The administration of monoclonal antibodies against malignant plasma cells can affect the interpretation of the myeloma markers: for example, since daratumumab is a monoclonal IgG-kappa protein, the determination of a complete response in a patient with IgG-kappa myeloma can be affected by a false positive result in the SPEP or serum IFE.




Daratumumab (Darzalex ®, Jannsen Biotech Inc.) is a human IgG1-kappa monoclonal antibody directed against CD38, an antigen expressed by myeloma cells. CD38 is a transmembrane glycoprotein, expressed at low levels in solid organs, myeloid cells, and lymphoid cells, and at high levels in MM cells.

Mechanisms of action:
 - Direct apoptosis, with CD38 degradation and inhibition of cellular signaling pathways
 - Complement-dependent cytotoxicity
 - Antibody-dependent cellular cytotoxicity (ADCC) by NK cells and phagocytosis by macrophages

It was approved by the FDA in November 2015, to be administered as a single agent after at least 3 prior lines of therapy (including an IMiD and a proteasome inhibitor). It was subsequently approved for administration in combination with other agents, such as lenalidomide or bortezomib, after at least 1 line of therapy.

Dose: 16 mg/Kg IV once a week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks indefinitely, until tumor progression.
Premedication is recommended: corticosteroid, acetaminophen, and antihistamine.
The infusion can last several hours: the solution is prepared in 1000 mL for the first dose, and 500 mL for the subsequent doses. This is administered at an initial rate of 50 mL/hour in the first hour, and, if tolerated, it is increased at the rate of 50 mL/hour every hour up to a maximum infusion rate of 200 mL/hour.

In heavily pretreated patients, response rate is about 35% and the median duration of response is 7 months.

The most common side effect is an infusion-related reaction, which usually manifests with mild and transient headache, fever, dyspnea, and bronchospasm. Most reactions occur during the first infusion. Some experts recommend herpes zoster prophylaxis, due to the increased risk of this viral infection.

  - Interference with blood typing
Since daratumumab binds to the CD38 expressed on RBCs, it causes panreactive agglutination in the indirect Coombs' test used by blood banks for antibody screening and cross-matching. As a result, blood banks can find false positive antibody screens (positive Coombs test but no evidence of hemolysis). This positivity can persist for up to 6 months after the daratumumab infusion. Due to the interference with blood compatibility testing, blood banks should be notified about the use of daratumumab in a patient who needs a blood transfusion.
  - Interference with response assessment
Since daratumumab is a monoclonal antibody, serum protein electrophoresis (SPEP) and immunofixation (IFE) may result positive (daratumumab plasma concentrations reach up to 100 mg/dL). This creates problems of interpretation of test results, because the definition of complete remission requires negative SPEP and IFE. A specific IFE reflex assay can be used to abrogate the interference.


Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.
N Engl J Med. 2015 Sep 24;373(13):1207-19.
Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG.
In the phase 2 of this trial, 72 patients with myeloma refractory to at least two prior lines of therapy were treated with daratumumab. These were heavily pretreated patients, because the median number of prior treatments was 4, and the median time since diagnosis was 5.7 years. 76% of patients had an autologous stem cell transplant, and 79% of them were refractory to the last line of therapy. Results:
  - Response rate: 36%
  - Median progression-free survival (with 16 mg/Kg): 5.6 months. 67% of the patients who responded did not have disease progression at 1 year.
  - Adverse reactions: infusion-related reactions (71% of patients, but of grade 3 in only 1%), thrombocytopenia, and pneumonia.

Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma.
Blood. 2016 Jul 7;128(1):37-44.
Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, Lokhorst HM, Voorhees PM, Richardson PG, Chari A, Sasser AK, Axel A, Feng H, Uhlar CM, Wang J, Khan I, Ahmadi T, Nahi H.
This study analyzed data pooled from 2 studies of single agent daratumumab in 148 patients with relapsed/refractory myeloma. Patient received at least 2 prior lines of therapy (median was 5), and the vast majority of them (86%) were resistant to both a proteasome inhibitor and an IMiD. Response rate was 31%, and 7 patients achieved CR/sCR. Median progression-free survival was 4 months, and median overall survival was 20 months.

