The structure of bendamustine includes an alkylating moiety and a purine-like benzimidazole ring.
It was used in East Germany since the early 1970s. It was approved in Europe for front-line treatment for patients with myeloma in 2010.

Standard dose: 90-100 mg/m2 IV over 30-60 min for 2 consecutive days, every 4 weeks.

Dose adjustment is not necessary if the CrCl is >10 mL/min.
Alopecia is very rare.


The efficacy and toxicity of bendamustine in recurrent multiple myeloma after high-dose chemotherapy.
Haematologica. 2005 Sep;90(9):1287-8.
Knop S, Straka C, Haen M, Schwedes R, Hebart H, Einsele H.
This is a dose-escalation study of bendamustine in 31 patients with multiple myeloma that had progressed after high-dose chemotherapy. The maximal tolerated dose was 100 mg/m2 on days 1-2. The response rate was 55%, and the median progression-free survival was 26 weeks (range 0-61). Toxicity was mainly hematologic.

Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone - a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO).
J Cancer Res Clin Oncol. 2006 Apr;132(4):205-12.
P÷nisch W, Mitrou PS, Merkle K, Herold M, Assmann M, Wilhelm G, Dachselt K, Richter P, Schirmer V, Schulze A, Subert R, Harksel B, Grobe N, Stelzer E, Schulze M, Bittrich A, Freund M, Pasold R, Friedrich T, Helbig W, Niederwieser D; East German Study Group of Hematology and Oncology (OSHO).
This randomized phase III study compared bendamustine and prednisone (BP) (68 patients) to melphalan and prednisone (MP) (63 patients) in the treatment of newly diagnosed multiple myeloma.
  BP: bendamustine 150 mg /m2 on days 1-2 + prednisone 60 mg/m2 on days 1-4, cycles repeated every 28 days
  MP: melphalan 15 mg/m2 on day 1+ prednisone 60 mg/m2 on days 1-4, cycles repeated every 28 days
BP proved to be superior to MP:
  - Response rate was 75% with BP and 70% with MP
  - Complete remission was 32% with BP and 13% with MP (p=0.007)
  - The maximum response was achieved in about 7 cycles with BP and 9 cycles with MP
  - Duration  of remission was longer with BP group

Efficacy of bendamustine in relapsed/refractory myeloma patients: results from the French compassionate use program.
Leuk Lymphoma. 2012 Apr;53(4):632-4.
Damaj G, Malard F, Hulin C, Caillot D, Garidi R, Royer B, Marit G, Stoppa AM, Banos A, Morineau N, Moreau P, Fitoussi O, Tiab M, Moreau P.
Bendamustine was given to 110 patients with relapsed/refractory multiple myeloma. Results:
  - Response rate: 30%
  - Complete response rate: 2%
  - Median progression-free survival: 9.3 months
  - Median overall survival: 12.4 months



Bendamustine in combination with thalidomide and dexamethasone is an effective therapy for myeloma patients with end stage renal disease.
Br J Haematol. 2011 Dec;155(5):632-4.
Ramasamy K, Hazel B, Mahmood S, Corderoy S, Schey S.
The authors treated 9 myeloma patients with the combination bendamustine-thalidomide-dexamethasone. Interestingly, 4 patients were on hemodialysis, and they did not require dose reduction. This is presumably due to the limited renal excretion of bendamustine.



Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2<sup>nd</sup> -line therapy for relapsed and refractory multiple myeloma - a phase II trial.
Br J Haematol. 2017 Mar;176(5):770-782.
Mey UJ, Brugger W, Schwarb H, Pederiva S, Schwarzer A, Dechow T, Jehner P, Rauh J, Taverna CJ, Schmid M, Schmidt-Hieber M, Doerfel S, Fischer N, Ruefer A, Ziske C, Knauf W, Cathomas R, von Moos R, Hitz F, Sauter R, Hiendlmeyer E, Cantoni N, Bargetzi M, Driessen C.
In this study, 50 patients with relapsed/refractory myeloma received bendamustine 75 mg/m2 IV on days 1 and 2 every 28 days, lenalidomide 25 mg on days 1-21 every 28 days, and dexamethasone 20-40 mg once a week. Among 45 evaluable patients, 51% achieved a deep response (VGPR/CR). Grade 4 neutropenia occurred in 34% of patients, and grade 4 thrombocytopenia in 16% of them.

