JULY 2016

Clinical responses with T lymphocytes targeting malignancy-associated κ light chains.
J Clin Invest. 2016 Jul 1;126(7):2588-96.
Ramos CA, Savoldo B, Torrano V, Ballard B, Zhang H, Dakhova O, Liu E, Carrum G, Kamble RT, Gee AP, Mei Z, Wu MF, Liu H, Grilley B, Rooney CM, Brenner MK, Heslop HE, Dotti G.
In this study, 7 patients with myeloma were treated with a CAR specific for the kappa light chain. This was done with the intent of minimizing the depletion of the normal B cells and the consequent hypogammaglobulinemia. This stratagem allowed sparing of the lambda-restricted B lymphocytes. Of the 7 patients, 4 had stable disease, lasting from 2 to 17 months.

An observational study assessing peripheral neuropathy related to multiple myeloma.
Neurol Sci. 2016 Jul;37(7):1141-3.
Leone C, Federico V, La Cesa S, Russo E, Di Stefano G, Finsinger P, Labriola R, Cruccu G, Petrucci MT, Truini A.
These authors performed neurological examination and nerve conduction studies in 153 patients with newly diagnosed myeloma, before treatment, and found that 7.2% of them had myeloma-related peripheral neuropathy.

Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma.
Cancer. 2016 Jul 1;122(13):2050-6.
Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF.
The original study of 646 patients was published in 2007, and it showed a survival advantage of patients with relapsed/refractory myeloma when treated with bortezomib + liposomal doxorubicin compared to those treated with bortezomib alone. This study has a much longer follow-up, and it showed a similar overall survival in the two groups: 31 months with bortezomib alone, and 33 months with bortezomib + liposomal doxorubicin (p=61). The disappearance of the survival advantage was attributed to the possible effect of the subsequent lines of chemotherapy.

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.



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).

Assessment of tumoral plasma cells in apheresis products for autologous stem cell transplantation in multiple myeloma.
Bone Marrow Transplant. 2016 Aug;51(8):1143-5.
Wuillème S, Lok A, Robillard N, Dupuis P, Stocco V, Migné H, Dusquesne A, Touzeau C, Tiab M, Béné MC, Moreau P.
This is a prospective study that analyzed the clinical outcomes of the contamination of the apheresis products by myeloma plasma cells. 43 patients received 3-4 cycles of induction chemotherapy with a modern triplet regimen, i.e, VTD (bortezomib, thalidomide, dexamethasone), VCD (bortezomib, cyclophosphamide, and dexamethasone), or KRD (carfilzomib, lenalidomide, and dexamethasone). The median number of myeloma plasma cells in the apheresis collections was 0%. With a single-tube, seven-color flow cytometry, 10 (23%) samples showed presence of myeloma plasma cells in the collection products at the time of stem cell collection, with a range of 0.05-76% of the total plasma cell number. At the time of reinfusion, myeloma plasma cells were detectable in 4 of 22 (18%) samples. This difference was not statistically significant, indicating that normal plasma cells and myeloma cells do not behavior differently after thawing. Interestingly, there was a clinical advantage in those patients without contamination by myeloma plasma cells. The progression rate was higher in those patients with contaminating myeloma plasma cells in the apheresis product: after a median follow-up of 15 months, their median progression-free survival was 16 months, whereas it was not reached in the other group of patients.

Clinical course and outcomes of patients with multiple myeloma who relapse after autologous stem cell therapy.
Bone Marrow Transplant. 2016 Aug;51(8):1156-8.
Gonsalves WI, Rajkumar SV, Gertz MA, Dispenzieri A, Lacy MQ, Buadi FK, Dingli D, Go RS, Leung N, Kapoor P, Hayman SR, Lust JA, Russell SJ, Zeldenrust SR, Hwa YL, Kourelis TV, Kyle RA, Kumar SK.
This is a retrospective study of 672 patients with myeloma who underwent an autologous stem cell transplant (SCT) at the Mayo Clinic and experienced a disease relapse, between 2000 and 2012. It showed that a subset of patients can have prolonged remissions and survival even after relapse post-SCT. 468 patients received an "upfront" transplant (i.e., within 12 months from the diagnosis of myeloma), and 204 patients received a "delayed" transplant (i.e., done more than 12 months from the diagnosis). Results:
 - Median survival after progression post-SCT was 39 months with upfront transplant, and 27 months with delayed transplant
 - With upfront transplant: median survival after progression post-SCT was 29 months with a relapse within 2 years post-SCT, and 60 months with relapse after 2 years post-SCT
 - With delayed transplant: median survival after progression post-SCT was 23 months with a relapse within 2 years post-SCT, and 66 months with relapse after 2 years post-SCT
 - Median survival after progression post-SCT was 41 months with SCT done before first relapse, and 23 months with SCT done after at least one relapse.

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.

Fractionated stem cell infusions for patients with plasma cell myeloma undergoing autologous hematopoietic cell transplantation.
Leuk Lymphoma. 2016 Aug;57(8):1781-5.
Landau H, Wood K, Chung DJ, Koehne G, Lendvai N, Hassoun H, Lesokhin A, Hoover E, Zheng J, Devlin SM, Giralt S.
In this study, 22 patients with myeloma underwent an autologous stem cell transplant with fractionated stem cell infusions, i.e., with multiple cell infusions at days 0,, +2, +4, and +6. The results were compared to those of 77 patients who received the stem cells in the traditional way, i.e., with all cells on day 0. The results of the study were negative, because the fractionation did not shorten the number of days of neutropenia, the days of fever, infections, antibiotic use, diarrhea, and length of hospital admission.

