0005
`
`

`

`Acta Oncologica 39 (2000)
`
`Management of refractory multiple myeloma
`
`847
`
`tiple myeloma: up-front or rescue treatment? Results of a
`multicenter sequential randomized clinical trial. Blood 1998; 92:
`3131 ± 6.
`7. Alexanian R, Dimopoulos MA, Hester J, Delasalle K, Cham-
`plin R. Early myeloablative therapy for multiple myeloma.
`Blood 1994; 84: 4278 ± 82.
`8. Vesole DH, Barlogie B, Jagannath S, et al. High-dose therapy
`for refractory multiple myeloma:
`improved prognosis with
`better supportive care and double transplants. Blood 1994; 84:
`950 ± 6.
`9. Alexanian R, Barlogie B, Dixon D. High-dose glococorticoid
`treatment of resistant myeloma. Ann Intern Med 1986; 105:
`8 ± 11.
`10. Blade J, San Miguel JF, Sanz-Sanz MA, et al. Treatment of
`melphalan-resistant multiple myeloma with vincristine, BCNU,
`doxorubicin, and high-dose dexamethasone (VBAD). Eur J
`Cancer 1993; 29A: 57 ± 60.
`11. Bergsagel DE. Use a gentle approach for refractory myeloma
`patients. J Clin Oncol 1988; 6: 757 ± 8.
`12. Paccagnella A, Cartei G, Fosser V, et al. Treatment of multiple
`myeloma with M-2 protocol and without maintenance therapy.
`Eur J Cancer Clin Oncol 1983; 19: 1345 ± 51.
`13. Blade J, Rozman C, Montserrat E, et al. Treatment of resistant
`multiple myeloma with vincristine, BCNU, doxorubicin and
`prednisone (VBAP). Eur J Cancer Clin Oncol 1986; 22: 1193 ± 7.
`14. Bonnet J, Alexanian R, Salmon S, et al. Vincristine, BCNU,
`doxorubicin, and prednisone (VBAP) combination in the
`treatment of relapsing or resistant multiple myeloma: a South-
`west Oncology Group Study. Cancer Treat Rep 1982; 66:
`1267 ± 71.
`15. Barlogie B, Smith L, Alexanian R. Effective treatment of
`advanced multiple myeloma refractory to alkylating agents. N
`Engl J Med 1984; 310: 1353 ± 6.
`16. Monconduit M, Loet Le X, Bernard JF, Michaux JL. Combi-
`nation chemotherapy with vincristine, doxorubicin, dexam-
`ethasone for refractory or relapsing multiple myeloma. Br J
`Haematol 1986; 63: 599 ± 601.
`17. Scheithauer W, Cortelezzi A, Kutzmits R, Baldini L, Ludwig
`H. VAD protocol for treatment of advanced refractory multiple
`myeloma. Blut 1987; 55: 145 ± 52.
`18. Salmon SE, Dalton WS, Grogan T, et al. Multidrug-resistant
`myeloma:
`laboratory and clinical effects of verapamil as
`chemosensitizer. Blood 1991; 78: 44± 50.
`19. Sonneveld P, Durie B, Lokhorst HM. Modulation of multi-
`drug-resistant myeloma by cyclosporin. Lancet 1992; 340:
`255 ± 9.
`20. Cornelissen JJ, Sonneveld P, Schoester M, et al. MDR-1
`expression and response to vincristine, doxorubicin and dexam-
`ethasone chemotherapy in multiple myeloma refractory to
`alkylating agents. J Clin Oncol 1994; 12: 115 ± 9.
`21. Raaijmakers HGP, Izquierdo MAI, Lokhorst HM, et al. Lung
`resistance related protein expression is a negative predictive
`factor for response to conventional low but no intensi® ed dose
`alkylating chemotherapy in multiple myeloma. Blood 1998; 91:
`1029 ± 36.
`22. Barlogie B, Velasquez WS, Alexanian R, Cabanillas F.
`Etoposide, dexamethasone, cytarabine, and cisplatin in vin-
`cristine, doxorubicin and dexamethasone-refractory myeloma.
`J Clin Oncol 1989; 10: 1514 ± 7.
`23. Dimopoulos MA, Delasalle KB, Champlin R, Alexanian R.
`Cyclophosphamide and etoposide therapy with GM-CSF for
`VAD-resistant multiple myeloma. Br J Haematol 1993; 83:
`240 ± 4.
`24. Leoni F, Ciolli S, Salti F, Teodori P, Perrini PR. Teniposide,
`dexamethasone and continuous-infusion cyclophosphamide in
`advanced refractory myeloma. Br J Haematol 1991; 77: 180 ± 4.
