The impact of induction regimen on transplant outcome in newly diagnosed multiple myeloma in the era of novel agents.
Bone Marrow Transplant. 2017 Jan;52(1):34-40.
Chakraborty R, Muchtar E, Kumar S, Buadi FK, Dingli D, Dispenzieri A, Hayman SR, Hogan WJ, Kapoor P, Lacy MQ, Leung N, Gertz MA.
This is a retrospective study of 1017 patients with multiple myeloma treated with different induction chemotherapy regimens, followed by an early (within 12 months of diagnosis) autologous stem cell transplant. The regimens used were:
  - VRD (bortezomib, lenalidomide, and dexamethasone) - 126 pts
  - CyBorD (cyclophosphamide, bortezomib, and dexamethasone) - 193 pts
  - VD (bortezomib and dexamethasone) - 64 pts
  - RD (lenalidomide and dexamethasone) - 251 pts
  - TD (thalidomide and dexamethasone) - 155 pts
  - VAD (vincristine, doxorubicin, and dexamethasone) or Dex - 228 pts
After a median follow-up of 67 months, the 5-year overall survival rate was as follows: VRD 79%, CyborD 79%, RD 79%, VD 72%,  TD 57%, VAD/Dex 63%, TD 57%. In a multivariate analysis, after controlling for several patient and tumor characteristics, VRD induced higher response rates and better progression-free and overall survival among the several regimens (HR 0.32 for OS).

Cryotherapy reduces oral mucositis and febrile episodes in myeloma patients treated with high-dose melphalan and autologous stem cell transplant: a prospective, randomized study.
Bone Marrow Transplant. 2017 Jan;52(1):154-156.
Marchesi F, Tendas A, Giannarelli D, Viggiani C, Gumenyuk S, Renzi D, Franceschini L, Caffarella G, Rizzo M, Palombi F, Pisani F, Romano A, Spadea A, Papa E, Canfora M, Pignatelli A, Cantonetti M, Arcese W, Mengarelli A.
In this study, 72 patients with multiple myeloma undergoing an autologous stem cell transplant were randomized in two groups: one (32 patients) received oral cryotherapy with ice chips or cold water during the infusion of melphalan, and the other (32 patients) did not. Oral cryotherapy reduced the incidence of grade 3-4 mucositis to 6% (vs 44% without it), use of opioids, TPN, and IV antibiotics.

Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial.
JAMA. 2017 Jan 3;317(1):48-58.
Himelstein AL, Foster JC, Khatcheressian JL, Roberts JD, Seisler DK, Novotny PJ, Qin R, Go RS, Grubbs SS, O'Connor T, Velasco MR Jr, Weckstein D, O'Mara A, Loprinzi CL, Shapiro CL.
This is a randomized study of zoledronic acid in 1822 patients with cancer involving the bones. Among them, 278 patients had multiple myeloma. Patients were randomized into 2 groups: one (911 patients) received zoledronic acid, at standard schedule, i.e., once a month, and the other (911 patients) received zoledronic acid every 3 months. Treatment was continued for 2 years (= 24 vs 8 doses). The clinical outcomes (skeletal-related events) of the longer dosing interval were similar to those of the monthly infusions.  

Acupuncture combined with methylcobalamin for the treatment of chemotherapy-induced peripheral neuropathy in patients with multiple myeloma.
BMC Cancer. 2017 Jan 9;17(1):40.
Han X, Wang L, Shi H, Zheng G, He J, Wu W, Shi J, Wei G, Zheng W, Sun J, Huang H, Cai Z.
This is a clinical trial of 104 myeloma patients with a common problem, peripheral neuropathy, randomized into a group who received methylcobalamin (a form of vitamin B12) and another group who received methylcobalamin + three cycles of acupuncture. The group receiving acupuncture had a statistically significant improvement of the painful neuropathy.