Efficacy of daratumumab-based therapies in patients with relapsed, refractory multiple myeloma treated outside of clinical trials.
Am J Hematol. 2017 Nov;92(11):1146-1155.
Lakshman A, Abeykoon JP, Kumar SK, Rajkumar SV, Dingli D, Buadi FK, Gonsalves WI, Leung N, Dispenzieri A, Kourelis TV, Go RS, Lacy MQ, Hobbs MA, Lin Y, Warsame R, Lust J, Fonder AL, Hwa YL, Hayman SR, Russell SJ, Kyle RA, Gertz MA, Kapoor P.
The authors studied the outcomes of combination therapies containing daratumumab in 126 patients with relapsed/refractory multiple myeloma in the "real world", i.e., outside of the context of clinical trial. The other drugs given with daratumumab were bortezomib, lenalidomide, pomalidomide, and others. The patients in the study were heavily pretreated. Median number of previous lines of therapy was 4 (range, 1-14), and 33% of patients had high-risk cytogenetics. The median time between the diagnosis of myeloma and the therapy with daratumumab was 4.3 years (range, 0.4 - 13 years). The response rate was 47%, and the median progression-free survival was 5.5 months.

Daratumumab resistance is frequent in advanced-stage multiple myeloma patients irrespective of CD38 expression and is related to dismal prognosis.
Eur J Haematol. 2018 May;100(5):494-501.
Pick M, Vainstein V, Goldschmidt N, Lavie D, Libster D, Gural A, Grisariu S, Avni B, Ben Yehuda D, Gatt ME.
This is a retrospective study of 30 myeloma patients with heavily pretreated disease. Their median number of therapies was 5. Response rate was 36%, median progression-free survival 2.3 months, and overall survival 6.6 months. CD38 expression, detected by flow cytometry, was not predictive of response.



Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma.
N Engl J Med. 2016 Aug 25;375(8):754-66.
Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators.
This is a randomized phase III trial, in which 498 patients with relapsing/refractory myeloma received either bortezomib + dexamethasone (VD) or bortezomib + dexamethasone + daratumumab (VD-Dara). About 60% of patients in both groups previously received an autologous stem cell transplant, and about 68% of them a proteasome inhibitor. Median follow-up was 7.4 months. The results favored the VD-Dara group:
  - Response rate: 63% with VD, and 83% with VD-Dara
  - Progression-free survival at 1 year: 27% with VD, and 61% with VD-Dara
  - Median PFS: 7.2 months with VD, and not reached with VD-Dara
  - Toxicity: infusion-related reactions with daratumumab were seen in 45% of patients (grade 3 in 9%), and 98% of them occurred during the first infusion.


Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.
N Engl J Med. 2016 Oct 6;375(14):1319-1331.
Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators.
This is a phase III trial which randomized 569 patients with relapsed myeloma in a group receiving RD (lenalidomide and dexamethasone) and another group receiving RD-daratumumab. At a mnedian follow-up of 13.5 months, the results favored the addition of daratumumab:
  - Response rate: 76.4% with RD (CR 19.2%) vs 92.9% with RD-daratumumab (CR 43.1%)
  - Progression-free survival at 12 months: 60.1% with RD vs 83.2% with RD-daratumumab (median PFS 18.4 months vs not reached)


Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma.
Blood. 2017 Aug 24;130(8):974-981.
Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, Weiss BM, Krishnan A, Lentzsch S, Comenzo R, Wang J, Nottage K, Chiu C, Khokhar NZ, Ahmadi T, Lonial S.
In this phase II trial, 103 patients with relapsed/refractory myeloma were treated with Dara-Pom-Dex:
  - Daratumumab 16 mg/Kg in standard schedule
  - Pomalidomide 4 mg on days 1-21 every 28 days
  - Dexamethasone 40 mg once a week (20 mg if age >75)
Patient needed to be in relapse after at least 2 prior lines of therapy in order to participate to the trial. The median number of prior therapies was 4 (range, 1-13), and the majority of them (76%) had at least 3 lines of therapy. Results, after a median follow-up of 13 months:
  - Response rate: 60%. VGPR or better: 42%. CR or better: 17%
  - Median progression-free survival: 8.8 months
  - Median overall survival: 17.5 months
  - 1-year overall survival: 66%
  - Toxicity was similar to that observed with Pom-Dex, with the exception of infusion-related reactions to daratumumab (50%), and neutropenia (but without increase in the rate of infections) 


Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma.
N Engl J Med. 2018 Feb 8;378(6):518-528.
Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators.
In this trial, 706 patients with multiple myeloma ineligible for stem cell transplant were randomized in two groups: the first (354 patients, control group) were treated with VMP:
  - Bortezomib 1.3 mg/m2 SC twice a week on weeks 1, 2, 4, and 5 of cycle 1, and once a week on weeks 1, 2, 4, and 5 of cycles 2-9
  - Melphalan 9 mg/m2 PO on days 1-4
  - Prednisone 60 mg/m2 on days 1-4
Cycles were repeated every 42 days x9.
The second group (350 patients, Dara-VMP group) was treated with VMP and daratumumab, 16 mg/Kg IV once a week in cycle 1, and every 3 weeks in cycles 2-9, then every 4 weeks.
The dara-VMP group has better results:
  - Response rate: 74% with VMP, and 91% with Dara-VMP (CR/sCR: 24% with VMP, and 43% with Dara-VMP)
  - Progression-free survival at 18 months: 50% with VMP, and 72% with Dara-VMP (p<0.01)



CD38-negative relapse in multiple myeloma after daratumumab-based chemotherapy.
Eur J Haematol. 2017 Aug;99(2):186-189.
Minarik J, Novak M, Flodr P, Balcarkova J, Mlynarcikova M, Krhovska P, Pika T, Pikalova Z, Bacovsky J, Scudla V.
This is a case report. Based on their immune phenotype analysis, the authors believe that the resistance to daratumumab was not associated to the development and expansion of a CD38-negative clone within the malignant plasma cell population, but it involved just the loss of the CD38 surface molecules in the same cells.





Elotuzumab (Empliciti ®) is a humanized IgG1 monoclonal antibody directed against CS1 (cell-surface glycoprotein CD2 subset 1, CD319), also called SLAMF7 (Signaling Lymphocytic Activation Molecule Family 7).

CS1 is a cell membrane glycoprotein and a member of the immunoglobulin superfamily.
CS1 is highly expressed on myeloma cells, whereas its expression in normal tissues is absent (with the exception of normal plasma cells, NK cells, and CD8+ T-cells). Soluble CS1 is present in the serum of MM patients.

Elotuzumab prevents adhesion of MM cells to the bone marrow stromal cells. It is an immunostimulatory monoclonal antibody, which exerts a direct activation of NK cells, and induces antibody-dependent cell-mediated cytotoxicity of myeloma cells.

It was approved by the FDA in November 2015.

Regimen approved by the FDA:
- Elotuzumab 10 mg/Kg IV once a week for 8 weeks, then once every 2 weeks indefinitely, until tumor progression.
- Lenalidomide 25 mg PO on days 1-21 every 28 days.
- Dexamethasone 8 mg IV prior to the elotuzumab infusion + 28 mg PO (40 mg PO in the weeks without elotuzumab).
Premedication is recommended (acetaminophen, H1 blocker, and H2 blocker).



Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma.
Mol Cancer Ther. 2009 Sep;8(9):2616-24.
van Rhee F, Szmania SM, Dillon M, van Abbema AM, Li X, Stone MK, Garg TK, Shi J, Moreno-Bost AM, Yun R, Balasa B, Ganguly B, Chao D, Rice AG, Zhan F, Shaughnessy JD Jr, Barlogie B, Yaccoby S, Afar DE.
Bortezomib enhanced the anti-myeloma activity of elotuzumab, both in vitro and in vivo, in a myeloma xenograft model.

A phase 2 safety study of accelerated elotuzumab infusion, over less than 1 h, in combination with lenalidomide and dexamethasone, in patients with multiple myeloma.
Am J Hematol. 2017 May;92(5):460-466.
Berenson J, Manges R, Badarinath S, Cartmell A, McIntyre K, Lyons R, Harb W, Mohamed H, Nourbakhsh A, Rifkin R.

Gross Z, Rahbari A, Wirtschafter E, Spektor TM, Udd KA, Bujarski S, Ghermezi M, Nosrati JD, Vidisheva A, Eades B, Cecchi G, Maluso T, Swift R, Berenson JR.
Elotuzumab and dexamethasone for relapsed or refractory multiple myeloma patients: A retrospective study.
Eur J Haematol. 2018 Jun;100(6):621-623.
In this study, 21 patients with relapsed or refractory myeloma received elotuzumab and dexamethasone, without lenalidomide. The response rate was 10%, and the median progression-free survival was about 2 months. The problem with this study is its retrospective nature, and therefore one can argue that the same results could have been achieved by dexamethasone alone.  



Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma.
J Clin Oncol. 2012 Jun 1;30(16):1953-9.
Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, Kaufman JL, Leleu X, Tsao LC, Westland C, Singhal AK, Jagannath S.
This is a phase I study of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed or refractory myeloma. Response rate was 82%. After a median follow-up of 16 months, median time to progression was not reached. These results are better than those historically seen with lenalidomide and dexamethasone alone. Infusion reactions were only mild or moderate in the majority of patients.

Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma.
N Engl J Med. 2015 Aug 13;373(7):621-31.
Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators.
This is a phase 3 study which randomized 646 patients with relapsed or refractory myeloma to either lenalidomide + dexamethasone (RD group, 325 patients) vs lenalidomide + dexamethasone + elotuzumab (RD-Elo group, 321 patients). Median follow-up was about 24 months. Results favored the RD-Elo group:
  - Response rate: 66% with RD vs 79% with RD-Elo
  - Median progression-free survival: 14.9 months with RD vs 19.4 months with RD-Elo
  - Progression-free survival at 2 years: 27% with RD vs 41% with RD-Elo



Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma.
Br J Haematol. 2016 Nov;175(3):448-456.
Mateos MV, Granell M, Oriol A, Martinez-Lopez J, Blade J, Hernandez MT, Martín J, Gironella M, Lynch M, Bleickardt E, Paliwal P, Singhal A, San-Miguel J.
In this study, 40 patients with relapsed/refractory myeloma received the a combination of elotuzumab, thalidomide 50-200 mg daily, and dexamethasone 40 mg weekly. Cyclophosphamide 50 mg daily was added to the regimen if at least a partial response was not reached by cycle 5, or the myeloma progressed between cycles 2 and 5. The response rate was 38%, and the median progression-free survival was 3.9 months.



Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma.
J Clin Oncol. 2012 Jun 1;30(16):1960-5.
Jakubowiak AJ, Benson DM, Bensinger W, Siegel DS, Zimmerman TM, Mohrbacher A, Richardson PG, Afar DE, Singhal AK, Anderson KC.

Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM.
Blood. 2016 Jun 9;127(23):2833-40.
Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A.
In this study, 152 patients with relapsed/refractory myeloma were randomized to receive either bortezomib + dexamethasone (VD) or bortezomib + dexamethasone + elotuzumab (E-VD). No significant increase of toxicities was observed in the arm receiving elotuzumab. Infusion reactions were uncommon (5%) and usually mild. The results favored the arm with the addition of elotuzumab. Response rate was 63% with VD and 66% with E-VD. Median progression-free survival 6.9 months with VD and 9.7 months with E-VD.








The PD-1 (programmed death 1) receptor is a membrane protein that inhibits the immune response by T lymphocytes.


Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study.
J Clin Oncol. 2016 Aug 10;34(23):2698-704.
Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, Millenson MM, Cohen AD, Schuster SJ, Lebovic D, Dhodapkar M, Avigan D, Chapuy B, Ligon AH, Freeman GJ, Rodig SJ, Cattry D, Zhu L, Grosso JF, Bradley Garelik MB, Shipp MA, Borrello I, Timmerman J.
In this study, 81 patient with various hematologic malignancies were treated with nivolumab, a fully human IgG4 monoclonal antibody that potentiates the T-cell activity by targeting the membrane PD-1 (programmed death-1) receptor on T cells. The patients with multiple myeloma were 27. Although antitumoral activity was observed in lymphomas, the results were disappointing in myeloma, because disease remissions were not observed. Seventeen (63%) of myeloma patients had stable disease, which lasted a median of 3 months (range, <1 month to about 11 months).


Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma.
Blood. 2017 Sep 7;130(10):1189-1197.
Badros A, Hyjek E, Ma N, Lesokhin A, Dogan A, Rapoport AP, Kocoglu M, Lederer E, Philip S, Milliron T, Dell C, Goloubeva O, Singh Z.
In this phase II study, 48 patients with relapsed/refractory myeloma were treated with pembrolizumab and 200 mg IV every 2 weeks, pomalidomide 4 mg daily for 21 days, and dexamethasone 40 mg once a week. with cycles repeated every 28 days. Patients were heavily pretreated: 73% of them were refractory to both an IMiD and a proteasome inhibitor, and 70% had an autologous transplant. 62% of them had high-risk cytogenetics. Nonetheless, 48 patients (60%) had an objective response (CR/sCR 8%). After a median follow-up of about 16 months, progression-free survival was 17.4 months, and overall survival was not reached. Autoimmune events, known side effects of pembrolizumab, included pneumonitis (13%) and hypothyroidism (10%).