Bendamustine, Low-dose dexamethasone, and lenalidomide (BdL) for the treatment of patients with relapsed/refractory multiple myeloma confirms very promising results in a phase I/II study.
Leuk Lymphoma. 2017 Mar;58(3):552-559.
Pozzi S, Gentile M, Sacchi S, Marcheselli R, Corso A, Cocito F, Musto P, Guarini A, Minoia C, Vincelli I, Ria R, Rivolti E, Mele G, Bari A, Mazzone C, Badiali S, Marcheselli L, Palumbo A, Morabito F.
In this study, 23 patients with relapsed/refractory myeloma received bendamustine 40 mg/m2 IV on days 1 and 2 every 28 days, lenalidomide 10 mg on days 1-21 every 28 days, and dexamethasone 40 mg once a week. Response rate was 47%, and median PFS 10 months.



Newly diagnosed myeloma

A single-center retrospective analysis of first-line therapy of multiple myeloma with bendamustine-bortezomib-dexamethasone.
Leuk Lymphoma. 2016 Sep;57(9):2065-70.
Zwickl H, Zwickl-Traxler E, Pecherstorfer M.
This is a retrospective study of 20 patients with newly diagnosed myeloma (ineligible for stem cell transplant), treated with bendamustine, bortezomib, and dexamethasone:
  - Bendamustine 120 mg/m2 on day 1
  - Bortezomib 1-1.3 mg/m2 on days 1, 4, 8, 11
  - Dexamethasone 20 mg on the same days of bortezomib
Cycles were repeated every 21 days. Response rate was 80%, median time to best response was 87 days, and progression-free survival 22 months. 

Relapsed/refractory myeloma

Escalation therapy with bortezomib, dexamethasone and bendamustine for patients with relapsed or refractory multiple myeloma.
Leuk Lymphoma. 2007 Dec;48(12):2345-51.
Fenk R, Michael M, Zohren F, Graef T, Czibere A, Bruns I, Neumann F, Fenk B, Haas R, Kobbe G.
In this study, 50 patients with relapsed/refractory multiple myeloma were treated with an escalation therapy consisting of bortezomib, dexamethasone, and bendamustine (50-100 mg/m2 on days 1 + 8).
  - Bortezomib monotherapy was sufficient in 23 (46%) patients
  - Addition of dexamethasone was necessary in 20 (40%) patients
  - Triple combination therapy was necessary in 7 (14%) patients
Overall response rate was 84%. Median time to progression was 8 months, and overall survival was 20 months.

Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma.
Blood. 2014 Feb 13;123(7):985-91.
Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, Greil R, Seebacher A, Pour L, Wei▀mann A, Adam Z.
In this study, 79 patients with relapsed/refractory myeloma received the following combination chemotherapy:
  - Bendamustine 70 mg/m2 IV on days 1, 4
  - Bortezomib 1.3 mg/m2 on days 1, 4, 8, 11
  - Dexamethasone 20 mg on days 1, 4, 8, 11
Cycles were repeated every 28 days x 8. Results:
  - Response rate: 61% (76% when including minor responses)
  - Median progression-free survival: 10 months
  - Median overall survival: 26 months







Phase II trial of nab-paclitaxel in patients with relapsed or refractory multiple myeloma.
Am J Hematol. 2016 Dec;91(12):E504-E505.
Jain T, Dueck AC, Kosiorek HE, Ginos BF, Mayo A, Reeder CB, Chesi M, Mikhael J, Keith Stewart A, Leif Bergsagel P, Fonseca R.
This was a trial with disappointing clinical results. Nab-paclitaxel was administered to 13 patients with relapsed/refractory myeloma, and only 2 patients (13%) responded to it. The study was terminated after the enrollment of the first cohort.



The treatment of multiple myeloma with docetaxel (an ECOG study).
Leuk Res. 2003 Aug;27(8):751-4.
Friedenberg WR, Graham D, Greipp P, Blood E, Winston RD.
31 patients with relapsing or refractory multiple myeloma were treated with docetaxel 75 mg/m2 IV every 3 weeks. Docetaxel was inactive: no responses (PR or CR) were found. Median survival was 9.9 months.



The evaluation of gemcitabine in resistant or relapsing multiple myeloma, phase II: a Southwest Oncology Group study.
Invest New Drugs. 2002 Feb;20(1):117-21.
Weick JK, Crowley JJ, Hussein MA, Moore DF, Barlogie B; Southwest Oncology Group.
SWOG-9803 evaluated gemcitabine (1,000 mg/m2 IV on days 1, 8, and 15 of a 28-day cycle) in 29 patients with resistant or relapsing multiple myeloma. No responses were seen. Stable disease was observed in 16 patients (57%). Median survival was 8 months.

Evaluation of gemcitabine in relapsed or refractory multiple myeloma.
Haematologica. 2004 Nov;89(11):ELT15.
Leleu X, Troncy J, Bouafia F, Michallet M, Facon T, Dumontet C.