Impact of pre-transplant bone marrow plasma cell percentage on post-transplant response and survival in newly diagnosed multiple myeloma.
Leuk Lymphoma. 2017 Feb;58(2):308-315.
Chakraborty R, Muchtar E, Kumar SK, Buadi FK, Dingli D, Dispenzieri A, Hayman SR, Hogan WJ, Kapoor P, Lacy MQ, Leung N, Gertz MA.
This is a retrospective study of 1070 patients with newly diagnosed myeloma, who underwent an autologous stem cell transplant as upfront therapy. The authors showed that those patients who had <5% plasma cells in the bone marrow aspirate before the transplant had better clinical outcomes than those who had 5% plasma cells: the chance to achieve complete remission after the transplant was higher (46% vs 16%), and the progression-free survival was longer (115 months vs 31 months). This study may have practical relevance, because a bone marrow biopsy is not always performed before the stem cell transplant (it is routinely done after it, to establish the depth of response, at about day +100). Of note, patients who achieved a stringent complete remission after the stem cell transplant had similar progression-free survival and overall survival, regardless of whether their pre-transplant plasma cells in the bone marrow were lower or higher than 5%.

Maintenance versus Induction Therapy Choice on Outcomes after Autologous Transplantation for Multiple Myeloma.
Biol Blood Marrow Transplant. 2017 Feb;23(2):269-277.
Cornell RF, D'Souza A, Kassim AA, Costa LJ, Innis-Shelton RD, Zhang MJ, Huang J, Abidi M, Aiello J, Akpek G, Bashey A, Bashir Q, Cerny J, Comenzo R, Diaz MA, Freytes C, Gale RP, Ganguly S, Hamadani M, Hashmi S, Holmberg L, Hossain N, Kamble RT, Kharfan-Dabaja M, Kindwall-Keller T, Kyle R, Kumar S, Lazarus H, Lee C, Maiolino A, Marks DI, Meehan K, Mikhael J, Nath R, Nishihori T, Olsson RF, Ramanathan M, Saad A, Seo S, Usmani S, Vesole D, Vij R, Vogl D, Wirk BM, Yared J, Krishnan A, Mark T, Nieto Y, Hari P.
In this retrospective analysis of 693 patients with myeloma transplanted within 12 months of diagnosis, the PFS at 3 year was better in those patients who received maintenance than in those who did not (55% vs 39%). Importantly, for the clinical outcome, the type of induction regimen (for example VD, RD, VRD, CVD) was less important than the use of post-transplant maintenance.

Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma.
Biol Blood Marrow Transplant. 2017 Feb;23(2):262-268.

Sivaraj D, Green MM, Li Z, Sung AD, Sarantopoulos S, Kang Y, Long GD, Horwitz ME, Lopez RD, Sullivan KM, Rizzieri DA, Chao NJ, Gasparetto C.
In this retrospective study, 102 patients with myeloma who underwent an autologous stem cell transplant were given maintenance therapy with bortezomib. This was started between 2 and 3 months after the transplant. Lenalidomide was added in 10 patients. Bortezomib was given at the dose of 1.3 mg/m2 every 2 weeks indefinitely, until progression or unacceptable toxicity. Only 2% of patients required discontinuation of bortezomib due to toxicity. The median progression-free survival, calculated from the date of initiation of maintenance, was 36.5 months, and the median overall survival 73 months (6.1 years). Importantly, 42% of patients had high-risk cytogenetics, and the PFS of those patients did not differ from those with standard-risk cytogenetics.

Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.
Lancet. 2017 Feb 4;389(10068):519-527.
Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A.
In this prospective clinical trial, 525 patients with newly diagnosed myeloma in need of induction chemotherapy were randomized in two groups: VRD (bortezomib, lenalidomide, and dexamethasone) vs RD (lenalidomide and dexamethasone. The winner was VRD:
  - Response rate (PR or better): 72% with RD, and 82% with VRD
  - Rate of complete response: 8% with RD, and 16% with VRD
  - Median progression-free survival: 30 months with RD, and 43 months with VRD
  - Median overall survival: 64 months with RD, and 75 months with VRD
Of note, VRD was slightly more toxic, because 23% of patients on VRD had to stop therapy due to adverse events, as opposed to 10% of patients on RD.


MARCH 2017

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.

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.



Giampaolo Talamo, MD