Effect of melphalan 140 mg/m(2) vs 200 mg/m(2) on toxicities and outcomes in multiple myeloma patients undergoing single autologous stem cell transplantation-a single center experience.
Clin Transplant. 2016 Aug;30(8):894-900.
Katragadda L, McCullough LM, Dai Y, Hsu J, Byrne M, Hiemenz J, May S, Cogle CR, Norkin M, Brown RA, Wingard JR, Chang M, Moreb JS.
In this retrospective study, 96 patients with myeloma received an autologous stem cell transplant using melphalan 200 mg/m2, and 33 patients using melphalan 140 mg/m2. After a median follow-up of 74 months, relapse-free survival and overall survival were similar in the two groups.



A systematic study comparing aspirate versus trephine for quantifying plasma cell infiltration in newly-diagnosed myeloma.
Br J Haematol. 2016 Sep;174(5):818-20.
Gabriel J, McGovern A, Robinson S, Wright D, Chevassut T.
The diagnosis of multiple myeloma is based on the presence of 10% or more of malignant plasma cells in the bone marrow. In this retrospective study, the authors reviewed data in 87 patients with myeloma, and compared the number of plasma cells found in the bone marrow aspirate to those found in the biopsy. Aspirate samples underestimated the number of plasma cells compared to the trephine biopsy. The causes of the lower number of plasma cells in the aspirate is possibly due to niche adherence or fibrosis that compromises the aspiration of cells. When enumerating the plasma cells in the marrow for diagnostic purposes, it is recommended that the higher infiltration number is used.

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. 

Outcomes of unrelated cord blood transplantation in patients with multiple myeloma: a survey on behalf of Eurocord, the Cord Blood Committee of Cellular Therapy and Immunobiology Working Party, and the Chronic Leukemia Working Party of the EBMT.
Haematologica. 2016 Sep;101(9):1120-7.
Paviglianiti A, Xavier E, Ruggeri A, Ceballos P, Deconinck E, Cornelissen JJ, Nguyen-Quoc S, Maillard N, Sanz G, Rohrlich PS, Garderet L, Volt F, Rocha V, Kroeger N, Gluckman E, Fegueux N, Mohty M.
This is a retrospective study of 95 patients with multiple myeloma treated in several institutions with a single or double umbilical cord transplant, over a period of 12 years. Plasma cell leukemia was present in 10 patients. Median follow-up was 41 months. Results:
  - Acute GVHD at day 100: 41%. Chronic GVHD at 2 years: 22%.
  - Non-relapse mortality at 3 years: 29%. Relapse mortality at 3 years: 47%.
  - Progression-free survival at 3 years: 24%. Overall survival at 3 years: 40%. 

Donor Monoclonal Gammopathy May Cause Lymphoproliferative Disorders in Solid Organ Transplant Recipients.
Am J Transplant. 2016 Sep;16(9):2676-83.
Felldin M, Ekberg J, Polanska-Tamborek D, Hansson U, Sender M, Rizell M, Svanvik J, Mölne J.
This is an interesting study, which showed that individuals with MGUS who are donors for solid organ transplant recipients may cause donor-transmitted lymphoproliferative diseases in the recipients. A donor had an IgM-kappa paraprotein (3.7 g/dL), and this caused a lymphoplasmacytic lymphoma in 2 kidney recipients, and an MGUS in a liver recipient. A second donor had an IgG-lambda paraprotein (0.8 g/dL), and this caused a myeloma in 2 kidney and 1 liver recipient, and an MGUS in a heart recipient (for a total of 7 organ recipients from 2 different donors). The authors state that this donor-transmitted neoplasms develop via passenger lymphoplasmacytic cells/plasma cells in solid organ recipient.

Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up.
Blood Cancer J. 2016 Sep 2;6(9):e466.
Biran N, Jacobus S, Vesole DH, Callander NS, Fonseca R, Williams ME, Abonour R, Katz MS, Rajkumar SV, Greipp PR, Siegel DS.

In the E4A03 clinical trial, 431 patients with newly diagnosed multiple myeloma had the option of proceeding to an autologous stem cell transplant upfront, vs continuing the treatment with lenalidomide and dexamethasone and leave the transplant for later, as a salvage modality. 21% of patients decided to undergo an upfront autologous transplant. The overall survival at 5 years was superior in the group of patients with upfront transplant: 80% vs 57%. 

Phase II open-label study of recombinant circularly permuted TRAIL as a single-agent treatment for relapsed or refractory multiple myeloma.
Chin J Cancer. 2016 Sep 8;35(1):86.
Leng Y, Qiu L, Hou J, Zhao Y, Zhang X, Yang S, Xi H, Huang Z, Pan L, Chen W.
Circulating permutated TRAIL (CPT) is a recombinant form of Apo2L/TRAIL (apoptosis ligand 2/TNF-related apoptosis-inducing ligand), a member of the TNF superfamily that binds to death receptors 4 and 5 (DR4 and DR5), and induces apoptosis. I this study, the authors administered CPT in 27 patients with relapsed/refractory multiple myeloma, and obtained a response rate of 33%.

Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma.
Blood. 2016 Sep 29;128(13):1735-44.
Weinhold N, Ashby C, Rasche L, Chavan SS, Stein C, Stephens OW, Tytarenko R, Bauer MA, Meissner T, Deshpande S, Patel PH, Buzder T, Molnar G, Peterson EA, van Rhee F, Zangari M, Thanendrarajan S, Schinke C, Tian E, Epstein J, Barlogie B, Davies FE, Heuck CJ, Walker BA, Morgan GJ.



Giampaolo Talamo, MD