A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma.
Blood. 2017 Jun 22;129(25):3294-3303.
Martin T, Baz R, Benson DM, Lendvai N, Wolf J, Munster P, Lesokhin AM, Wack C, Charpentier E, Campana F, Vij R.
Isatuximab is a monoclonal antibody against CD38, like daratumumab. In this trial, 57 patients with heavily pretreated relapsed/refractory myeloma were given isatuximab + lenalidomide and dexamethasone. Among 52 evaluable patients, response rate was 56%, and median progression-free survival was 8.5 months. Of note, 83% of enrolled patients were previously refractory to lenalidomide.



Rationale for studying rituximab in MM:
1) the identification of a population of clonotypic CD20+ B cells, believed to be precursors of malignant plasma cells
2) CD20 is expressed on about 15% of myeloma plasma cells

Rituximab treatment provides no clinical benefit in patients with pretreated advanced multiple myeloma.
Leuk Lymphoma. 2006 Jun;47(6):1103-9.
Zojer N, Kirchbacher K, Vesely M, Hübl W, Ludwig H.
This phase II study evaluated the efficacy of a single course of rituximab (375 mg/m2 IV for 4 weeks) in 10 patients with relapsed myeloma. None of the patients achieved an objective response. CD20 was expressed on 10% and 50% of bone marrow plasma cells in 2 patients.

Rituximab in CD20 positive multiple myeloma.
Leukemia. 2007 Apr;21(4):835-6.
Moreau P, Voillat L, Benboukher L, Mathiot C, Dumontet C, Robillard N, Hérault O, Garnache F, Garand R, Varoqueaux N, Avet-Loiseau H, Harousseau JL, Bataille R; IFM group.
This phase II study evaluated the efficacy of a single course of rituximab (375 mg/m2 IV for 4 weeks) in 14 MM patients expressing CD20 on at least 33% of tumor cells. 1 patient had minor response for 18 months (100% of plasma cells were CD20+), and 5 patients had stable disease. Therefore, rituximab did not show a significant clinical activity even in a cohort of CD20+ MM.

Anti-CD20 monoclonal antibody therapy in multiple myeloma.
Kapoor P, Greipp PT, Morice WG, Rajkumar SV, Witzig TE, Greipp PR.
Br J Haematol. 2008 Apr;141(2):135-48.



A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma.
Br J Haematol. 2012 Oct;159(1):58-66.
Bensinger W, Maziarz RT, Jagannath S, Spencer A, Durrant S, Becker PS, Ewald B, Bilic S, Rediske J, Baeck J, Stadtmauer EA.
With the limits of data from a phase 1 study (the goal is to find the proper dose, not to assess effectiveness), the clinical activity of single-agent lucatumumab was overall modest. Among 28 patients, there was only 1 patient with partial response, and 12 patients (43%) with stable disease.



Siltuximab (CNTO 328) is a monoclonal antibody directed against interleukin-6.

A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma.
Br J Haematol. 2013 May;161(3):357-66.
Voorhees PM, Manges RF, Sonneveld P, Jagannath S, Somlo G, Krishnan A, Lentzsch S, Frank RC, Zweegman S, Wijermans PW, Orlowski RZ, Kranenburg B, Hall B, Casneuf T, Qin X, van de Velde H, Xie H, Thomas SK.
Fifty-three patients with relapsed/refractory myeloma were treated with siltuximab +/- dexamethasone. Single-agent siltuximab was ineffective (no responses), and combination therapy with siltuximab + dexamethasone had a modest effect: RR was 17% (partial responses), and median progression-free survival was 3.7 months.

Complete remission achieved with single agent CNTO 328, an anti-IL-6 monoclonal antibody, in relapsed and refractory myeloma.
Clin Lymphoma Myeloma Leuk. 2013 Jun;13(3):333-7.
Chari A, Pri-Chen H, Jagannath S.

Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma.
Blood. 2014 Jun 26;123(26):4136-42.
San-Miguel J, Bladé J, Shpilberg O, Grosicki S, Maloisel F, Min CK, Polo Zarzuela M, Robak T, Prasad SV, Tee Goh Y, Laubach J, Spencer A, Mateos MV, Palumbo A, Puchalski T, Reddy M, Uhlar C, Qin X, van de Velde H, Xie H, Orlowski RZ.
This is a phase II randomized study of VMP vs VMP + siltuximab in 106 patients with newly diagnosed multiple myeloma, transplant ineligible. Siltuximab was given at 11 mg/Kg every 3 weeks during induction, and for maintenance as well. All clinical outcomes, including response rates, median progression-free survival, and median overall survival, were similar in the two arms of the study, and, therefore, this was a negative trial. Of note, siltuximab was approved by the FDA for the treatment of multicentric Castleman disease in April 2014, two months before this study was published.



Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma.
Br J Haematol. 2017 Mar;176(5):783-795.
Raje NS, Moreau P, Terpos E, Benboubker L, Grząśko N, Holstein SA, Oriol A, Huang SY, Beksac M, Kuliczkowski K, Tai DF, Wooldridge JE, Conti I, Kaiser CJ, Nguyen TS, Cronier DM, Palumbo A.
This is a negative study, because talabumab did not significantly improve the median PFS when added to bortezomib and dexamethasone in 220 patients with relapsed/refractory myeloma.



Anti-epidermal growth factor receptor antibody cetuximab in refractory or relapsed multiple myeloma: a phase II prospective clinical trial.
Leuk Lymphoma. 2014 Mar;55(3):695-7.
von Tresckow B1, Boell B, Eichenauer D, Beschorner D, Knop S, Goebeler ME, Chemnitz JM, Hallek M, Engert A, Huebel K.
A total of 15 patients with relapsed/refractory myeloma were treated with cetuximab, a monoclonal antibody against EGFR (= epidermal growth factor receptor). EGFR is a protein expressed by malignant plasma cells and also by bone marrow stromal cells. Preclinical models previously indicated that cetuximab is able to induce apoptosis of myeloma cells. The results of the clinical trial, after 4 months of therapy, indicated an overall response rate of only 7% (1 partial remission). The "clinical benefit", defined by the percentage of patient in remission or with stable disease, was 47% (6 patients had stable disease). Of note, the majority of patients received dexamethasone as well.



Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulinlike growth factor type 1 Receptor monoclonal antibody CP-751,871 in patients with multiple myeloma.
J Clin Oncol. 2008 Jul 1;26(19):3196-203.
Lacy MQ, Alsina M, Fonseca R, Paccagnella ML, Melvin CL, Yin D, Sharma A, Enriquez Sarano M, Pollak M, Jagannath S, Richardson P, Gualberto A.
CP-751,871 (Figitumumab) is an anti-insulin-like growth factor 1 receptor (IGF-IR) monoclonal antibody. It blocks ligand binding of IGF-1and IGF-2, and it down-regulates IGF-1R. 47 patients with relapsed/refractory myeloma. Dexamethasone and rapamycin could be added in patients with less than a partial response. There were 9 responses in 27 patients treated with CP-751,871 + dexamethasone.

Phase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myeloma.
Leukemia. 2011 May;25(5):872-4.
Moreau P, Cavallo F, Leleu X, Hulin C, Amiot M, Descamps G, Facon T, Boccadoro M, Mignard D, Harousseau JL.
26 patients with relapsed/refractory myeloma received AVE1642, a humanized monoclonal antibody against CD221, the insulin-like growth factor-1 receptor. Among the first 15 patients treated with single agent AVE1642, there was only 1 minor response. Therefore, the activity of this agent was overall negligible (but we need to acknowledge the important limitations of assessing clinical benefit in a phase I study).



Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed/refractory multiple myeloma: a California Cancer Consortium trial.
Br J Haematol. 2011 Aug;154(4):533-5.
Somlo G, Lashkari A, Bellamy W, Zimmerman TM, Tuscano JM, O'Donnell MR, Mohrbacher AF, Forman SJ, Frankel P, Chen HX, Doroshow JH, Gandara DR.
This is a phase II trial, which was closed prematurely due to poor accrual. Results were not encouraging, as median EFS among 12 evaluable patients was less than 2 months.





See "Treatment of bone disease".



Giampaolo Talamo, M.D.