`
`25. Ballester OF, Moscinski LC, Fields KK, et al. Dexamethasone,
`cyclophosphamide, idarubicin and etoposide (DC-IE): a novel,
`intensive induction chemotherapy regimen for patients with
`high-risk multiple myeloma. Br J Haematol 1997; 96: 746 ± 8.
`26. San Miguel JF, Moro MJ, Blade J, et al. ombination of
`interferon and dexamethasone in refractory multiple myeloma.
`Hematol Oncol 1990; 8: 185 ± 9.
`27. Alexanian R, Barlogie B, Gutterman J. Alpha-interferon com-
`bination therapy of resistant myeloma. Am J Clin Oncol 1991;
`14: 188 ± 92.
`28. Kraut EH, Crowley JJ, Wade JL, et al. Evaluation of topotecan
`in resistant and relapsing multiple myeloma: a Southwest
`Oncology Group Study. J Clin Oncol 1998; 16: 589 ± 92.
`29. Dammacco F, San Miguel JF, Attal M, et al. Vinorelbine
`(VNR) plus high-dose dexamethasone (DEX) for treatment of
`relapsing multiple myeloma (MM): a phase II study. Blood
`1998; 92 (Suppl 1): 319a.
`30. Bataille R, Barlogie B, Lu ZY, et al. Biologic effects of
`anti-interleukin-6 murine monoclonal antibody in advanced
`multiple myeloma. Blood 1995; 86: 685 ± 91.
`31. Singhal S, Metha J, Eddlemon P, et al. Marked anti-tumor
`effect from anti-angiogenesis (AA) therapy with thalidomide
`(T) in high risk refractory multiple myeloma (MM). Blood
`1998; 92 (Suppl 1): 318a.
`32. Barlogie B, Hall R, Sander A, Dicke K, Alexanian R. High-
`dose melphalan with autologous bone marrow transplantation
`for multiple myeloma. Blood 1986; 67: 1298 ± 301.
`33. Barlogie B, Alexanian R, Dicke KA, et al. High-dose chemora-
`diotherapy and autologous bone marrow transplantation for
`resistant multiple myeloma. Blood 1987; 70: 869 ± 72.
`34. Dimopoulos MA, Alexanian R, Przepiorka D, et al. Thiotepa,
`busulphan, and cyclophosphamide: a new preparative regimen
`for autologous marrow or blood stem cell transplantation in
`high-risk multiple myeloma. Blood 1993; 82: 2324 ± 8.
`35. Vesole DH, Crowley JJ, Catchatourian R, et al. High-dose
`melphalan with autotransplantation for refractory multiple
`myeloma: results of a Southwest Oncology Group Phase II trial.
`J Clin Oncol 1999; 17: 2173 ± 9.
`36. Gahrton G, Tura S, Ljungman P, et al. Prognostic factors in
`allogeneic bone marrow transplantation for multiple myeloma.
`J Clin Oncol 1995; 13: 1312 ± 22.
`37. Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N,
`Barlogie B. Graft-versus myeloma effect: proof of principle.
`Blood 1996; 87: 1196 ± 8.
`38. Alyea EP, Soiffer RJ, Canning C, et al. Toxicity and ef® cacy
`of de® ned doses of CD34» donor lymphocytes for treatment
`of relapse after allogeneic bone marrow transplant. Blood 1998;
`91: 3671 ± 80.
`39. Aschan J, LoÈ nnqvist B, Ringden O, Kumtien G, Gahrton G.
`Graft-versus-myeloma effect. Lancet 1996; 348: 346.
`40. Kolb H, Schattenberg A, Golman JM, et al. Graft-versus-
`leukemia effect of donor lymphocyte transfusions in marrow
`grafted patients. Blood 1995; 86: 2041 ± 50.
`41. Lokhorst HM, Schattenberg A, Cornelissen JJ, Thomas LLM,
`Verdonck LF. Donor leukocyte infusions are effective in
`relapsed multiple myeloma after allogeneic bone marrow trans-
`plantation. Blood 1997; 90: 4206 ± 11.
`42. Tricot G, Jagannath S, Vesole DH, Crowley J, Barlogie B.
`Relapse of multiple myeloma after autologous transplantation:
`survival after salvage therapy. Bone Marrow Transplant 1995;
`16: 7 ± 11.
`43. Vesole DH, Tricot G, Jagannath S, et al. Autotransplants in
`multiple myeloma: what have we learned? Blood 1996; 88:
`838 ± 47.
`44. Brandes LJ, Israels LG. Weekly low-dose cyclophosphamide
`and alternate-day prednisone: an effective low toxicity regimen
`for advanced myeloma. Eur J Haematol 1987; 39: 362 ± 8.
`
`Downloaded by [38.122.49.66] at 13:55 20 November 2017
`
`ALVOGEN, Exh. 1035, p. 0006
`
`