A Phase I-II trial of polyethylene glycol-conjugated L-asparaginase in patients with multiple myeloma.
Cancer. 2003 Jul 1;98(1):94-9.
Agrawal NR, Bukowski RM, Rybicki LA, Kurtzberg J, Cohen LJ, Hussein MA.
This is a phase I/II trial with PEG-L-asparaginase as a single agent in 22 patients with relapsing or refractory myeloma. Maximal tolerated dose was found to be 1000 mg/m2 every 4 weeks. 53% of patients had response or stable disease: among 17 evaluable patients, 1 patient reached CR, 8 patients had stable disease, and 8 patients progressive disease. Median survival was 31.7 months.





Melphalan-prednisone versus alternating combination VAD/MP or VND/MP as primary therapy for multiple myeloma: final analysis of a randomized clinical study.
Haematologica. 2002 Sep;87(9):934-42.
Cavo M, Benni M, Ronconi S, Fiacchini M, Gozzetti A, Zamagni E, Cellini C, Tosi P, Baccarani M, Tura S; Writing Committee of the "Bologna 90" Clinical Trial.
527 patients with newly diagnosed myeloma were randomized to receive one of 3 induction regimens:
  - MP alone (Melphalan and Prednisone)
  - Alternating MP/VAD (Vincristine, Doxorubicin, Dexamethasone)
  - Alternating MP/VND (Vincristine, Mitoxantrone, Dexamethasone)
  - Response rate was 53% with MP, 47% with MP/VAD, and 49% with MP/VND
  - Median survival was 36.5 months with MP, 29 months with MP/VAD, and 32.5 months with MP/VND (difference not statistically significant)
Neuropenia and infections were more frequent with the MP/VND regimen. The conclusion of the study was that alternating MP/VAD and MP/VND did not improve clinical outcomes compared to MP alone.

Induction with oral chemotherapy (CID) followed by early autologous stem cell transplantation for de novo multiple myeloma patients.
Hematol J. 2004 May;5(3):216-21.
Spencer A, Seldon M, Deveridge S, Cobcroft R, Cull G, Marlton P, Enno A, Gill D.
36 patients with newly diagnosed multiple myeloma received chemotherapy with CID (Cyclophosphamide, Idarubicin, Dexamethasone), given orally, as induction therapy before stem cell transplantation. Response rate was 66% (CR 9%). Overall survival at 4 years was 77%.

Etoposide, methylprednisolone, cytarabine and cisplatin successfully cytoreduces resistant myeloma patients and mobilizes them for transplant without adverse effects.
Br J Haematol. 2004 Jun;125(6):756-65.
D'Sa S, Yong K, Kyriakou C, Bhattacharya S, Peggs KS, Foulkes B, Watts MJ, Ings SJ, Ardeshna KM, Goldstone AH, Williams CD.
42 patients with myeloma, most of them resistant to VAD chemotherapy, were treated with ESHAP (Etoposide, Methylprednisolone, Cytarabine, Cisplatin) as second-line therapy. Response rate was 67%, and 58% of those with minor response converted to PR. Stem cell mobilization was done in 32 patients, and 87% of them collected >2 million CD34+ cells/Kg. Overall survival at 4 years was 62%, not significantly different from historical controls with VAD-responsive patients.

Phase II study of topotecan and cyclophosphamide in patients with relapsed and refractory multiple myeloma.
Leuk Res. 2005 Oct;29(10):1233-4.
Kraut EH, Young D, Farag S, James AG, Solove RJ.
The combination of cyclophosphamide and topotecan did not show antitumor activity in 11 patients with relapsed or refractory myeloma.

A phase II trial with gemcitabine and paclitaxel for the treatment of refractory and relapsed multiple myeloma patients.
Oncol Rep. 2006 Oct;16(4):877-84.
Gazitt Y, Shaughnessy P, Rothenberg ML.
This is a phase II clinical trial of paclitaxel 150 mg/m2 IV + gemcitabine 2,000-3,000 mg/m2 IV q2weeks for 6 cycles in 12 patients with relapsed or refractory MM. Treatment with this combination was active, because among 8 evaluable patients there were 1 CR, 3 PR, 1 minor response, and 1 stable disease. The patient in CR remianed in remission for more than 6 months.

A comparison of salvage infusional chemotherapy regimens for recurrent/refractory multiple myeloma.
Cancer. 2015 Oct 15;121(20):3622-30.
Griffin PT, Ho VQ, Fulp W, Nishihori T, Shain KH, Alsina M, Baz RC.

This is a retrospective study comparing the outcomes of 3 different regimens of conventional IV agents:
  - CVAD = cyclophosphamide, vincristine, doxorubicin, dexamethasone (33 patients)
  - DCEP = dexamethasone, cyclophosphamide, etoposide, cisplatin (52 patients)
  - VDT-PACE = bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide (22 patients)
 All clinical outcomes were similar, with response rate 55%, median progression-free survival 4.5 months, and median overall survival 8.5 months. DCEP was probably the least toxic regimen.



DCEP for relapsed or refractory multiple myeloma after therapy with novel agents.
Ann Hematol. 2014 Jan;93(1):99-105.
Park S, Lee SJ, Jung CW, Jang JH, Kim SJ, Kim WS, Kim K.
DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) was administered as salvage chemotherapy to 59 patients with relapsed or refractory myeloma. Response rate was 45% (stable disease in 10 patients, minor response in 8, PR in 21, VGPR in 1, and CR in 1). Death secondary to chemotherapy occurred in 8 patients, and in 7 of them (12%), it was related to neutropenic fever. 



DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma.
J Clin Oncol. 2003 Jul 15;21(14):2732-9.
Lee CK, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J, van Rhee F, Cottler-Fox M, Muwalla F, Tricot G.
DT-PACE is a 4-day chemotherapy regimen which consists of Dexamethasone, Thalidomide, cisPlatin, doxorubicin (Adriamycin), Cyclophosphamide, and Etoposide. 236 patients with previously treated myeloma (at least 2 cycles of prior therapy) received DT-PACE. 63% of them had refractory disease. Results after 2 cycles of DT-PACE:
  - PR: 32%
  - CR or near-CR: 16%

D(T)PACE as salvage therapy for aggressive or refractory multiple myeloma.
Br J Haematol. 2013 Jun;161(6):802-10.
Gerrie AS, Mikhael JR, Cheng L, Jiang H, Kukreti V, Panzarella T, Reece D, Stewart KA, Trieu Y, Trudel S, Chen CI.
This is a retrospective study of 75 patients with relapsed/refractory myeloma treated with D(T)-PACE chemotherapy. Overall response rate was 49% (PR 33%, VGPR 16%). The duration of remission was short, because median progression-free survival was 5.5 months. Median OS was 14 months.

Efficacy of VDT PACE-like regimens in treatment of relapsed/refractory multiple myeloma.
Am J Hematol. 2018 Feb;93(2):179-186.
Lakshman A, Singh PP, Rajkumar SV, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Dingli D, Hwa YL, Fonder AL, Hobbs M, Hayman SR, Zeldenrust SR, Lust JA, Russell SJ, Leung N, Kapoor P, Go RS, Lin Y, Gonsalves WI, Kourelis T, Warsame R, Kyle RA, Kumar SK.
VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) is an aggressive combination chemotherapy which was used, along with tandem transplants, in the Total Therapy protocols designed by Dr. Barlogie at the University of Arkansas. This regimen is widely adopted outside those protocols, particularly in patients with very aggressive myeloma, when the disease becomes refractory to novel agents such as IMiDs and proteasome inhibitors. However, efficacy and overall impact on the disease course have not be precisely defined in the "real world", i.e., off protocol. These authors administered VDT-PACE-like chemotherapy regimens in in 141 patients with relapsed/refractory myeloma between 2006 and 2017. Of note, these patients were heavily pretreated, with a median number of prior therapies of 4 (range 1-14), and 67% of them had a stem cell transplant. 52% of them had high-risk cytogenetics. Median number of cycles was 1 (range 1-9). Results:
  - Response rate: 54%, with VGPR/CR in 10% of cases
  - Median progression-free survival: 3.1 months
  - Median overall survival: 8.1 months



Modified HyperCVAD Versus Bortezomib-HyperCAD in Patients With Relapsed/Refractory Multiple Myeloma.
Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e77-e84.
Saraceni MM, Scott E, Maziarz RT, Siegel MB, Bassale S, Jiing S, Medvedova E.



Metronomic therapy is an effective salvage treatment for heavily pre-treated relapsed/refractory multiple myeloma.
Haematologica. 2013 Jul;98(7):1147-53.
Papanikolaou X, Szymonifka J, Rosenthal A, Heuck CJ, Mitchell A, Johann D Jr, Keller J, Waheed S, Usmani SZ, Van Rhee F, Bailey C, Petty N, Hoering A, Crowley J, Barlogie B.
The term metronomic refers to the administration of chemotherapy at low continuous doses. The authors used bortezomib, dexamethasone, thalidomide, cisplatin, and doxorubicin at low doses. The results were modest (median overall survival was 11 months, and progression-free survival 3.6 months - with 25% of patients subsequently treated with salvage autologous stem cell transplant), but we need to keep in mind that many of those patients were heavily pretreated and with end-stage myeloma, i.e., hospice candidates.



Giampaolo Talamo, M.D.